Current Gene Therapy

45

Send Orders for Reprints to [email protected] Current Gene Therapy, 2018, 18, 45-63

REVIEW ARTICLE ISSN: 1566-5232 eISSN: 1875-5631

Dysfunction in Brain-Derived Neurotrophic Factor Signaling Pathway and Susceptibility to Schizophrenia, Parkinson’s and Alzheimer’s Diseases

Impact Factor:

2.78

BENTHAM SCIENCE

Alireza Mohammadi1,*, Vahid Ghasem Amooeian2 and Ehsan Rashidi2 1

Neuroscience Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran; 2Students' Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran

ARTICLE HISTORY Received: November 10, 2017 Revised: January 27, 2018 Accepted: February 27, 2018 DOI: 10.2174/1566523218666180302163029

Abstract: Brain-Derived Neurotrophic Factor (BDNF) is a dominant neurotrophic factor in the brain which plays a crucial role in differentiation, regeneration and plasticity mechanisms. Binding of the BDNF to its high-affinity Tropomyosin-related kinase B (TrkB) receptor leads to phosphorylation of TrkB, thus activating the three important downstream intracellular signaling cascades within the neural cells including phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), Phospholipase C-γ (PLCγ), and mitogen-activated protein kinase/extracellular signal-related kinase (MAPK/ERK) pathways. Transcription of these pathways is regulated by cAMP Response Element-Binding protein (CREB) transcription factor, which can upregulate gene expression. In this review, we attempted to explore the role of BDNF and its associated pathways in susceptibility to Schizophrenia (Scz), Alzheimer's (AD), and Parkinson's (PD) diseases. Furthermore, we discuss dysfunction in BDNF signaling pathway and the therapeutic potential of BDNF in the treatment of these disorders. The review covers various therapeutic strategies including BDNF gene therapy, transplantation of BDNFexpressing cell grafts, epigenetic manipulation, and intraparenchymal BDNF protein infusion as well. This review seeks to achieve these goals by reviewing recent studies on BDNF and examining the details of BDNF pathway in any of the above-mentioned diseases.

Keywords: Gene delivery, BDNF, PLCγ, MAPK/ERK, Susceptibility, PI3K/AKT.

Current Gene Therapy

1. INTRODUCTION Neurotrophins are a group of important dimeric polypeptides in the brain which are highly involved in neuronal health. They are known to play crucial roles in the survival, development, and function of neurons. Neurotrophins consist of five members including Nerve Growth Factor (NGF), Brain-Derived Neurotrophic Factor (BDNF), Neurotrophin-3 and Neurotrophin-4 (NT-3 and NT-4), and Dehydroepiandrosterone (DHEA) or DHEA sulfate [1, 2]. BDNF is significantly involved in various aspects of neuron development and differentiation, plasticity, and repair mechanisms [3]. BDNF also supports the survival of some neurons, including mesencephalic dopaminergic, septal cholinergic and striatal GABAergic neurons. It was reported that homozygous mutation of BDNF gene causes remarkable degeneration in sensory ganglia and vestibular ganglion as well as a severe disturbance in coordination [4]. It is well documented that BDNF inhibits neuronal death induced by ischemia, oxidative stress, glutamate toxicity and proteins such as amyloidβ. These neuroprotective effects of BDNF have been confirmed by in vivo studies on animal models of ischemia, *Address correspondence to this author at the Neuroscience Research Center, Baqiyatallah University of Medical Sciences, P.O. Box: 19395-6558 Postal Code: 1413643561 Tehran, Iran; Tel: +98 (21) 26127286; E-mail: [email protected] 1875-5631/18 $58.00+.00

oxidative stress associated with Parkinson’s disease, glutamate toxicity associated with seizure, and amyloidβ overexpression associated with Alzheimer’s disease [5]. It has been established that BDNF affects the dopamine receptor expression, thus it has been implicated in the pathophysiology of schizophrenia and mood disorders as well as in the treatment of various related conditions [6, 7]. The gene responsible for the production of BDNF is located on chromosome 11p13 and p14 [8]. BDNF is produced from a precursor protein called pre-pro-BDNF which is cleaved to proBDNF. Afterward, pro-BDNF is cleaved to mature BDNF [9]. Recent evidence indicates that pro-BDNF has some activities in the Central Nervous System (CNS) independent from mature BDNF. They are both identified to activate different intracellular signaling pathways through different receptors [10, 11]. Pro-BDNF interacts with low-affinity neurotrophin receptor p75 (p75NTR), while mature BDNF activates the high-affinity Tropomyosin-related kinase B (TrkB) receptor. TrkB starts to dimerize upon binding with mature BDNF. This activates a signaling cascade within the target cell with at least three different transduction pathways which results in the maintenance of survival, growth, and synaptic plasticity of neurons (Fig. 1) [12]. The pro-survival effects of BDNF along with its synapse-enhancing function make the BDNF-TrkB pathway a potential therapeutic target for neurodegenerative diseases [13]. © 2018 Bentham Science Publishers

46 Current Gene Therapy, 2018, Vol. 18, No. 1

Mohammadi et al.

Fig. (1). BDNF-TrkB signaling pathways and downstream intracellular signaling cascades. The activation of the intracellular tyrosine kinase is initiated upon the attachment of BDNF to the extracellular domain of TrkB. This leads to autophosphorylation of intracellular parts of TrkB which provokes the activation of intracellular signaling cascades including PI3K/Akt, PLCγ, and MAPK/ERK pathways. Phosphorylation of TrkB tyrosine recruits the Src homology 2 domain-containing (Shc) adaptor protein, followed by recruitment of Growth factor receptor-bound protein 2 (Grb2) and Son of Sevenless (SOS) which activates the Ras–MAPK pathway [8]. Moreover, Shc–Grb2 recruits Grb2-associated binder-1 (GAB1) and activates the PI3K-Akt pathway (left). Moreover, phosphorylation of the remaining TrkB tyrosine results in the recruitment of PLCγ which leads to the formation of IP3 as well as the regulation of intracellular Ca2+ and Diacylglycerol (DAG). DAG can activate Ca2+/calmodulin-dependent protein kinase (CAMK) and Protein Kinase C (PKC). The described signaling pathways are known to have major involvements with neuronal growth, survival and plasticity.

In the current review article, we focused on these pathways particularly their involvement with different neurological diseases. We have described how the BDNF triggers a cascade of intracellular messengers, each of which plays a vital role in susceptibility to Scz, PD, and AD. 2. BDNF SIGNALING THROUGH TROPOMYOSINRELATED KINASE B RECEPTORS TrkB receptor starts to dimerize when BDNF is bound to its domain. Dimerized TrkB causes auto-phosphorylation of receptor tyrosine kinase. This leads to the activation of intracellular signaling pathways. There are at least three signal transduction pathways regulated by BDNF-TrkB activation including PI3K/AKT, PLCγ, and MAPK/ERK pathways which activates protein kinase C, serine/threonine kinase AKT, and numerous downstream molecules, respectively. These signaling pathways indicate the unique role of BDNF [14]. 2.1. PI3K/AKT Signaling Pathway and Neural Survival Following the binding of BDNF to TrkB receptor, phosphatidylinositol 3-kinase (PI3K) pathway is activated [15]. PI3K activates numerous proteins and pathways, including protein kinase B (Akt) [16] which are a key role-player in mitogenic signaling and cell survival [17]. It has been demonstrated that BDNF is highly necessary for the survival of

cholinergic, dopaminergic, GABAergic, and serotonergic neurons [18]. Owing to the identified involvements of the mentioned neurons in disorders such as AD, PD, Scz, Huntington’s disease, Major Depression Disorder (MDD), anxiety disorders, addiction, Attention Deficit Hyperactivity Disorder (ADHD), autism, epilepsy, stiff-person syndrome, and premenstrual dysphoric disorder, disturbance in BDNF signaling pathway is assumed to be associated with these conditions [19-23]. The interactions between neuronal death and survival during the early development of the nervous system have been recapitulated in in-vivo studies. Researches have demonstrated that the sympathetic, hippocampal, cortical, cerebellar, and motor neurons can be cultured in vivo in the presence of proper neurotrophic stimuli and die by apoptosis after withdrawal of neuro-trophic agents. BDNF is an important factor required for neural survival. These findings are supported by the fact that genetically modified BDNF deficient mice showed an elevation in apoptotic cell death in the cerebellum [24, 25]. As it has been previously described in this review, PIP3 leads to the activation of several serine/threonine kinases, including Akt/protein kinase B, upon activations of specific pathways [26]. Akt is attached to the inner surface of the plasma membrane through its interaction with the phospholipid products of PI3K. Researchers have shown that the ability of neurotrophins to enhance neural survival requires a functional PI3K-Akt pathway [27]. The PI3K-Akt pathway also regu-

Dysfunction in BDNF Signaling Pathway

lates cell proliferation and metabolism, however, it is important to identify which particular Akt targets mediate its neural survival effects. An article by Yamaguchi et al. reported that Akt enhances neural survival in the hippocampus by inhibiting the activity of the tumor suppressor p53 [28]. p53 initiates the expression of genes related to cellular death such as Bcl-2 family member BAX [29]. These findings raise the possibility that Akt’s survival function is partly dependent on the inhibition of p53 activity which diminishes BAX transcription. Currently, the mechanism by which Akt inhibits the activity of p53 remains unclear mainly because Akt does not phosphorylate p53 directly [28]. Furthermore, the PI3KAkt pathway directly regulates the cytoplasmic apoptotic pathway. Akt has been reported to act prior to the release of cytochrome c, regulating the activity of Bcl-2 family members as well as mitochondrial function, and subsequent to the release of cytochrome C, regulating components of the apoptosome [30, 31]. 2.2. PLCγ Signaling Pathway and Neural Plasticity PLC-γ pathway is initiated upon the activation of TrkB receptor. This pathway is believed to activate inositol trisphosphate (IP3) receptor which releases the intracellular calcium stores. Elevated levels of intracellular calcium increase the activity of CaMK which increases neuron’s synaptic plasticity [32]. Impaired synaptic plasticity is connected to several conditions including epilepsy, Scz, bipolar disorder [14], HD, depression and AD [33]. Therefore, BDNF appears to have major impressions in these diseases as well. Synaptic plasticity is referred to as modulation of the structure or function of synapses which totally depends on synaptic activity. Measurement of synaptic Long-Term Potentiation (LTP) is known as a powerful way for investigating neuronal plasticity. LTP is a sustained elevation of synaptic efficacy. There are two kinds of LTPs. Early-phase LTP (ELTP) is referred to as a short-term LTP, lasting about 1–2 hours which is induced by a single short high-frequency tetanic stimulation. Late-phase LTP (L-LTP) is known as a long-lasting LTP induced by multiple strong tetanic stimuli. L-LTP might last for several days. Unlike E-LTP, L-LTP requires genomic transcription and translation. L-LTP is generally accompanied by morphological alterations of the synapses. It has been reported that gradual perfusion of BDNF through the hippocampus of neonate rats facilitates E-LTP at hippocampal synapses [34, 35]. Simultaneously, slow perfusion of BDNF through adult rat hippocampus has been reported to convert induced short-term synaptic potentiation into LTP. A recent study showed the long-standing effects of BDNF in facilitating basal synaptic transmission [36]. Application of acute BDNF results in a rapid increase in BDNF levels and transient activation of the TrkB receptor, leading to a rapid improvement in synaptic transmission. In contrast, slow perfusion of BDNF causes gradual elevation in BDNF levels and a sustained activation of TrkB signaling, which results in an increase in the magnitude of LTP [36]. Application of BDNF to the induced E-LTP leads to sustained LLTP in hippocampal slices [37]. Likewise, it has been reported that in mice with high levels of BDNF, weak tetanus stimulation was able to induce L-LTP. This is reported to be reversed by TrkB-specific immunoglobulin G [38]. The extracellular conversion of pro-BDNF to mature BDNF is a

Current Gene Therapy, 2018, Vol. 18, No. 1

47

crucial step that is mediated by a tissue plasminogen activator (t-PA) [37]. The L-LTP impairment is observed in mice lacking t-PA. 2.3. MAPK/ERK Signaling Pathway and Neural Growth The Mitogen-Activated Protein Kinase (MAPK) and Extracellular signal-Related Kinase (ERK) pathways are initiated by Ras small GTP-binding protein which is a membrane-bounded intracellular molecule. This GTP-binding protein which itself is activated by TrkB receptor can cause numerous functions including proliferation. Studies have shown that disturbances of these pathways may cause βamyloid dependent disorders and Tauopathies such as AD, Pick’s disease, progressive supranuclear palsy, and corticobasal degenerative diseases [39-41]. Such relationships are founded between these particular pathways and PD as well as Scz [42-44]. BDNF is a well-known promoter of axonal branching, dendritic growth and plasticity. Synaptic growth is defined as the increase in the number or size of the synapses [5]. Researches have shown that treatment of hippocampal slices with BDNF for 2–3 days increases the expression level of synaptic proteins [45]. Chronic exposure to BDNF is strongly reported to increase spinal motility which leads to increased potential to form new synapses [46]. Investigations of BDNF knockout mice showed reduced expression of synaptic proteins and a reduction in the number of synaptic vesicles [47]. Analysis of TrkB knockout mice indicated changes in synaptic vesicles, synaptic protein expression and synaptic density [48]. On the other hand, genetically modified mice overexpressing BDNF were reported to have increased number of synapses [49]. Re-expression of BDNF in neurons derived from BDNF knockout mice leads to the increased number of synapses within hours [50]. Although structural alterations of the synapses are indeed primary functional changes, these might be linked to activitydependent BDNF secretion [51]. It was reported that synaptic stimulation followed by postsynaptic spiking can induce LTP and a gradual enlargement of spine heads, whereas blocking of BDNF-TrkB signaling inhibits the spine head enlargement. These findings point towards the fact that activity-dependent BDNF secretion induces LTP and synaptic growth [51]. 3. BDNF GENE POLYMORPHISMS IN Scz, PD, AND AD 3.1. BDNF and its Receptors Polymorphisms in Scz A Single-Nucleotide Polymorphism (SNP) which causes a Valine (Val) to Methionine (Met) substitution at 66th position in the prodomain of the BDNF protein (Val66Met) affects 20-30% of the human population. Val66Met causes alterations in the intracellular distribution of substances. It also induces a reduction in activity-induced secretion of the BDNF [52]. Individuals with the Met allele show disturbances in performing motor-based learning tasks as well as a declined motor cortex plasticity [53, 54]. Researchers have investigated the relationship between Val66Met polymorphism and brain volume changes in Scz patients. Remarkable alterations have been reported in fron-


tal lobe gray matter volume as well as lateral ventricles [55]. BDNF variants may cause alterations in the brain of Scz patients including reductions in the volume of frontal gray matter alongside with an increase in the volume of lateral ventricles and sulcal Cerebrospinal Fluid (CSF). Authors have also reported relationships between Val66Met and C-207T polymorphisms [56, 57]. It has also been revealed that neurotrophic tyrosine kinase receptor 2 (NTRK2) gene (encoding TrkB) decreased in schizophrenic patients [58]. In this case, Lin and colleagues (2013) did not observe any significant differences between patients with paranoid schizophrenia and healthy controls in rs1387923, rs2769605 and rs1565445 polymorphisms in NTRK2 gene as well as rs6265 in BDNF gene. However, they concluded that the interaction of NTRK2 and BDNF genes polymorphisms (NTRK2-rs2769605, NTRK2rs1387923 and BDNF-rs6265) may have a role in susceptibility to paranoid schizophrenia [59]. BDNF functional polymorphism rs6265 can also increase secretion of BDNF in an activity-dependent manner [60]. Likewise, several studies found no association between BDNF and NTRK2 polymorphisms (G-712A, C270T, Val66Met, rs6265) and the susceptibility to schizophrenia [61-65]. 3.2. BDNF and its Receptors Polymorphisms in PD The association of BDNF 196 G/A and 270 C/T polymorphisms with PD has been studied by scientists. The BDNF 196G/A (Val66Met) polymorphism causes reduced BDNF expression at the cell surface [60]. BDNF 270 C/T polymorphism also alters BDNF expression [66]. The relationship between the presence of these polymorphisms and PD is a matter of controversy since some researchers have reported positive correlations [67-71] while others did not [72-84]. In the other words, some studies have stated that the 712A/G AG/AA, G196A, NR4A2 IVS6 +18insG, 270 C/T, and p.V66M polymorphisms of BDNF significantly increased the risk of PD [67-71], while others have reported no association between the Val66Met (rs6265, G196A), 270 C/T, and 240 C/T variants of BDNF gene and the susceptibility to PD [72-84]. However, Parsian and coworkers (2004) showed that the C270T variant is associated with a mutation in coding region of the BDNF gene, suggesting that C270T may play a crucial role in the progress of familial PD [70]. Regarding the involvement of BDNF in memory function, it can be concluded that BDNF alterations are highly involved in the pathophysiology of PD. Over time, studies have evaluated the relationship between PD and the presence of Val66Met polymorphism. Several articles have suggested a relationship between the Met variant of BDNF Val66Met polymorphism and cognitive performance in healthy individuals [85, 86]. A positive correlation between this polymorphism of BDNF gene and cognitive impairment [87] as well as early development of dyskinesia [88] have been reported in PD patients [89]. The effect of Val66Met polymorphism on cognition in PD patients has also been reported [90]. Valuable meta-analyses have successfully indicated the association between the BDNF 196 G/A polymorphism and PD. However, such associations have not been found between the BDNF 270 C/T polymorphism and PD [74].

Mohammadi et al.

3.3. BDNF and its Receptors Polymorphisms in AD It has been shown that BDNF gene regulates executive functions, including Spatial Working Memory (SWM) [91]. Hippocampal-dependent episodic memory is also affected by the Val66Met polymorphism [60]. BDNF is strongly involved in hippocampal-dependent memory because of its profound effect on neural plasticity. This assumption is backed-up by the fact that disruption of BDNF or TrkB signaling impairs a hippocampal-dependent form of memory in rodents. BDNF Val66Met polymorphism has been shown to be associated with abnormal hippocampal structure and function in humans [60, 85]. Memory function tests have shown that humans with two copies of the Met allele suffer impairments in short-term memory. In addition, the BDNF Met allele has been associated with decreased hippocampal volumes [60]. It has been reported that BDNF Met carriers are at increased risk for developing early-onset AD. On the contrary, BDNF Val carriers have shown an increased risk for developing late-onset AD [92]. A recent study has demonstrated that healthy individuals with BDNF Met show a faster and more significant reduction in episodic memory as well as hippocampal volume [93]. Consistent with these findings, inhibition of TrkB signaling has been shown to amplify spatial memory impairment in animal models of AD [94]. It was stated that the BDNF 270C/T SNP has associations with late-onset AD [95, 96]. It has been strongly suggested that this polymorphism is a positive risk factor for AD [97]. The role of this SNP in the AD is still conflicting since negative results have also been reported by scientists [98, 99]. Moreover, the insignificance of conclusions was reported by metaanalyses [98, 100]. The association of BDNF 11757 G/C polymorphism with AD was also reported in Italian populations [99]. Some studies have investigated the relationship between NTRK2 and AD. Nonetheless, there are conflicting results about BDNF and its receptors polymorphisms in patients with the AD. A series of studies have been reported the association of the rs1624327, rs1443445, and rs3780645 with the AD [101] as well as the rs2289656 with the risk of both familial and sporadic AD [102]. There are two reports enclosed the SNPs in the promoter region of the NTRK2 gene [103, 104]. Although Cozza et al. [102] and Vepsalainen et al. [103] stated the association of rs2289656 with the both familial and sporadic AD, Zeng and colleagues (2013) could not replicate this connection [104]. Although NTRK2 seems to be a good candidate in the pathogenesis of AD, the SNPs in the selected region of this gene did not confer the susceptibility of AD [101, 102, 105, 106]. 4. BDNF AND SCHIZOPHRENIA Schizophrenia is a chronic complex neuropsychiatric disease with approximately 80% heredity [107]. Symptoms typically appear in the late second to third decades of life and include hallucination, delusion, thought disturbance, blunted affect, impaired cognition, abnormal insight, and damaged social interaction [108-110]. The concordance rate of 50% among monozygotic twins [111] suggests a mixture of environmental and developmental risk factors for this disease [112]. As it was discussed in previous sections, BDNF is


involved in various aspects of development and function of brain neurons. It has been proposed that this neurotrophic factor is also involved in the pathophysiology of Scz. Previous studies have shown that developmental abnormalities, as well as cognitive, emotional, behavioral, and neuronal disturbances that occur in the course of Scz, are caused by changes in BDNF expression [113]. Post-mortem investigations on brains of Scz patients have claimed that alterations in BDNF levels are seen in certain regions of the brain. Recently, it has been shown that the expression of BDNF is elevated in frontal cortices of Scz patients compared to the control [114]. On the contrary, a number of articles have indicated that BDNF expression is reduced in the cortices of patients with Scz [58, 115]. Such discrepancy also exists between the levels of BDNF in the hippocampus region [116]. Results from investigations on living Scz patients have shown structural alterations such as increased ventricle volumes and decreased gray matter size particularly in the cortex and hippocampus. Other reported alterations include abnormal serum level of BDNF in these patients [117, 118]. Some studies have reported decreased serum BDNF levels [18], while others have reported otherwise [119]. These conflicts in reports might be related to the fact that participants of these studies were treated with different drugs. Some studies have reported a decreased serum levels of BDNF in drug naïve patients with Scz (Table 1) [120-123]. The hypothesis that abnormal regulation of BDNF is involved in the pathophysiology of schizophrenia is supported by data from animal studies. The total level of BDNF in brain tissues has been reported to be reduced [124, 125]. Reports from investigations on 157 drug-naive chronic substance abuser patients with schizophrenia have indicated up to 34% elevation in serum BDNF concentrations [126]. In situ hybridization studies have demonstrated that animals with lesions in the hippocampus show reduced levels of BDNF mRNA in the prefrontal cortex, cingulate cortex, and hippocampus [127129]. It is noteworthy that the molecular mechanisms of typical and atypical antipsychotics used for the treatment of schizophrenia are generally unknown. Studies have shown that chronic antipsychotic administration significantly changes the levels of hippocampal BDNF mRNA. It has also been declared that chronic treatment of rodents with typical antipsychotics decreases the levels of brain BDNF whereas atypical antipsychotics cause an elevation in BDNF expression [130]. 5. BDNF AND PARKINSON’S DISEASE PD accounts for the second most common degenerative disorder of the CNS [43]. It usually affects motor neurons causing symptoms such as tremor, rigidity, bradykinesia and postural instability [131, 132]. BDNF is known as an important neurotrophin in the maintenance of nigral dopaminergic neurons of the brain [133]. BDNF-TrkB signaling pathways have been reported to be involved in the nigrostriatal dopaminergic survival in aging brain [134], and its synthesis is highly regulated by neural activity [135]. Studies have demonstrated that the level of BDNF expression is reduced in the nigrostriatal pathway of PD patients [136, 137]. Although current therapies for PD have limited effectiveness in enhancing motor impairments and quality of life [138], transduction of astrocytes encoding the human BDNF gene into


49

the striatum has shown promising results in motor dysfunctions as well as neurodegeneration process in the rat model of PD [139]. Evidence has suggested that BDNF is a major role-player in cognition in normal and neuropathological disorders [140]. Therefore, numerous post-mortem, serum, and CSF studies have been conducted on the levels of BDNF in PD patients. These studies also include some conflicts similar to Scz studies. Knott et al. have conducted a postmortem investigation on 11 PD patients and demonstrated an increase in the levels of BDNF in nigral neurons. They have also found no alterations in BDNF levels in caudate-putamen neurons [141]. Parain et al. reported a reduction in the expression of BDNF in substantia nigra of PD patients [142]. Such discrepancies have also been found in serum and CSF levels of BDNF. Most of the articles have demonstrated a reduction in serum levels of BDNF in PD patients [143-145]. On the other hand, a study by Ventriglia et al. has reported different results, showing an elevation in serum BDNF levels in 30 PD patients compared to 169 healthy controls [146]. We have also found controversial reports of BDNF changes in the CSF of patients. Salehi et al. (2009) have observed a decrease in CSF levels of BDNF in 40 PD patients [148]. However, they have reported that the BDNF levels of CSF were significantly elevated in PD patients [148]. Such conflicts in reports might be related to different medication strategies or the stages of the disease. Studies have so far indicated the association between serum and urine levels of BDNF and cognitive functions in healthy elderly [149, 150]. Reports have claimed that BDNF Val66Met polymorphism in interaction with other compounds such as sortilin is responsible for proBDNF intracellular trafficking [151]. These results suggest that carriers of the Met allele have an elective deficiency in hippocampal-dependent memory. Moreover, it may lead to BDNF secretion impairments in the hippocampus of mice [60], which is currently linked to impaired episodic memory function [152]. This polymorphism has not yet been associated with PD susceptibility directly, however, it has been shown to have associations with cognitive impairment as well as planning disability in PD [81, 87, 88]. Nevertheless, two studies have failed to find any significant relationships between this polymorphism and cognitive functioning in PD patients [83, 84]. The gold-standard surgical treatment of PD is currently Deep Brain Stimulation (DBS) which usually targets Sub-Thalamic Nucleus (STN). It has been suggested that BDNF plays a role in STN-DBSassociated neuroprotection. STN-DBS has been reported to increase activity-dependent BDNF release in targeted areas [153, 154] and elevate BDNF levels in the nigrostriatal system as well as in the primary motor cortex [155, 156]. 6. BDNF AND ALZHEIMER’S DISEASE AD is a progressive neurodegenerative disease and the most common cause of dementia in elderly individuals [157, 158]. There are numerous assumptions regarding the pathophysiology of the disease, but there is still no clear cause and definitive treatment for the disease [159]. Studies have shown that all three signaling pathways related to BDNF can cause AD and dementia. This illustrates the importance of BDNF related signaling pathways. Post-mortem studies on the brains of AD patients have suggested that BDNF expression is decreased in the hippocampus and the cortex. Many


Table 1.

Mohammadi et al.

BDNF alterations in Schizophrenia, Alzheimer, and Parkinson’s disease.

Study

Sample Size

Sources & Regions

Alteration

Takahashi et al., 2000 [114]

18 Scz 36 HC

Post-mortem Frontal cortices

Increased

Schizophrenia

Hashimoto et al., 2005 [58]

Weickert et al., 2003 [115]

Iritani et al., 2003 [116]

Sotiropoulou M et al., 2013 [120]

Pirildar S et al., 2004 [121]

Rizos EN et al., 2008 [122]

Jindal RD et al., 2010 [123]

Durany et al., 2004 [190]

Durany N et al., 2004 [190]

Buckley PF et al., 2007 [192]

27 Scz

Post-mortem

27 HC

All part of cortices

57 Scz

Post-mortem

60 HC

All part of cortices

8 Scz 4 HC 50 Scz 50 HC 22 Scz 22 HC 14 Scz 15 HC 41 Scz 41 HC 11 Scz 11 HC 11 Scz 11 HC 15 Scz 14 HC

Decreased

Decreased

Post-mortem hippocampus

Increased

Serum levels

Decreased

Serum levels

Decreased

Serum levels

Decreased

Serum levels

Decreased

Post-mortem hippocampus

Decreased

Post-mortem cortical areas

Increased

Serum levels

Decreased

Parkinson’s disease Knott C et al., 2002 [141]

11 PD 9 HC

Post-mortem nigral neurons Caudate-putamen

Increased No changed

Parain K et al., 1999 [142]

5 PD 5 HC

post-mortem expression of BDNF in brain

Decreased

Wang Y et al., 2017 [143]

96 PD 102 HC

Serum levels

Decreased

Wang Y et al., 2016 [144]

97 PD 102 HC

Serum levels

Decreased

Khalil H et al., 2016 [145]

29 PD 30 HC

Serum levels

Decreased

Ventriglia M et al., 2013 [146]

30 PD 169 HC

Serum levels

Increased

Salehi Z et al., 2009 [148]

24 PD 24 HC

CSF levels

Increased

Zhang J et al., 2008 [147]

40 PD 95 HC

CSF levels

Decreased

(Table 1) contd….


Study


Sample Size

Sources & Regions

Alteration

CSF levels

Decreased

Post-mortem expression of BDNF in hippocampus

Decreased

Post-mortem expression of BDNF in hippocampus

Decreased

Post-mortem entorhinal cortex

Decreased

Plasma levels

Increased

Serum levels

Decreased

CSF levels

Decreased

Serum levels

Decreased

51

Alzheimer’s disease Zhang J et al., 2008 [147]

Phillips HS et al., 1991 [160]

Murray KD et al., 2000 [161]

Narisawa-Saito et al., 1996 [162]

Faria MC et al., 2014 [164]

Leyhe C et al., 2008 [163]

Leyhe C et al., 2008 [163]

Ventriglia M et al., 2013 [146]

48 AD 95 HC 9 AD 6 HC 25 AD 10 HC 10 AD 10 HC 50 AD 56 HC 27 AD 28 HC 27 AD 10 HC 266 AD 169 HC

of the articles have the same theoretical view [160-162]. In 2013, Ventriglia et al. reported a significant decrease in BDNF serum levels in 266 patients with AD [146]. Leyhe et al. have also reported a noteworthy decrease in BDNF serum levels [163]. In 2014, Faria et al. found that the plasma levels of BDNF are increased in AD patients [164]. Recent studies demonstrated that CSF levels of BDNF are found to be lower in AD patients than in the controls [87, 147, 165]. Scientists hope that it is possible to increase patient’s quality of life by preventing dementia. To achieve this, further studies on the relationship between BDNF and AD should be performed. BDNF enhances the glutamatergic transmission [166-170] and elevates the phosphorylation of the subunits of N-methyl-D-aspartate (NMDA) receptors [171, 172]. It also improves the release rate of acetylcholine [173]. Nuclease protection assay and in situ hybridization studies have demonstrated that learning upregulates the expression of the hippocampal level of BDNF mRNA in rats [174]. It was reported that BDNF mRNA level in the dentate gyrus of the hippocampus plays a crucial role in memory consolidation and LTP in rats [175]. Tokuyama et al. reported that the BDNF mRNA is elevated in the inferior temporal cortex during the formation of visual pair-association memory in monkeys [176]. By testing the reference and working memory using an 8-arm radial maze, scientists reported that spatial learning is associated with an elevation in hippocampus BDNF mRNA levels [177]. These findings suggest that spatial memory is dependent on the enhancement of BDNF release in response to the information to be remembered [177, 178]. Nitric Oxide (NO) is a free radical which is believed to play a role in synaptic plasticity [35-37], spatial working memory formation, and in the regulation of monoamine metabolism [179-181]. Regarding the mutual regulations between the BDNF and NO, BDNF may be connected to NO-

sensitive learning. This hypothesis is supported by in vitro and in vivo studies [182]. The relationship between BDNF and learning and memory has also been investigated using anti-BDNF antibodies. Intraventricular infusion of the antiBDNF antibodies has been shown to be related to the impairment of spatial learning in a water maze test in rats [183]. Researchers have found that TrkB-CRE mutant mice completely failed the more stressful water maze test [184]. This report suggests the role of BDNF-TrkB receptor signaling in complex learning. 7. BDNF SIGNALING PATHWAY DYSFUNCTIONS This section is devoted to discuss the mechanisms by which BDNF signaling pathway dysfunctions can affect the pathophysiology of diseases including PD, AD, and Scz. During the progress of Scz, neuroplasticity of the brain is highly influenced by BDNF activity [185]. BDNF also regulates production, secretion, and metabolism of neurotransmitters. It also modulates neuronal LTP and influences synaptic plasticity [186]. It has been revealed that the BDNF interacts with other neurotransmitters, including dopamine, glutamate, serotonin, and GABA, and is involved in schizophrenia [187]. Abnormal changes in brain circuit and transmission can occur secondary to altered neurotrophin activities. These abnormalities may cause dysfunctions in the developing brain. Such dysfunctions account for the etiology of psychiatric disorders including Scz [188]. It has been strongly proposed that Scz is the result of abnormal brain development [189]. Considering this suggestion, BDNF has been hypothesized as a part of Scz pathogenesis. An abnormally developed brain, as in Scz patients, often fails in neuroplasticity and synaptic connectivity. It may also be abnormal in terms of morphology, neurochemistry, and structure.


All the above-mentioned dysfunctions can be partly due to BDNF dysfunctions as it has also been supported by previous studies [190-192]. Insufficient neurotrophic support may also cause reduced adaptive capabilities of adult brain and can be a predisposing factor for neurotoxic damage [193]. The function of the synaptic system is altered in the brains of Scz patients. Such alterations can be due to abnormal BDNF signaling since it has been proven that BDNF is involved in maintaining the survival and plasticity of dopaminergic, cholinergic, and serotonergic neurons [194]. It has been identified that GABA synthesis is highly reduced in the dorsolateral prefrontal cortex of Szc patients due to insufficient BDNF-TrkB signaling. These disturbances may lead to working memory impairments [195]. Given the current knowledge of PD, BDNF seems to be deeply involved in the pathogenesis of this disease due to its vital roles in the survival of dopaminergic neurons. This assumption has been supported by experimental models of PD. Studies have described that insufficient BDNF expression causes loss of substantia nigra pars compacta’s dopaminergic neurons [196]. It should be observed that the trophic factor which is involved in the pathophysiology amyloidopathies and tauopathies is highly influenced by BDNF, regarding the effects of BDNF on tau and amyloid β42 hyperphosphorylation [197, 198]. It has been implicated that tau phosphorylation greatly diminishes after neuronal stimulation with BDNF [197]. Evidence has suggested that BDNF-TrkB interactions might be involved in dephosphorylation of tau protein. Therefore, it can be concluded that decreased levels of BDNF might be the underlying cause of tau hyperphosphorylation in the AD. Post-mortem studies claimed that the concentration of BDNF protein is reduced within the entorhinal cortex and hippocampus of deceased AD patients [162, 199]. Recent evidence pointed towards the assumption that BDNF may have neuroprotective effects against Aβ peptide neurotoxicity [200]. It has been demonstrated that BDNF improves the number of cholinergic neurons as well as learning and memory in the rat model of AD upon neural stem cells transplantation [201]. Reports have shown that intra-hippocampal transplantation of neural stem cells improves spatial learning and memory in transgenic mice that express Amyloid Precursor Protein (APP), presenilin (a form of amyloid precursor protein), and tau. These improvements in cognitive functions of mice models of AD have been linked to enhancements in BDNF mediated hippocampal synaptic density [202]. Generally, BDNF has been reported as a potential diagnostic, prognostic, and therapeutic factor in AD. 8. THERAPEUTIC POTENTIAL OF BDNF IN Scz, PD, AND AD BDNF has recently become an interesting therapeutic target due to its protective and regenerative functions. Regarding some structural and pharmacokinetic issues, the use of BDNF as a therapeutic agent has limitations including the inability of BDNF to efficiently cross the Blood-Brain Barrier (BBB) [203, 204] and its limited half-life in the blood [205]. Such issues motivate researchers to investigate new delivery strategies to achieve proper levels of BDNF in the brain. BDNF receptor changes may significantly affect the success rate of BDNF enhancement therapeutic strategies, however,

Mohammadi et al.

this method remains one of the most effective therapeutic strategies for neural protection. In this section, we describe current treatment methods available for increasing BDNF levels in human and animal models. 8.1. Intraventricular BDNF Injection Direct intracranial administration of BDNF is currently known as the best long-lasting method for elevating the levels of BDNF within the neurons. Recent studies have reported that direct administration of BDNF into the brain ventricles may decrease neural loss in the cortex, which inhibits memory deterioration in the patients [206, 207]. It has been confirmed that brain’s age-related alterations, the hippocampus-dependent learning, and memory function of elderly rats have been improved following BDNF infusion into the entorhinal cortex. BDNF has also been stated to reduce cell death in the entorhinal cortex in aged rats [199]. This therapeutic method has only been tested in animal models and it is currently lacking sufficient human studies due to the invasive nature of the method. The invasive nature of this method also prevents its long-term usage. Another issue for testing this potent method is the fact that there is no concrete insurance that BDNF affects only the targeted areas without affecting other parts of the brain. Excess levels of BDNF may also increase the levels of pro-BDNF which induce P75NTR-mediated cell death and cause undesired outcomes. It should be mentioned that the preservation of BDNF therapeutic levels is an important issue as lower levels of BDNF than its therapeutic amounts will not induce desired effects and higher levels will cause adverse effects [208]. Placebocontrolled clinical trials have used an intrathecal infusion of BDNF to increase the duration of BDNF effects on motor neurons in the Amyotrophic Lateral Sclerosis (ALS). However, they have failed to produce significant clinical benefits [209, 210]. Studies have demonstrated that injection of T3 into the ventricular system of the brain causes memory and learning enhancement in rats. This method has also been used to increase hippocampal BDNF levels in cerebral ischemic stroke cases [211]. One of the present solutions for solving the aforementioned issue is the use of small molecules mimicking BDNF which can easily cross the BBB and penetrate brain tissue and is more suitable than BDNF analogues in terms of size and half-life [205, 212]. Another solution may be controlling the release of BDNF with Poly Lactic-co-Glycolic Acid (PLGA) micro-particle which can lead to longer-time delivery of BDNF [213, 214]. Intraparenchymal injection of BDNF is a direct and effective method for administering BDNF. Implanted infusion pumps were used in clinical trials in order to provide a sustained intra-parenchymal level of BDNF in PD patients [215]. However, researchers have failed to adjust the flow rate required for best results [216]. Currently, this method requires further development to effectively deliver the BDNF to targeted areas. Challenging issues include adverse side effects caused by high flow rates and reflux up of the infusion needle tract leading to the distribution of BDNF within the CSF which causes neuronal death [217]. 8.2. Gene and Epigenetic Therapy This strategy is based on the direct administration of BDNF gene into degenerating cells. Afterward, survived


cells mediate BDNF expression which leads to improved function or regeneration of neurons. Long-term effects are provided without continuous administration of BDNF. Currently, viral-based delivery systems of neurotrophic factors use fine-needle injections guided by real-time imaging [218]. In vivo studies have demonstrated that viral-based delivery systems are the most effective methods due to their high cell transfection efficiency, however, immune reactions remain a matter of concern. Direct administration of BDNF into a specific brain region of the host may solve the localization of its effects on the issue and minimize its spread to nontargeted regions. Direct gene transfer may be a suitable method for safe and effective growth factor delivery. This method is supported by several preclinical trials [219-221]. Studies have been conducted to investigate the safety and effectiveness of BDNF-gene therapy in neuro-degenerative diseases including PD [219, 220]. Researchers have demonstrated that in the rat models of PD, BDNF-gene delivery into nigral dopaminergic neurons prevents their degeneration process [222]. Although, this therapeutic strategy has so far shown promising results in animal models, but the efficacy of this method is time-sensitive as any delay in diagnosis would cause a dramatic decline in the effectiveness of the treatment. Moderate to a severe form of neurodegenerative diseases often represent widespread areas of damaged cells. According to localized effects of the current method, full coverage of affected areas is doubtful. Long-term elevation of genes transcription can be achieved by DNA methylation manipulations. Such manipulations can be done using pharmacological agents, which down-regulate histone deacetylase 5 resulting in reduced BDNF methylation and elevated BDNF gene expression [223]. Gadd45b-mediated demethylation of BDNF also accounts as a manipulation target [224]. MicroRNAs such as miR-613, which was reported to target the 3'-UTR of BDNF [225], and microRNA-1, which plays a key in suppressing BDNF production [226], can also be manipulated to change the availability of BDNF. 8.3. Cell Transplantation Strategy Bone Marrow-Derived Stem Cells (BMSCs) have the capability to secrete a variety of substances including BDNF [223, 224]. It is believed that these valuable cells can mediate protection and regeneration upon transplantation [225227]. As these cells have no antigenicity, the rejection risks decrease, therefore, they can be used for long-term BDNF secretion [228]. Their additional capability for the secretion of VEGF and anti-inflammatory substances can function alongside with BDNF [229, 230]. However, grafts may be less useful than other therapeutic strategies, BMSCs are shown to poorly migrate into injured regions [231] and their secreted BDNF levels may only be sufficient to mediate neuronal survival [232]. Studies have reported that transplantation of neural precursor cells significantly affects cognition due to enhanced expression levels of BDNF [233]. In addition to the safety and accessibility issues, the expensiveness of sterilization and surgical setting remains a challenging problem. There are a lot of stem cell-based clinical trials in PD and AD, whereas there is not outstanding report in Scz (Table 2).


53

It has been hypothesized that autologous adult Neural Stem Cells (NSCs) from the RMS (rostral migratory stream) and SVZ (subventricular zone) could be ideal sources for the treatment of PD and AD [234]. The early open-label trials had relatively satisfactory results [235-239]. It has been shown that Fetal Ventral Mesencephalic (fVM) cells-derived dopaminergic neurons survive more than 18 years after transplantation [240-242]. However, some reports failed to show any significant improvement in patients who had received fVM cells compared to controls [243, 244]. In contrast, others have been stated the beneficial effects of intrastriatal fVM grafts in patients with PD [245, 246]. Mendez et al. (2008) revealed that fVM -derived dopaminergic neurons survive without pathology for 9-14 years after transplantation [247]. Similarly, Hallett and colleagues (2014) have shown the long-term survival and nonatrophied morphology of fVM-derived dopaminergic neurons in the reinnervated striatum [248]. It has been suggested that the nigral and intrastriatal transplanted cells can lead to significant improvement in the total Unified Parkinson’s Disease Rating Scale (UPDRS) for several years without any problems [247, 249, 250]. Garitaonandia et al. (2016) and Gonzalez et al. (2016) confirmed the lack of residual undifferentiated stem cells and tumorigenic potential by human Neural and Pluripotent Stem Cells (h-NSC and h- PSCs) [251, 252]. Moreover, it has been shown that the morphology, phenotype, and differentiation capacity of PD-derived BMSCs are similar to normal BMSCs [253]. Kim et al. (2015) demonstrated that bilateral intra-hippocampal and precuneus transplantation of human Umbilical Cord-derived Mesenchymal Stem Cell (UC-MSC) is safe, feasible, and well tolerated in severe AD subjects, however, they found no significant clinical benefits [254]. It has been revealed that UC-MSC protects against Aß42-induced cell loss by releasing galectin-3 [255]. 8.4. Indirect Drug Therapy The use of drugs for induction of BDNF expression is the first BDNF therapy strategy which has been equipped. Lithium, which is a mood-stabilizer agent, has been stated to affect Glycogen Synthase-Kinase 3 (GSK-3) which increases BDNF levels [256-258]. Approximately 30% elevation of serum BDNF levels in AD patients treated with lithium has been reported [259]. Studies have demonstrated that lithium also induces anti-apoptotic, anti-inflammatory and proregenerative effects [260]. It also enhances the migration of BMSCs to target areas [261]. Positive effects of Venlafaxine and mood stabilizers such as Valproic acid on BDNF levels have been indicated by studies [262, 263]. Acetylcholinesterase inhibitors including donepezil and galantamine are the choices of treatment in Mild Cognitive Impairment (MCI) and early AD patients. These agents have been testified to increase BDNF levels in AD patients and animal models, however, the effects of long-term treatment with these agents are a matter of conflict [163, 264, 265]. This enhancement in BDNF level might be related to the effects of these drugs on phosphorylation of AKT kinase which affects the BDNF–TrkB signaling pathways [264]. In addition to Acetylcholinesterase inhibitors, NMDA antagonists such as memantine that is used for the treatment of moderate to the severe AD, have also been revealed to promote BDNFTrkB signaling pathway [266, 267]. Estrogens have been


Table 2.

Mohammadi et al.

Stem cell-based clinical trials in Schizophrenia, Alzheimer, and Parkinson’s disease.

Status

ClinicalTrials.gov Identifier

Publications (PMID)

Cell Sources

Phase

Unknown

NCT01943175

---

AMSCs

---

Recruiting

NCT02442817

---

---

---

Suspended

NCT00976430

19467573

BMSCs

----

Enrolling by invitation

NCT03128450

24910427, 24217017

h-NSC

Phase 2 Phase 3

Unknown

NCT01446614

18040857, 17610906, 20129484, 20544825, 20542127, 19465139, 18401666, 18665911

BMSCs

Phase 1 Phase 2

Active, not recruiting

NCT02780895

---

OK99

Phase 1

Recruiting

NCT02611167

---

BMSCs

Phase 1 Phase 2

Enrolling by invitation

NCT01329926

---

h-NSC

---

Not yet recruiting

NCT03309514

---

NSC-n

Phase 1 Phase 2

Recruiting

NCT02538315

f-DSCs

---

Withdrawn

NCT01453803

---

AMSCs

---

Recruiting

NCT02452723

27686862, 27213850

h-NSC

Phase 1

Recruiting

NCT03119636

---

NPC

Phase 1 Phase 2

Active, not recruiting

NCT02184546

---

AMSCs

---

Unknown

NCT00927108

---

h-NSC

Phase 2

Completed

NCT02511015

---

IPS-Cs

---

Recruiting

NCT03421899

---

Recruiting

NCT03297177

9008506, 18819991, 17898010, 25733984, 18344392, 2841426, 23487540, 22725961, 12401395

Autologous stem cell

---

Recruiting

NCT02795052

23135822, 21417782, 24693196, 23456256, 22963567, 26296458, 25206912

BMSCs

---

Recruiting

NCT00874783

18029452

IPS

---

Recruiting

NCT02600130

---

AMSCs

Phase 1

Recruiting

NCT02833792

---

AMSCs

Phase 2

Unknown

NCT01547689

---

UC-MSC

Phase 1 Phase 2

Recruiting

NCT02054208

---

UC-MSC

Phase 1 Phase 2

Completed

NCT01297218

---

UC-MSC

Phase 1

Unknown

NCT00927108

---

h-NSC

Phase 2

Schizophrenia

Parkinson’s disease

19037637

---

Alzheimer’s disease

(Table 2) contd….


Status


ClinicalTrials.gov Identifier

Publications (PMID)

Cell Sources

Phase

Recruiting

NCT03117738

---

AMSCs

Phase 1 Phase 2

Not yet recruiting

NCT02672306

---

UC-MSC

Phase 1 Phase 2

Recruiting

NCT03172117

---

UC-MSC

Phase 1 Phase 2

Not yet recruiting

NCT02899091

---

CB-AC-02

Phase 1 Phase 2

Unknown

NCT01696591

---

UC-MSC

Phase 1

Withdrawn

NCT02912169

---

ASVF

Phase 1 Phase 2

Recruiting

NCT03297177

9008506, 18819991, 17898010, 25733984, 18344392, 2841426, 23487540, 22725961, 12401395

Autologous stem cell

---

Recruiting

NCT00874783

18029452

IPS

---

55

Alzheimer’s disease

AMSCs: Adipose- derived mesenchymal stem cells; BMSCs: Bone marrow-derived mesenchymal stem cells; h-NSC: Human neural stem cell; NSC-n: Neural Stem Cell-Derived Neurons; f-DSCs: Fetal dopaminergic stem cell; NPC: Human embryonic stem cells-derived neural precursor cells; IPS: Induced Pluripotential Stems Cells; IPS-Cs: Induced Pluripotential Stems Cells-derived neurons; ASVF: Autologous adipose-derived stromal vascular fraction; AMSCs: Allogeneic Human Mesenchymal Stem Cell; UC-MSC: Human Umbilical Cord-Derived Mesenchymal Stem Cell

presented to affect brain’s BDNF expression levels both during development [268] and adulthood [269]. Regarding the role of BDNF in the brain and the neurodegenerative nature of AD, estrogens hypothetically might partly improve AD symptoms via upregulating BDNF expression levels [270]. Another pharmacological agent that can cross the BBB is Erythropoietin (EPO) [271]. EPO has been identified to upregulate BDNF expression and promote neuroprotection [272] as well as neuro-regeneration [273]. Currently, clinical trials have been conducted on remarkable new drugs including Phenserine, which have neuroprotective effects against oxidative stress as well as glutamate activity caused by its inhibitory effects on cholinesterase. It is hoped that the Phenserine lowers the development pace of AD by increasing the levels of BDNF [274]. A hypoxanthine derivative, Neotrofin, is another drug that is being tested for the treatment of AD. Neotrofin elevates the production rate of BDNF as well as the production of nerve growth factors. This results in increased synthesis of BDNF and enhanced memory function [274]. It has been described that herbal extracts such as curcumin, which is a low molecular weight polyphenol, can upregulate the brain’s BDNF level in rat [275]. Tripchlorolide extracted from Tripterygium wilfordii Hook F (TWHF) has also been reported to elevate BDNF levels and compensate NMDA receptor dysfunction [276]. 8.5. Life Style A growing body of evidence during the past decade suggests that environment and lifestyle are important factors associated with the regulation of BDNF levels. It has been implicated that long-term stress may affect BDNF signaling [277]. On the other hand, morphine, cocaine, and nicotine have been identified to improve BDNF gene expression in

animal models [278-280]. The other lifestyle dependent influencers of BDNF are acute aerobic exercises [281]. Animal studies have shown that long-term voluntary wheel running in mice leads to enhanced hippocampal BDNF gene expression [277, 282]. Besides these reports, a healthy elderly population who engage in regular physical exercises have been reported to have increased circulatory levels of BDNF [283]. Recently, it has been found that placing mice in an enriched environment containing complex and exciting objects, enhances neurogenesis in hippocampus accompanied with higher BDNF levels [284]. Neurogenesis and synaptic plasticity are also affected by Calorie Restriction (CR) diet. This claim is supported by animal studies which have reported higher BDNF concentration in mice undergoing postnatal nutrient restriction than those of the controls [285]. Additionally, rats fed by high-fat diets have been reported to show decreased BDNF levels as well as cognitive states [286]. CONCLUSION AND SUGGESTION With regards to the role of BDNF in the three signaling pathways which result in growth, survival, and neuronal plasticity, it seems that BDNF is the most important substance in the maintenance of neural health in the brain. Growing body of evidence suggests that it might be more effective to treat the pathophysiology underlying the clinical syndromes, including AD and PD than to interact with the pathogenesis. According to the fact that synaptic dysfunction is potentially the principal pathophysiological characteristic of all neurodegenerative disorders such as AD and PD, and that synapse loss is reversible, improvement of neurostabilizing, neuro-protecting, neuro-repairing, and synapses regenerating mechanisms can be accounted as new therapeu-


Mohammadi et al.

Fig. (2). Mechanism of BDNF dysfunctions in SCZ, PD, and AD.

tic targets. Scientists have collected a large amount of information regarding the BDNF-TrkB biology and the role of BDNF in synaptic plasticity and synaptic growth. The direction of future studies should shift to the new therapeutic strategies for neurodegenerative disorders. BDNF is currently known as the most efficient synaptogenic and synaptic regulator molecule. BDNF also promotes synaptic growth. Animal-based studies have also established the role of BDNF in cognitive functions. Moreover, BDNF is known as a neuro-protective agent that can repair synaptic deficits. Furthermore, the BDNF Val66Met polymorphism influences synaptic localization and activity-dependent secretion of BDNF. These show the importance of BDNF and its related intracellular signaling pathways on the pathophysiology of neurological and psychiatric diseases such as AD, PD, and Scz. The most important pathologies caused by BDNF dysfunction include impairments of brain development, dysregulation of neurotransmitters, neuronal plasticity disturbances, increased susceptibility against neurotoxic damage, elevated neuronal death, impaired neuronal growth, diminished GABA levels, and degeneration of dopaminergic neurons (Fig. 2).

1. The difference in the type and duration of medication in various diseases may cause variations in results, especially with regard to serum BDNF levels.

In terms of new therapeutic targets, BDNF has recently caught the majority of researcher’s attention due to its protective and regenerative functions. Using BDNF, as a therapeutic target has currently faced some issues including limited efficiency for crossing the BBB as well as short half-life in the bloodstream. BDNF receptor changes are another issue in the way of using BDNF as a therapeutic target. In order to achieve proper levels of BDNF in the brain, new drug delivery strategies are required. A significant amount of variations have been reported in CNS, serum, and brain BDNF levels in PD, AD, and Scz. Likely causes of these discrepancies are:

This review was supported by a grant from the Neuroscience Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran (Grant no. BMSU.96083).

2. The difference in methods of the studies and the lack of adjustability of the studied population in terms of age and sex can affect the results. 3. A low sample size, especially in cases of post-mortem studies can be a limitation for studies. 4. Each of the mentioned diseases has different stages, which may be one of the reasons for the differences in the results of studies. CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise. ACKNOWLEDGEMENTS

REFERENCES [1] [2] [3]

Hempstead BL. Dissecting the diverse actions of pro- and mature neurotrophins. Curr Alzheimer Res 2006; 3(1): 19-24. Lewin GR, Barde YA. Physiology of the neurotrophins. Annu Rev Neurosci 1996; 19: 289-317. Lykissas MG, Batistatou AK, Charalabopoulos KA, Beris AE. The role of neurotrophins in axonal growth, guidance, and regeneration. Curr Neurovasc Res 2007; 4(2): 143-51.

Dysfunction in BDNF Signaling Pathway [4]

[5] [6]

[7]

[8] [9] [10] [11]

[12] [13] [14]

[15] [16] [17] [18]

[19] [20]

[21] [22]

[23]

[24]

[25]

[26] [27] [28]

[29]

Yamada K, Mizuno M, Nabeshima T. Role for brain-derived neurotrophic factor in learning and memory. Life Sci 2002; 70(7): 73544. Lu B, Nagappan G, Guan X, Nathan PJ, Wren P. BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases. Nat Rev Neurosci 2013; 14(6): 401-16. Guillin O, Diaz J, Carroll P, et al. BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization. Nature 2001; 411(6833): 86-9. Azadmarzabadi E, Haghighatfard A, Mohammadi A. Low resilience to stress is associated with candidate gene expression alterations in the dopaminergic signalling pathway. 2018. doi: 10.1111/ psyg.12312. [Epub ahead of print]. Hanson IM, Seawright A, van Heyningen V. The human BDNF gene maps between FSHB and HVBS1 at the boundary of 11p13p14. Genomics 1992; 13(4): 1331-3. Sen A, Nelson TJ, Alkon DL. ApoE isoforms differentially regulates cleavage and secretion of BDNF. Mol Brain 2017; 10(1): 19. Yang J, Siao CJ, Nagappan G, et al. Neuronal release of proBDNF. Nat Neurosci 2009; 12(2): 113-5. Matsumoto T, Rauskolb S, Polack M, et al. Biosynthesis and processing of endogenous BDNF: CNS neurons store and secrete BDNF, not pro-BDNF. Nat Neurosci 2008; 11(2): 131-3. Binder DK, Scharfman HE. Brain-derived neurotrophic factor. Growth Factors 2004; 22(3): 123-31. Cattaneo A, Capsoni S, Paoletti F. Towards non invasive nerve growth factor therapies for Alzheimer's disease. J Alzheimers Dis 2008; 15(2): 255-83. Lewin GR CB. Neurotrophic Factors. In: Handbook of Experimental Pharmacology. SpringerLink (Online service) (2014); pp VIII, 520 p. 537 illus., 527 illus. in color. Berlin Heidelberg: Imprint: Springer. Wymann MP, Pirola L. Structure and function of phosphoinositide 3-kinases. Biochim Biophys Acta 1998; 1436(1-2): 127-50. Huang EJ, Reichardt LF. Trk receptors: roles in neuronal signal transduction. Annu Rev Biochem 2003; 72: 609-42. Song G, Ouyang G, Bao S. The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med 2005; 9(1): 59-71. Pillai A. Brain-derived neurotropic factor/TrkB signaling in the pathogenesis and novel pharmacotherapy of schizophrenia. Neurosignals 2008; 16(2-3): 183-93. Tata AM, Velluto L, D'Angelo C, Reale M. Cholinergic system dysfunction and neurodegenerative diseases: Cause or effect? CNS Neurol Disord Drug Targets 2014; 13(7): 1294-303. Scarr E. Muscarinic receptors: Their roles in disorders of the central nervous system and potential as therapeutic targets. CNS Neurosci Ther 2012; 18(5): 369-79. Lin SH, Lee LT, Yang YK. Serotonin and mental disorders: A concise review on molecular neuroimaging evidence. Clin Psychopharmacol Neurosci 2014; 12(3): 196-202. Wong CG, Bottiglieri T, Snead OC, 3rd. GABA, gammahydroxybutyric acid, and neurological disease. Ann Neurol 2003; 54 (Suppl 6): S3-12. Standaert DG WR. "Pharmacology of dopaminergic neurotransmission". In Tashjian AH, Armstrong EJ, Golan DE. Principles of pharmacology: The pathophysiologic basis of drug therapy. Lippincott Williams & Wilkins. 2011; pp. 186-206. ISBN 1-45111805-8. Minichiello L, Klein R. TrkB and TrkC neurotrophin receptors cooperate in promoting survival of hippocampal and cerebellar granule neurons. Genes Dev 1996; 10(22): 2849-58. Schwartz PM, Borghesani PR, Levy RL, Pomeroy SL, Segal RA. Abnormal cerebellar development and foliation in BDNF-/- mice reveals a role for neurotrophins in CNS patterning. Neuron 1997; 19(2): 269-81. Vanhaesebroeck B, Alessi DR. The PI3K-PDK1 connection: More than just a road to PKB. Biochem J 2000; 346 (Pt 3): 561-76. Kuruvilla R, Ye H, Ginty DD. Spatially and functionally distinct roles of the PI3-K effector pathway during NGF signaling in sympathetic neurons. Neuron 2000; 27(3): 499-512. Yamaguchi A, Tamatani M, Matsuzaki H, et al. Akt activation protects hippocampal neurons from apoptosis by inhibiting transcriptional activity of p53. J Biol Chem 2001; 276(7): 5256-64. Miyashita T, Reed JC. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 1995; 80(2): 293-9.

Current Gene Therapy, 2018, Vol. 18, No. 1 [30]

[31] [32] [33] [34]

[35] [36]

[37] [38]

[39]

[40]

[41]

[42]

[43] [44]

[45]

[46]

[47]

[48] [49]

[50]

57

Datta SR, Dudek H, Tao X, et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997; 91(2): 231-41. del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G. Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 1997; 278(5338): 687-9. Berridge MJ, Irvine RF. Inositol phosphates and cell signalling. Nature 1989; 341(6239): 197-205. Yang YR, Kang DS, Lee C, et al. Primary phospholipase C and brain disorders. Adv Biol Regul 2016; 61: 80-5. Patterson SL, Abel T, Deuel TA, et al. Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron 1996; 16(6): 1137-45. Huber KM, Sawtell NB, Bear MF. Brain-derived neurotrophic factor alters the synaptic modification threshold in visual cortex. Neuropharmacology 1998; 37(4-5): 571-9. Ji Y, Lu Y, Yang F, et al. Acute and gradual increases in BDNF concentration elicit distinct signaling and functions in neurons. Nat Neurosci 2010; 13(3): 302-9. Pang PT, Teng HK, Zaitsev E, et al. Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science 2004; 306(5695): 487-91. Barco A, Patterson SL, Alarcon JM, et al. Gene expression profiling of facilitated L-LTP in VP16-CREB mice reveals that BDNF is critical for the maintenance of LTP and its synaptic capture. Neuron 2005; 48(1): 123-37. Dineley KT, Westerman M, Bui D, et al. Beta-amyloid activates the mitogen-activated protein kinase cascade via hippocampal alpha7 nicotinic acetylcholine receptors: In vitro and in vivo mechanisms related to Alzheimer's disease. J Neurosci 2001; 21(12): 4125-33. Gasparini L, Gouras GK, Wang R, et al. Stimulation of betaamyloid precursor protein trafficking by insulin reduces intraneuronal beta-amyloid and requires mitogen-activated protein kinase signaling. J Neurosci 2001; 21(8): 2561-70. Ferrer I, Blanco R, Carmona M, et al. Phosphorylated map kinase (ERK1, ERK2) expression is associated with early tau deposition in neurones and glial cells, but not with increased nuclear DNA vulnerability and cell death, in Alzheimer disease, Pick's disease, progressive supranuclear palsy and corticobasal degeneration. Brain Pathol 2001; 11(2): 144-58. Liu Y, Song Y, Zhu X. MicroRNA-181a regulates apoptosis and autophagy process in parkinson's disease by inhibiting p38 mitogen-activated protein kinase (MAPK)/c-Jun N-Terminal kinases (JNK) signaling pathways. Med Sci Monit 2017; 23: 1597-1606. Kyosseva SV. The role of the extracellular signal-regulated kinase pathway in cerebellar abnormalities in schizophrenia. Cerebellum 2004; 3(2): 94-9. Funk AJ, McCullumsmith RE, Haroutunian V, Meador-Woodruff JH. Abnormal activity of the MAPK- and cAMP-associated signaling pathways in frontal cortical areas in postmortem brain in schizophrenia. Neuropsychopharmacology 2012; 37(4): 896-905. Tartaglia N, Du J, Tyler WJ, et al. Protein synthesis-dependent and-independent regulation of hippocampal synapses by brainderived neurotrophic factor. J Biol Chem 2001; 276(40): 3758537593. Horch HW, Kruttgen A, Portbury SD, Katz LC. Destabilization of cortical dendrites and spines by BDNF. Neuron 1999; 23(2): 35364. Pozzo-Miller LD, Gottschalk W, Zhang L, et al. Impairments in high-frequency transmission, synaptic vesicle docking, and synaptic protein distribution in the hippocampus of BDNF knockout mice. J Neurosci 1999; 19(12): 4972-83. Otal R, Martínez A, Soriano E. Lack of TrkB and TrkC signaling alters the synaptogenesis and maturation of mossy fiber terminals in the hippocampus. Cell and Tissue Res 2005; 319(3): 349-358. Aguado F, Carmona MA, Pozas E, et al. BDNF regulates spontaneous correlated activity at early developmental stages by increasing synaptogenesis and expression of the K+/Cl- co-transporter KCC2. Development 2003; 130(7): 1267-80. Singh B, Henneberger C, Betances D, et al. Altered balance of glutamatergic/GABAergic synaptic input and associated changes in dendrite morphology after BDNF expression in BDNF-deficient hippocampal neurons. J Neurosci 2006; 26(27): 7189-200.

58 Current Gene Therapy, 2018, Vol. 18, No. 1 [51]

[52]

[53] [54]

[55]

[56]

[57]

[58]

[59] [60]

[61]

[62]

[63] [64]

[65]

[66]

[67]

[68]

[69] [70]

[71]

Tanaka J, Horiike Y, Matsuzaki M, et al. Protein synthesis and neurotrophin-dependent structural plasticity of single dendritic spines. Science 2008; 319(5870): 1683-7. Chen ZY, Patel PD, Sant G, et al. Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons. J Neurosci 2004; 24(18): 4401-11. Kleim JA, Chan S, Pringle E, et al. BDNF val66met polymorphism is associated with modified experience-dependent plasticity in human motor cortex. Nat Neurosci 2006; 9(6): 735-737. McHughen SA, Rodriguez PF, Kleim JA, et al. BDNF Val66Met polymorphism influences motor system function in the human brain. Cerebral Cortex 2010; 20(5): 1254-1262. Beng-Choon Ho, Nancy C. Andreasen MD, et al. Association between brain-derived neurotrophic Factor Val66Met gene polymorphism and progressive brain volume changes in schizophrenia. Am J Psychiat 2007; 164(12): 1890-1899. Kunugi H, Iijima Y, Tatsumi M, et al. No association between the Val66Met polymorphism of the brain-derived neurotrophic factor gene and bipolar disorder in a Japanese population: A multicenter study. Biol Psychiatry 2004; 56(5): 376-378. Hong C-J, Yu YWY, Lin C-H, Tsai S-J. An association study of a brain-derived neurotrophic factor Val66Met polymorphism and clozapine response of schizophrenic patients. Neurosci Lett 2003; 349(3): 206-208. Hashimoto T, Bergen SE, Nguyen QL, et al. Relationship of brainderived neurotrophic factor and its receptor TrkB to altered inhibitory prefrontal circuitry in schizophrenia. J Neurosci 2005; 25(2): 372-83. Lin Z, Su Y, Zhang C, et al. The interaction of BDNF and NTRK2 gene increases the susceptibility of paranoid schizophrenia. PLoS One 2013; 8(9): e74264. Egan MF, Kojima M, Callicott JH, et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 2003; 112(2): 25769. Sun MM, Yang LM, Wang Y, et al. BDNF Val66Met polymorphism and anxiety/depression symptoms in schizophrenia in a Chinese Han population. Psychiatr Genet 2013; 23(3): 124-9. Wang Y, Wang JD, Wu HR, et al. The Val66Met polymorphism of the brain-derived neurotrophic factor gene is not associated with risk for schizophrenia and tardive dyskinesia in Han Chinese population. Schizophr Res 2010; 120(1-3): 240-2. Sun RF, Zhu YS, Kuang WJ, Liu Y, Li SB. The G-712A polymorphism of brain-derived neurotrophic factor is associated with major depression but not schizophrenia. Neurosci Lett 2011; 489(1): 34-7. Zhang XY, Chen DC, Xiu MH, et al. Cognitive and serum BDNF correlates of BDNF Val66Met gene polymorphism in patients with schizophrenia and normal controls. Hum Genet 2012; 131(7): 1187-95. Yi Z, Zhang C, Wu Z, et al. Lack of effect of brain derived neurotrophic factor (BDNF) Val66Met polymorphism on early onset schizophrenia in Chinese Han population. Brain Res 2011; 1417: 146-50. Kishikawa S, Li JL, Gillis T, et al. Brain-derived neurotrophic factor does not influence age at neurologic onset of Huntington's disease. Neurobiol Dis 2006; 24(2): 280-5. Chen CM, Chen IC, Chang KH, et al. Nuclear receptor NR4A2 IVS6 +18insG and Brain Derived Neurotrophic Factor (BDNF) V66M polymorphisms and risk of Taiwanese Parkinson's disease. Am J Med Genet B Neuropsychiatr Genet 2007; 144b(4): 458-62. Chen L, Wang Y, Xiao H, et al. The 712A/G polymorphism of Brain-derived neurotrophic factor is associated with parkinson's disease but not major depressive disorder in a chinese han population. Biochem Biophys Res Commun 2011; 408(2): 318-21. Karamohamed S, Latourelle JC, Racette BA, et al. BDNF genetic variants are associated with onset age of familial parkinson disease: GenePD Study. Neurology 2005; 65(11): 1823-5. Parsian A, Sinha R, Racette B, Zhao JH, Perlmutter JS. Association of a variation in the promoter region of the brain-derived neurotrophic factor gene with familial Parkinson's disease. Parkinsonism Relat Disord 2004; 10(4): 213-9. Liu J, Zhou Y, Wang C, et al. Brain-derived neurotrophic factor (BDNF) genetic polymorphism greatly increases risk of leucinerich repeat kinase 2 (LRRK2) for Parkinson's disease. Parkinsonism Relat Disord 18(2): 140-3.

Mohammadi et al. [72]

[73]

[74] [75]

[76]

[77]

[78] [79]

[80] [81]

[82] [83]

[84]

[85]

[86]

[87] [88]

[89] [90]

[91] [92]

[93]

[94]

Karakasis C, Kalinderi K, Katsarou Z, Fidani L, Bostantjopoulou S. Association of Brain-Derived Neurotrophic Factor (BDNF) Val66Met polymorphism with parkinson’s disease in a Greek population. J Clini Neurosci 2011; 18(12): 1744-5. Benitez BA, Forero DA, Arboleda GH, et al. Exploration of genetic susceptibility factors for parkinson's disease in a south american sample. J Genet 2010; 89(2): 229-32. Lee YH, Song GG. BDNF 196 G/A and 270 C/T polymorphisms and susceptibility to Parkinson's disease: A meta-analysis. J Mot Behav 2014; 46(1): 59-66. Nishimura M, Kuno S, Kaji R, Kawakami H. Brain-derived neurotrophic factor gene polymorphisms in japanese patients with sporadic alzheimer's disease, parkin son's disease, and multiple system atrophy. Mov Disord 2005; 20(8): 1031-3. Xiromerisiou G, Hadjigeorgiou GM, Eerola J, et al. BDNF tagging polymorphisms and haplotype analysis in sporadic Parkinson's disease in diverse ethnic groups. Neurosci Lett 2007; 415(1): 59-63. Saarela MS, Lehtimaki T, Rinne JO, et al. No association between the brain-derived neurotrophic factor 196G>A or 270C>T polymorphisms and alzheimer's or parkinson's disease. Folia Neuropathologica 2006; 44(1): 12-6. Hong C-J, Liu H-C, Liu T-Y, et al. Brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms in parkinson's disease and age of onset. Neurosci Lett 2003; 353(1): 75-7. Håkansson A, Melke J, Westberg L, et al. Lack of association between the BDNF Val66Met polymorphism and parkinson's disease in a Swedish population. Ann Neurol 2003; 53(6): 823-3. Gao L, Díaz-Corrales FJ, Carrillo F, et al. Brain-derived neurotrophic factor G196A polymorphism and clinical features in Parkinson’s disease. Acta Neurologica Scandinavica 2010; 122(1): 41-5. Zintzaras E, Hadjigeorgiou GM. The role of G196A polymorphism in the brain-derived neurotrophic factor gene in the cause of Parkinson's disease: a meta-analysis. J Hum Genet 2005; 50(11): 560-6. Dai L, Wang D, Meng H, et al. Association between the BDNF G196A and C270T polymorphisms and parkinson's disease: A meta-analysis. Intl J Neurosci 2013; 123(10): 675-83. Svetel M, Pekmezovic T, Markovic V, et al. No association between brain-derived neurotrophic factor G196A polymorphism and clinical features of parkinson's disease. European Neurology 2013; 70(5-6): 257-62. Białecka M, Kurzawski M, Roszmann A, et al. BDNF G196A (Val66Met) polymorphism associated with cognitive impairment in Parkinson's disease. Neurosci Lett 2014; 561(Supplement C): 8690. Hariri AR, Goldberg TE, Mattay VS, et al. Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J Neurosci 2003; 23(17): 6690-4. Notaras M, Hill R, van den Buuse M. The BDNF gene Val66Met polymorphism as a modifier of psychiatric disorder susceptibility: progress and controversy. Mol Psychiatr 2015; 20(8): 916-30. Guerini FR, Beghi E, Riboldazzi G, et al. BDNF Val66Met polymorphism is associated with cognitive impairment in Italian patients with Parkinson's disease. Eur J Neurol 2009; 16(11): 1240-5. Foltynie T, Cheeran B, Williams-Gray CH, et al. BDNF val66met influences time to onset of levodopa induced dyskinesia in Parkinson's disease. J Neurol Neurosurg Psychiatry 2009; 80(2): 141-4. Masaki T, Matsushita S, Arai H, et al. Association between a polymorphism of brain-derived neurotrophic factor gene and sporadic Parkinson's disease. Ann Neurol 2003; 54(2): 276-7. Altmann V, Schumacher-Schuh AF, Rieck M, et al. Val66Met BDNF polymorphism is associated with Parkinson's disease cognitive impairment. Neurosci Lett 2016; 615: 88-91. Nagel T, Frontmatter, in MohammedLeben und Legende. 2008. Voineskos AN, Lerch JP, Felsky D, et al. The brain-derived neurotrophic factor Val66Met polymorphism and prediction of neural risk for Alzheimer disease. Arch Gen Psychiatry 2011; 68(2): 198206. Lim YY, Villemagne V, Laws S, et al. Modulation of betaamyloid-related cognitive decline by brain-derived neurotrophic factor Val66Met polymorphism in preclinical Alzheimer's disease. Alzheimer's & Dementia: The Journal of the Alzheimer's Association; 9(4): P446-7. Kemppainen S, Rantamaki T, Jeronimo-Santos A, et al. Impaired TrkB receptor signaling contributes to memory impairment in APP/PS1 mice. Neurobiol Aging 2012; 33(6): 1122.e23-39.


[96] [97]

[98]

[99]

[100]

[101]

[102]

[103] [104]

[105]

[106]

[107] [108]

[109] [110]

[111] [112]

[113]

[114]

[115]

[116]

Kunugi H, Ueki A, Otsuka M, et al. A novel polymorphism of the brain-derived neurotrophic factor (BDNF) gene associated with late-onset Alzheimer's disease. Mol Psychiatr 2001; 6(1): 83-6. Olin D, MacMurray J, Comings DE. Risk of late-onset Alzheimer's disease associated with BDNF C270T polymorphism. Neurosci Lett 2005; 381(3): 275-8. Riemenschneider M, Schwarz S, Wagenpfeil S, et al. A polymorphism of the brain-derived neurotrophic factor (BDNF) is associated with Alzheimer's disease in patients lacking the Apolipoprotein E epsilon4 allele. Mol Psychiatr 2002; 7(7): 782-5. Fukumoto N, Fujii T, Combarros O, et al. Sexually dimorphic effect of the Val66Met polymorphism of BDNF on susceptibility to Alzheimer's disease: New data and meta-analysis. Am J Med Genet B Neuropsychiatr Genet 2010; 153b(1): 235-42. Boiocchi C, Maggioli E, Zorzetto M, et al. Brain-derived neurotrophic factor gene variants and Alzheimer disease: An association study in an Alzheimer disease Italian population. Rejuvenation Res 2013; 16(1): 57-66. Lin Y, Cheng S, Xie Z, Zhang D. Association of rs6265 and rs2030324 polymorphisms in brain-derived neurotrophic factor gene with Alzheimer's disease: A meta-analysis. PLoS One 2014; 9(4): e94961. Chen Z, Simmons MS, Perry RT, et al. Genetic association of neurotrophic tyrosine kinase receptor type 2 (NTRK2) With Alzheimer's disease. Am J Med Genet B Neuropsychiatr Genet 2008; 147(3): 363-9. Cozza A, Melissari E, Iacopetti P, et al. SNPs in neurotrophin system genes and Alzheimer's disease in an Italian population. J Alzheimers Dis 2008; 15(1): 61-70. Vepsalainen S, Castren E, Helisalmi S, et al. Genetic analysis of BDNF and TrkB gene polymorphisms in Alzheimer's disease. J Neurol 2005; 252(4): 423-8. Zeng F, Zou HQ, Zhou HD, et al. The relationship between single nucleotide polymorphisms of the NTRK2 gene and sporadic Alzheimer's disease in the Chinese Han population. Neurosci Lett 2013; 550: 55-9. Zhang F, Kang Z, Li W, Xiao Z, Zhou X. Roles of brain-derived neurotrophic factor/tropomyosin-related kinase B (BDNF/TrkB) signalling in Alzheimer's disease. J Clin Neurosci 2012; 19(7): 9469. Li H, Wetten S, Li L, et al. Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease. Arch Neurol 2008; 65(1): 45-53. Cardno AG, Gottesman, II. Twin studies of schizophrenia: From bow-and-arrow concordances to star wars Mx and functional genomics. Am J Med Genet 2000; 97(1): 12-7. Mohammadi A, Hesami E, Kargar M, Shams J. Detecting allocentric and egocentric navigation deficits in patients with schizophrenia and bipolar disorder using virtual reality. Neuropsychol Rehabil 2018; 28(3): 398-415. Wong AH, Van Tol HH. Schizophrenia: from phenomenology to neurobiology. Neurosci Biobehav Rev 2003; 27(3): 269-306. Noori-daloii MR, Shahbazi A, Alizadeh Zendehrood S, et al. Knocking Down the DRD2 by shRNA expressing plasmids in the nucleus accumbens prevented the disrupting effect of apomorphine on prepulse inhibition in rat. J Sci 2015; 26(3): 205-12. Gottesman II WHF. Schizophrenia genesis: The origins of madness. 1991. Wong AH, Gottesman, II, Petronis A. Phenotypic differences in genetically identical organisms: the epigenetic perspective. Hum Mol Genet 2005; 14 (Spec No 1): R11-8. Misiak B, Stramecki F, Gaweda L, et al. Interactions between variation in candidate genes and environmental factors in the etiology of schizophrenia and bipolar disorder: A systematic review. Mol Neurobiol 2017; doi: 10.1007/s12035-017-0708-y. [Epub ahead of print] Takahashi M, Shirakawa O, Toyooka K, et al. Abnormal expression of brain-derived neurotrophic factor and its receptor in the corticolimbic system of schizophrenic patients. Mol Psychiatry 2000; 5(3): 293-300. Weickert CS, Hyde TM, Lipska BK, et al. Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia. Mol Psychiatr 2003; 8(6): 592-610. Iritani S, Niizato K, Nawa H, Ikeda K, Emson PC. Immunohistochemical study of brain-derived neurotrophic factor and its recep-


[117]

[118]

[119] [120]

[121]

[122] [123]

[124] [125]

[126]

[127]

[128]

[129]

[130]

[131] [132] [133]

[134] [135]

[136] [137]

[138]

59

tor, TrkB, in the hippocampal formation of schizophrenic brains. Prog Neuropsychopharmacol Biol Psychiatr 2003; 27(5): 801-7. Boos HB, Aleman A, Cahn W, Hulshoff Pol H, Kahn RS. Brain volumes in relatives of patients with schizophrenia: A metaanalysis. Arch Gen Psychiatr 2007; 64(3): 297-304. Steen RG, Mull C, McClure R, Hamer RM, Lieberman JA. Brain volume in first-episode schizophrenia: systematic review and metaanalysis of magnetic resonance imaging studies. Br J Psychiatr 2006; 188: 510-8. Autry AE, Monteggia LM. Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev 2012; 64(2): 238-58. Sotiropoulou M, Mantas C, Bozidis P, et al. BDNF serum concentrations in first psychotic episode drug-naive schizophrenic patients: associations with personality and BDNF Val66Met polymorphism. Life Sci 2013; 92(4-5): 305-10. Pirildar S, Gonul AS, Taneli F, Akdeniz F. Low serum levels of brain-derived neurotrophic factor in patients with schizophrenia do not elevate after antipsychotic treatment. Prog Neuropsychopharmacol Biol Psychiatr 2004; 28(4): 709-13. Rizos EN, Rontos I, Laskos E, et al. Investigation of serum BDNF levels in drug-naive patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatr 2008; 32(5): 1308-11. Jindal RD, Pillai AK, Mahadik SP, et al. Decreased BDNF in patients with antipsychotic naive first episode schizophrenia. Schizophr Res 2010; 119(1-3): 47-51. Freedman R, Stromberg I, Seiger A, et al. Initial studies of embryonic transplants of human hippocampus and cerebral cortex derived from schizophrenic women. Biol Psychiatr 1992; 32(12): 1148-63. Freedman R, Stromberg I, Nordstrom AL, et al. Neuronal development in embryonic brain tissue derived from schizophrenic women and grafted to animal hosts. Schizophr Res 1994; 13(3): 259-70. Jockers-Scherubl MC, Danker-Hopfe H, Mahlberg R, et al. Brainderived neurotrophic factor serum concentrations are increased in drug-naive schizophrenic patients with chronic cannabis abuse and multiple substance abuse. Neurosci Lett 2004; 371(1): 79-83. Ashe PC, Chlan-Fourney J, Juorio AV, Li XM. Brain-derived neurotrophic factor (BDNF) mRNA in rats with neonatal ibotenic acid lesions of the ventral hippocampus. Brain Res 2002; 956(1): 126-35. Lipska BK, Khaing ZZ, Weickert CS, Weinberger DR. BDNF mRNA expression in rat hippocampus and prefrontal cortex: Effects of neonatal ventral hippocampal damage and antipsychotic drugs. Eur J Neurosci 2001; 14(1): 135-44. Molteni R, Lipska BK, Weinberger DR, Racagni G, Riva MA. Developmental and stress-related changes of neurotrophic factor gene expression in an animal model of schizophrenia. Mol Psychiatr 2001; 6(3): 285-92. Chlan-Fourney J, Ashe P, Nylen K, Juorio AV, Li XM. Differential regulation of hippocampal BDNF mRNA by typical and atypical antipsychotic administration. Brain Res 2002; 954(1): 11-20. Sveinbjornsdottir S. The clinical symptoms of Parkinson's disease. J Neurochem 2016; 139 (Suppl 1): 318-324. Mohammadi A, Mehdizadeh AR. Deep brain stimulation and gene expression alterations in parkinson's disease. J Biomed Phys Eng 2016; 6(2): 47-50. Hyman C, Hofer M, Barde YA, et al. BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra. Nature 1991; 350(6315): 230-2. Baydyuk M, Nguyen MT, Xu B. Chronic deprivation of TrkB signaling leads to selective late-onset nigrostriatal dopaminergic degeneration. Exp Neurol 2011; 228(1): 118-25. Thoenen H, Sendtner M. Neurotrophins: from enthusiastic expectations through sobering experiences to rational therapeutic approaches. Nat Neurosci 2002; 5 (Suppl): 1046-50. Howells DW, Porritt MJ, Wong JY, et al. Reduced BDNF mRNA expression in the Parkinson's disease substantia nigra. Exp Neurol 2000; 166(1): 127-35. Mogi M, Togari A, Kondo T, et al. Brain-derived growth factor and nerve growth factor concentrations are decreased in the substantia nigra in Parkinson's disease. Neurosci Lett 1999; 270(1): 458. Sharma JC, Bachmann CG, Linazasoro G. Classifying risk factors for dyskinesia in Parkinson's disease. Parkinsonism Relat Disord 2010; 16(8): 490-7.


[140]

[141] [142]

[143] [144]

[145] [146]

[147] [148]

[149]

[150] [151]

[152] [153] [154]

[155]

[156]

[157]

[158]

[159] [160]

[161]

Yoshimoto Y, Lin Q, Collier TJ, et al. Astrocytes retrovirally transduced with BDNF elicit behavioral improvement in a rat model of Parkinson's disease. Brain Res 1995; 691(1-2): 25-36. Phillips HS, Hains JM, Laramee GR, Rosenthal A, Winslow JW. Widespread expression of BDNF but not NT3 by target areas of basal forebrain cholinergic neurons. Science 1990; 250(4980): 290294. Knott C, Stern G, Kingsbury A, Welcher AA, Wilkin GP. Elevated glial brain-derived neurotrophic factor in Parkinson's diseased nigra. Parkinsonism Relat Disord 2002; 8(5): 329-41. Parain K, Murer MG, Yan Q, et al. Reduced expression of brainderived neurotrophic factor protein in Parkinson's disease substantia nigra. Neuroreport 1999; 10(3): 557-61. Wang Y, Liu H, Du XD, et al. Association of low serum BDNF with depression in patients with Parkinson's disease. Parkinsonism Relat Disord 2017; 41: 73-8. Wang Y, Liu H, Zhang BS, Soares JC, Zhang XY. Low BDNF is associated with cognitive impairments in patients with Parkinson's disease. Parkinsonism Relat Disord 2016; 29: 66-71. Khalil H, Alomari MA, Khabour OF, Al-Hieshan A, Bajwa JA. Relationship of circulatory BDNF with cognitive deficits in people with Parkinson's disease. J Neurol Sci 2016; 362: 217-20. Ventriglia M, Zanardini R, Bonomini C, et al. Serum brain-derived neurotrophic factor levels in different neurological diseases. Biomed Res Int 2013; 2013: 901082. Zhang J, Sokal I, Peskind ER, et al. CSF multianalyte profile distinguishes Alzheimer and Parkinson diseases. Am J Clin Pathol 2008; 129(4): 526-9. Salehi Z, Mashayekhi F. Brain-derived neurotrophic factor concentrations in the cerebrospinal fluid of patients with Parkinson's disease. J Clin Neurosci 2009; 16(1): 90-3. Shimada H, Makizako H, Doi T, et al. A large, cross-sectional observational study of serum BDNF, cognitive function, and mild cognitive impairment in the elderly. Front Aging Neurosci 2014; 6: 69. Gunstad J, Benitez A, Smith J, et al. Serum Brain-Derived neurotrophic factor is associated with cognitive function in healthy older adults. J Geriatric Psychiatr Neurol 2008; 21(3): 166-70. Chen Z-Y, Ieraci A, Teng H, et al. Sortilin controls intracellular sorting of brain-Derived neurotrophic factor to the regulated secretory pathway. J Neurosci 2005; 25(26): 6156-66. Park H, Poo M-M. Neurotrophin regulation of neural circuit development and function. Nat Revi Neurosci 2013; 14(1): 7. Hartmann M, Heumann R, Lessmann V. Synaptic secretion of BDNF after high-frequency stimulation of glutamatergic synapses. EMBO J 2001; 20(21): 5887-97. Matsuda N, Lu H, Fukata Y, et al. Differential activity-dependent secretion of brain-derived neurotrophic factor from axon and dendrite. J Neurosci 2009; 29(45): 14185-98. Spieles-Engemann AL BM, Collier TJ, Steece-Collier K, Wohlgenant SL, Thompson VB, Lipton JW, Sortwell CE IL. Deep brain stimulation in a rodent model of parkinson's disease upregulates bdnf in subthalamic nucleus target structures. Society for Neuroscience Abstracts 46.1. Chicago, 2009. Spieles-Engemann AL, Steece-Collier K, Behbehani MM, et al. Subthalamic nucleus stimulation increases brain derived neurotrophic factor in the nigrostriatal system and primary motor cortex. J Parkinsons Dis 2011; 1(1): 123-36. Javadpour A, Mohammadi A. Improving Brain Magnetic Resonance Image (MRI) segmentation via a novel algorithm based on genetic and regional growth. J Biomed Phys Eng 2016; 6(2): 95108. Mohammadi A, Kargar M, Hesami E. Using virtual reality to distinguish subjects with multiple- but not single-domain amnestic mild cognitive impairment from normal elderly subjects. Psychogeriatrics 2018. doi: 10.1111/psyg.12301 [Epub ahead of print]. Ballard C, Gauthier S, Corbett A, et al. Alzheimer's disease. Lancet 2011; 377(9770): 1019-31. Phillips HS, Hains JM, Armanini M, et al. BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer's disease. Neuron 1991; 7(5): 695-702. Murray KD, Isackson PJ, Eskin TA, et al. Altered mRNA expression for brain-derived neurotrophic factor and type II calcium/calmodulin-dependent protein kinase in the hippocampus of patients with intractable temporal lobe epilepsy. J Comp Neurol 2000; 418(4): 411-22.

Mohammadi et al. [162]

[163]

[164] [165]

[166] [167]

[168]

[169] [170]

[171]

[172]

[173]

[174]

[175]

[176] [177]

[178] [179]

[180] [181]

[182]

[183]

Narisawa-Saito M, Wakabayashi K, Tsuji S, Takahashi H, Nawa H. Regional specificity of alterations in NGF, BDNF and NT-3 levels in Alzheimer's disease. Neuroreport 1996; 7(18): 2925-8. Leyhe T, Stransky E, Eschweiler GW, Buchkremer G, Laske C. Increase of BDNF serum concentration during donepezil treatment of patients with early Alzheimer's disease. Eur Arch Psychiatry Clin Neurosci 2008; 258(2): 124-8. Faria MC, Goncalves GS, Rocha NP, et al. Increased plasma levels of BDNF and inflammatory markers in Alzheimer's disease. J Psychiatr Res 2014; 53: 166-72. Diniz BS, Teixeira AL. Brain-derived neurotrophic factor and Alzheimer's disease: physiopathology and beyond. Neuromol Med 2011; 13(4): 217-22. Lohof AM, Ip NY, Poo MM. Potentiation of developing neuromuscular synapses by the neurotrophins NT-3 and BDNF. Nature 1993; 363(6427): 350-3. Lessmann V, Gottmann K, Heumann R. BDNF and NT-4/5 enhance glutamatergic synaptic transmission in cultured hippocampal neurones. Neuroreport 1994; 6(1): 21-5. Levine ES, Dreyfus CF, Black IB, Plummer MR. Brain-derived neurotrophic factor rapidly enhances synaptic transmission in hippocampal neurons via postsynaptic tyrosine kinase receptors. Proc Natl Acad Sci USA 1995; 92(17): 8074-7. Kang H, Schuman EM. Long-lasting neurotrophin-induced enhancement of synaptic transmission in the adult hippocampus. Science 1995; 267(5204): 1658-62. Kang H, Schuman EM. A requirement for local protein synthesis in neurotrophin-induced hippocampal synaptic plasticity. Science 1996; 273(5280): 1402-6. Suen PC, Wu K, Levine ES, et al. Brain-derived neurotrophic factor rapidly enhances phosphorylation of the postsynaptic Nmethyl-D-aspartate receptor subunit 1. Proc Natl Acad Sci USA 1997; 94(15): 8191-5. Lin SY, Wu K, Levine ES, et al. BDNF acutely increases tyrosine phosphorylation of the NMDA receptor subunit 2B in cortical and hippocampal postsynaptic densities. Brain Res Mol Brain Res 1998; 55(1): 20-7. Knipper M, da Penha Berzaghi M, Blochl A, et al. Positive feedback between acetylcholine and the neurotrophins nerve growth factor and brain-derived neurotrophic factor in the rat hippocampus. Eur J Neurosci 1994; 6(4): 668-71. Kesslak JP, So V, Choi J, Cotman CW, Gomez-Pinilla F. Learning upregulates brain-derived neurotrophic factor messenger ribonucleic acid: a mechanism to facilitate encoding and circuit maintenance? Behav Neurosci 1998; 112(4): 1012-9. Ma YL, Wang HL, Wu HC, Wei CL, Lee EH. Brain-derived neurotrophic factor antisense oligonucleotide impairs memory retention and inhibits long-term potentiation in rats. Neuroscience 1998; 82(4): 957-67. Tokuyama W, Okuno H, Hashimoto T, Xin Li Y, Miyashita Y. BDNF upregulation during declarative memory formation in monkey inferior temporal cortex. Nat Neurosci 2000; 3(11): 1134-42. Mizuno M, Yamada K, He J, Nakajima A, Nabeshima T. Involvement of BDNF receptor TrkB in spatial memory formation. Learn Mem 2003; 10(2): 108-15. Mizuno M, Yamada K, Takei N, et al. Phosphatidylinositol 3kinase: a molecule mediating BDNF-dependent spatial memory formation. Mol Psychiatr 2003; 8(2): 217-24. Yamada K, Noda Y, Nakayama S, et al. Role of nitric oxide in learning and memory and in monoamine metabolism in the rat brain. Br J Pharmacol 1995; 115(5): 852-8. Yamada K, Noda Y, Hasegawa T, et al. The role of nitric oxide in dizocilpine-induced impairment of spontaneous alternation behavior in mice. J Pharmacol Exp Ther 1996; 276(2): 460-6. Zou LB, Yamada K, Tanaka T, Kameyama T, Nabeshima T. Nitric oxide synthase inhibitors impair reference memory formation in a radial arm maze task in rats. Neuropharmacology 1998; 37(3): 32330. Xiong H, Yamada K, Han D, et al. Mutual regulation between the intercellular messengers nitric oxide and brain-derived neurotrophic factor in rodent neocortical neurons. Eur J Neurosci 1999; 11(5): 1567-76. Mu JS, Li WP, Yao ZB, Zhou XF. Deprivation of endogenous brain-derived neurotrophic factor results in impairment of spatial learning and memory in adult rats. Brain Res 1999; 835(2): 259-65.


[185] [186] [187]

[188] [189] [190] [191]

[192] [193] [194]

[195] [196] [197]

[198]

[199]

[200]

[201] [202]

[203]

[204] [205]

[206] [207]

[208] [209]

Minichiello L, Korte M, Wolfer D, et al. Essential role for TrkB receptors in hippocampus-Mediated learning. Neuron 1999; 24(2): 401-14. Frost DO, Tamminga CA, Medoff DR, et al. Neuroplasticity and schizophrenia. Biol Psychiatry 2004; 56(8): 540-3. Altar CA, Cai N, Bliven T, et al. Anterograde transport of brainderived neurotrophic factor and its role in the brain. Nature 1997; 389(6653): 856-60. Shoval G, Weizman A. The possible role of neurotrophins in the pathogenesis and therapy of schizophrenia. Eur Neuropsychopharmacol 2005; 15(3): 319-29. Favalli G, Li J, Belmonte-de-Abreu P, Wong AHC, Daskalakis ZJ. The role of BDNF in the pathophysiology and treatment of schizophrenia. J Psychiatric Res 2012; 46(1): 1-11. Ross CA, Margolis RL, Reading SAJ, Pletnikov M, Coyle JT. Neurobiology of Schizophrenia. Neuron 2006; 52(1): 139-53. Durany N, Thome J. Neurotrophic factors and the pathophysiology of schizophrenic psychoses. Eur Psychiatr 2004; 19(6): 326-37. Shoval H, Weizman A. The possible role of neurotrophins in the pathogenesis and therapy of schizophrenia. Neuropsychopharmacology 2005; 15: 319-29. Buckley PF, Mahadik S, Pillai A, Terry A. Neurotrophins and Schizophrenia. Schizophrenia Res 2007; 94(1): 1-11. Angelucci F, Brene S, Mathe AA. BDNF in schizophrenia, depression and corresponding animal models. Mol Psychiatr 2005; 10(4): 345-52. Palomino A, Vallejo-Illarramendi A, González-Pinto A, et al. Decreased levels of plasma BDNF in first-episode schizophrenia and bipolar disorder patients. Schizophrenia Res 2006; 86(1): 321-2. Lewis DA, Hashimoto T, Volk DW. Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 2005; 6(4): 312-24. Scalzo P, Kummer A, Bretas TL, Cardoso F, Teixeira AL. Serum levels of brain-derived neurotrophic factor correlate with motor impairment in Parkinson's disease. J Neurol 2010; 257(4): 540-5. Elliott E, Atlas R, Lange A, Ginzburg I. Brain-derived neurotrophic factor induces a rapid dephosphorylation of tau protein through a PI-3 Kinase signalling mechanism. Eur J Neurosci 2005; 22(5): 1081-9. Rohe M, Synowitz M, Glass R, et al. Brain-derived neurotrophic factor reduces amyloidogenic processing through control of SORLA gene expression. J Neurosci 2009; 29(49): 15472-8. Hock C, Heese K, Hulette C, Rosenberg C, Otten U. Regionspecific neurotrophin imbalances in Alzheimer disease: decreased levels of brain-derived neurotrophic factor and increased levels of nerve growth factor in hippocampus and cortical areas. Arch Neurol 2000; 57(6): 846-51. Arancibia S, Silhol M, Mouliere F, et al. Protective effect of BDNF against beta-amyloid induced neurotoxicity in vitro and in vivo in rats. Neurobiol Dis 2008; 31(3): 316-26. Xuan AG, Long DH, Gu HG, et al. BDNF improves the effects of neural stem cells on the rat model of Alzheimer's disease with unilateral lesion of fimbria-fornix. Neurosci Lett 2008; 440(3): 331-5. Blurton-Jones M, Kitazawa M, Martinez-Coria H, et al. Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease. Proc Natl Acad Sci USA 2009; 106(32): 135949. Poduslo JF, Curran GL. Permeability at the blood-brain and bloodnerve barriers of the neurotrophic factors: NGF, CNTF, NT-3, BDNF. Brain Res Mol Brain Res 1996; 36(2): 280-6. Thorne RG, Frey WH, 2nd. Delivery of neurotrophic factors to the central nervous system: pharmacokinetic considerations. Clin Pharmacokinet 2001; 40(12): 907-46. Price RD, Milne SA, Sharkey J, Matsuoka N. Advances in small molecules promoting neurotrophic function. Pharmacol Ther 2007; 115(2): 292-306. Nagahara AH, Mateling M, Kovacs I, et al. Early BDNF treatment ameliorates cell loss in the entorhinal cortex of APP transgenic mice. J Neurosci 2013; 33(39): 15596-602. Nagahara AH, Merrill DA, Coppola G, et al. Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease. Nat Med 2009; 15(3): 331-7. Cunha C, Angelucci A, D'Antoni A, et al. Brain-derived neurotrophic factor (BDNF) overexpression in the forebrain results in learning and memory impairments. Neurobiol Dis 2009; 33(3): 358-68. Beck M, Flachenecker P, Magnus T, et al. Autonomic dysfunction in ALS: A preliminary study on the effects of intrathecal BDNF.


[210]

[211]

[212] [213]

[214]

[215] [216]

[217]

[218] [219]

[220]

[221]

[222]

[223]

[224]

[225]

[226] [227]

[228]

61

Amyotroph Lateral Scler Other Motor Neuron Disord 2005; 6(2): 100-3. Ochs G, Penn RD, York M, et al. A phase I/II trial of recombinant methionyl human brain derived neurotrophic factor administered by intrathecal infusion to patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2000; 1(3): 201-6. Mokhtari T, Akbari M, Malek F, et al. Improvement of memory and learning by intracerebroventricular microinjection of T3 in rat model of ischemic brain stroke mediated by upregulation of BDNF and GDNF in CA1 hippocampal region. Daru 2017; 25(1): 4. Skaper SD. The biology of neurotrophins, signalling pathways, and functional peptide mimetics of neurotrophins and their receptors. CNS Neurol Disord Drug Targets 2008; 7(1): 46-62. Lampe KJ, Kern DS, Mahoney MJ, Bjugstad KB. The administration of BDNF and GDNF to the brain via PLGA microparticles patterned within a degradable PEG-based hydrogel: Protein distribution and the glial response. J Biomed Mater Res A 2011; 96(3): 595-607. Bertram JP, Rauch MF, Chang K, Lavik EB. Using polymer chemistry to modulate the delivery of neurotrophic factors from degradable microspheres: delivery of BDNF. Pharm Res 2010; 27(1): 8291. Nutt JG, Burchiel KJ, Comella CL, et al. Randomized, doubleblind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology 2003; 60(1): 69-73. Lang AE, Gill S, Patel NK, et al. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann Neurol 2006; 59(3): 459-66. Hovland DN, Jr., Boyd RB, Butt MT, et al. Six-month continuous intraputamenal infusion toxicity study of recombinant methionyl human glial cell line-derived neurotrophic factor (r-metHuGDNF in rhesus monkeys. Toxicol Pathol 2007; 35(7): 1013-29. Fiandaca MS, Varenika V, Eberling J, et al. Real-time MR imaging of adeno-associated viral vector delivery to the primate brain. Neuroimage 2009; 47 (Suppl 2): T27-35. Herzog CD, Brown L, Gammon D, et al. Expression, bioactivity, and safety 1 year after adeno-associated viral vector type 2mediated delivery of neurturin to the monkey nigrostriatal system support cere-120 for parkinson's disease. Neurosurgery 2009; 64(4): 602-12; discussion 612-3. Marks WJ, Jr., Ostrem JL, Verhagen L, et al. Safety and tolerability of intraputaminal delivery of CERE-120 (adeno-associated virus serotype 2-neurturin) to patients with idiopathic Parkinson's disease: an open-label, phase I trial. Lancet Neurol 2008; 7(5): 400-8. Makar TK, Bever CT, Singh IS, et al. Brain-derived neurotrophic factor gene delivery in an animal model of multiple sclerosis using bone marrow stem cells as a vehicle. J Neuroimmunol 2009; 210(12): 40-51. Hernandez-Chan NG, Bannon MJ, Orozco-Barrios CE, et al. Neurotensin-polyplex-mediated brain-derived neurotrophic factor gene delivery into nigral dopamine neurons prevents nigrostriatal degeneration in a rat model of early Parkinson's disease. J Biomed Sci 2015; 22: 59. Kurozumi K, Nakamura K, Tamiya T, et al. Mesenchymal stem cells that produce neurotrophic factors reduce ischemic damage in the rat middle cerebral artery occlusion model. Mol Ther 2005; 11(1): 96-104. Kaka G, Arum J, Sadraie SH, Emamgholi A, Mohammadi A. Bone marrow stromal cells associated with poly l-lactic-co-glycolic acid (PLGA) nanofiber scaffold improve transected sciatic nerve regeneration. Iranian J Biotechnol 2017; 15(3): 149-156. Nandoe Tewarie RD, Hurtado A, Levi AD, Grotenhuis JA, Oudega M. Bone marrow stromal cells for repair of the spinal cord: towards clinical application. Cell Transplant 2006; 15(7): 563-77. Parr AM, Tator CH, Keating A. Bone marrow-derived mesenchymal stromal cells for the repair of central nervous system injury. Bone Marrow Transplant 2007; 40(7): 609-19. Hosseini SR, Kaka G, Joghataei MT, et al. Assessment of neuroprotective properties of melissa officinalis in combination with human umbilical cord blood stem cells after spinal cord injury. ASN Neuro 2016; 8(6). Tse WT, Pendleton JD, Beyer WM, Egalka MC, Guinan EC. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation 2003; 75(3): 389-97.


[230]

[231] [232] [233]

[234] [235]

[236] [237]

[238] [239]

[240]

[241] [242]

[243] [244]

[245]

[246] [247] [248]

[249]

[250]

[251] [252]

Ohtaki H, Ylostalo JH, Foraker JE, et al. Stem/progenitor cells from bone marrow decrease neuronal death in global ischemia by modulation of inflammatory/immune responses. Proc Natl Acad Sci USA 2008; 105(38): 14638-14643. Wei L, Fraser JL, Lu ZY, Hu X, Yu SP. Transplantation of hypoxia preconditioned bone marrow mesenchymal stem cells enhances angiogenesis and neurogenesis after cerebral ischemia in rats. Neurobiol Dis 2012; 46(3): 635-45. Karp JM, Leng Teo GS. Mesenchymal stem cell homing: The devil is in the details. Cell Stem Cell 2009; 4(3): 206-16. Hess DC, Borlongan CV. Stem cells and neurological diseases. Cell Prolif 2008; 41 (Suppl 1): 94-114. Ben Menachem-Zidon O, Ben Menahem Y, Ben Hur T, Yirmiya R. Intra-Hippocampal transplantation of neural precursor cells with transgenic over-expression of IL-1 receptor antagonist rescues memory and neurogenesis impairments in an alzheimer's disease model. Neuropsychopharmacology 2015; 40(2): 524. Arias-Carrion O, Yuan TF. Autologous neural stem cell transplantation: A new treatment option for Parkinson's disease? Med Hypotheses 2009; 73(5): 757-9. Madrazo I, Leon V, Torres C, et al. Transplantation of fetal substantia nigra and adrenal medulla to the caudate nucleus in two patients with Parkinson's disease. N Engl J Med 1988; 318(1): 51. Lindvall O, Brundin P, Widner H, et al. Grafts of fetal dopamine neurons survive and improve motor function in Parkinson's disease. Science 1990; 247(4942): 574-7. Hagell P, Schrag A, Piccini P, et al. Sequential bilateral transplantation in Parkinson's disease: effects of the second graft. Brain 1999; 122 ( Pt 6): 1121-32. Wenning GK, Odin P, Morrish P, et al. Short- and long-term survival and function of unilateral intrastriatal dopaminergic grafts in Parkinson's disease. Ann Neurol 1997; 42(1): 95-107. Widner H, Tetrud J, Rehncrona S, et al. Bilateral fetal mesencephalic grafting in two patients with parkinsonism induced by 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). N Engl J Med 1992; 327(22): 1556-63. Politis M, Wu K, Loane C, et al. Serotonergic neurons mediate dyskinesia side effects in Parkinson's patients with neural transplants. Sci Transl Med 2010; 2(38): 38ra46. Kefalopoulou Z, Politis M, Piccini P, et al. Long-term clinical outcome of fetal cell transplantation for Parkinson disease: two case reports. JAMA Neurol 2014; 71(1): 83-7. Politis M, Wu K, Loane C, et al. Serotonin neuron loss and nonmotor symptoms continue in Parkinson's patients treated with dopamine grafts. Sci Transl Med 2012; 4(128): 128ra41. Freed CR, Greene PE, Breeze RE, et al. Transplantation of embryonic dopamine neurons for severe Parkinson's disease. N Engl J Med 2001; 344(10): 710-9. Olanow CW, Goetz CG, Kordower JH, et al. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson's disease. Ann Neurol 2003; 54(3): 403-14. Pogarell O, Koch W, Gildehaus FJ, et al. Long-term assessment of striatal dopamine transporters in Parkinsonian patients with intrastriatal embryonic mesencephalic grafts. Eur J Nucl Med Mol Imaging 2006; 33(4): 407-11. Politis M, Piccini P. Brain imaging after neural transplantation. Prog Brain Res 2010; 184: 193-203. Mendez I, Vinuela A, Astradsson A, et al. Dopamine neurons implanted into people with Parkinson's disease survive without pathology for 14 years. Nat Med 2008; 14(5): 507-9. Hallett PJ, Cooper O, Sadi D, et al. Long-term health of dopaminergic neuron transplants in Parkinson's disease patients. Cell Rep 2014; 7(6): 1755-61. Mendez I, Sanchez-Pernaute R, Cooper O, et al. Cell type analysis of functional fetal dopamine cell suspension transplants in the striatum and substantia nigra of patients with Parkinson's disease. Brain 2005; 128(Pt 7): 1498-510. Mendez I, Dagher A, Hong M, et al. Simultaneous intrastriatal and intranigral fetal dopaminergic grafts in patients with Parkinson disease: a pilot study. Report of three cases. J Neurosurg 2002; 96(3): 589-96. Garitaonandia I, Gonzalez R, Christiansen-Weber T, et al. Neural stem cell tumorigenicity and biodistribution assessment for phase I clinical trial in parkinson's disease. Sci Rep 2016; 6: 34478. Gonzalez R, Garitaonandia I, Poustovoitov M, et al. Neural stem cells derived from human parthenogenetic stem cells engraft and

Mohammadi et al.

[253]

[254]

[255]

[256]

[257]

[258]

[259]

[260] [261]

[262]

[263]

[264]

[265]

[266] [267]

[268]

[269]

[270]

[271] [272]

promote recovery in a nonhuman primate model of parkinson's disease. Cell Transplant 2016; 25(11): 1945-66. Zhang Z, Wang X, Wang S. Isolation and characterization of mesenchymal stem cells derived from bone marrow of patients with Parkinson's disease. In Vitro Cell Dev Biol Anim 2008; 44(5-6): 169-77. Kim HJ, Seo SW, Chang JW, et al. Stereotactic brain injection of human umbilical cord blood mesenchymal stem cells in patients with Alzheimer's disease dementia: A phase 1 clinical trial. Alzheimer's & Dementia: TRCI 2015; 1(2): 95-102. Kim JY, Kim DH, Kim DS, et al. Galectin-3 secreted by human umbilical cord blood-derived mesenchymal stem cells reduces amyloid-beta42 neurotoxicity in vitro. FEBS Lett 2010; 584(16): 3601-8. Chuang D-M, Wang Z, Chiu C-T. GSK-3 as a target for lithiuminduced neuroprotection against excitotoxicity in neuronal cultures and animal models of ischemic stroke. Front Mol Neurosci 2011; 4: 15. Fukumoto T, Morinobu S, Okamoto Y, Kagaya A, Yamawaki S. Chronic lithium treatment increases the expression of brain-derived neurotrophic factor in the rat brain. Psychopharmacology (Berl) 2001; 158(1): 100-6. Hashimoto R, Takei N, Shimazu K, et al. Lithium induces brainderived neurotrophic factor and activates TrkB in rodent cortical neurons: an essential step for neuroprotection against glutamate excitotoxicity. Neuropharmacology 2002; 43(7): 1173-9. Leyhe T, Eschweiler GW, Stransky E, et al. Increase of BDNF serum concentration in lithium treated patients with early Alzheimer's disease. J Alzheimers Dis 2009; 16(3): 649-56. Xu J, Culman J, Blume A, Brecht S, Gohlke P. Chronic treatment with a low dose of lithium protects the brain against ischemic injury by reducing apoptotic death. Stroke 2003; 34(5): 1287-92. Tsai LK, Leng Y, Wang Z, Leeds P, Chuang DM. The mood stabilizers valproic acid and lithium enhance mesenchymal stem cell migration via distinct mechanisms. Neuropsychopharmacology 2010; 35(11): 2225-37. Calabrese F, Luoni A, Guidotti G, et al. Modulation of neuronal plasticity following chronic concomitant administration of the novel antipsychotic lurasidone with the mood stabilizer valproic acid. Psychopharmacology (Berl) 2013; 226(1): 101-12. Martisova E, Aisa B, Guerenu G, Ramirez MJ. Effects of early maternal separation on biobehavioral and neuropathological markers of Alzheimer's disease in adult male rats. Curr Alzheimer Res 2013; 10(4): 420-32. Autio H, Matlik K, Rantamaki T, et al. Acetylcholinesterase inhibitors rapidly activate Trk neurotrophin receptors in the mouse hippocampus. Neuropharmacology 2011; 61(8): 1291-6. Sakr HF, Khalil KI, Hussein AM, et al. Effect of dehydroepiandrosterone (DHEA) on memory and brain derived neurotrophic factor (BDNF) in a rat model of vascular dementia. J Physiol Pharmacol 2014; 65(1): 41-53. Fumagalli F, Racagni G, Riva MA. The expanding role of BDNF: a therapeutic target for Alzheimer's disease? Pharmacogenomics J 2006; 6(1): 8-15. Wu HM, Tzeng NS, Qian L, et al. Novel neuroprotective mechanisms of memantine: increase in neurotrophic factor release from astroglia and anti-inflammation by preventing microglial activation. Neuropsychopharmacology 2009; 34(10): 2344-57. Solum DT, Handa RJ. Estrogen regulates the development of brainderived neurotrophic factor mRNA and protein in the rat hippocampus. J Neurosci 2002; 22(7): 2650-9. Singh M, Meyer EM, Simpkins JW. The effect of ovariectomy and estradiol replacement on brain-derived neurotrophic factor messenger ribonucleic acid expression in cortical and hippocampal brain regions of female Sprague-Dawley rats. Endocrinology 1995; 136(5): 2320-4. Scharfman HE, Maclusky NJ. Similarities between actions of estrogen and BDNF in the hippocampus: coincidence or clue? Trends Neurosci 2005; 28(2): 79-85. Brines ML, Ghezzi P, Keenan S, et al. Erythropoietin crosses the blood–brain barrier to protect against experimental brain injury. Proc Natl Acad Sci USA 2000; 97(19): 10526-31. Cherian L, Goodman JC, Robertson C. Neuroprotection with erythropoietin administration following controlled cortical impact injury in rats. J Pharmacol Exp Ther 2007; 322(2): 789-94.


[274] [275]

[276]

[277]

[278] [279]

Wang L, Chopp M, Gregg SR, et al. Neural progenitor cells treated with EPO induce angiogenesis through the production of VEGF. J Cereb Blood Flow Metab 2008; 28(7): 1361-8. Lilja AM, Luo Y, Yu QS, et al. Neurotrophic and neuroprotective actions of (-)- and (+)-phenserine, candidate drugs for Alzheimer's disease. PLoS One 2013; 8(1): e54887. Hoppe JB, Coradini K, Frozza RL, et al. Free and nanoencapsulated curcumin suppress beta-amyloid-induced cognitive impairments in rats: involvement of BDNF and Akt/GSK-3beta signaling pathway. Neurobiol Learn Mem 2013; 106: 134-44. Lin N, Pan XD, Chen AQ, et al. Tripchlorolide improves ageassociated cognitive deficits by reversing hippocampal synaptic plasticity impairment and NMDA receptor dysfunction in SAMP8 mice. Behav Brain Res 2014; 258: 8-18. Alvarez-Lopez MJ, Castro-Freire M, Cosin-Tomas M, et al. Longterm exercise modulates hippocampal gene expression in senescent female mice. J Alzheimers Dis 2013; 33(4): 1177-90. Liang DY, Li X, Clark JD. Epigenetic regulation of opioid-induced hyperalgesia, dependence, and tolerance in mice. J Pain 2013; 14(1): 36-47. Perna MK, Brown RW. Adolescent nicotine sensitization and effects of nicotine on accumbal dopamine release in a rodent model of increased dopamine D2 receptor sensitivity. Behav Brain Res 2013; 242: 102-9.

Current Gene Therapy, 2018, Vol. 18, No. 1 [280]

[281] [282]

[283]

[284]

[285]

[286]

63

Vassoler FM, White SL, Schmidt HD, Sadri-Vakili G, Pierce RC. Epigenetic inheritance of a cocaine-resistance phenotype. Nat Neurosci 2013; 16(1): 42-7. Coelho FG, Vital TM, Stein AM, et al. Acute aerobic exercise increases brain-derived neurotrophic factor levels in elderly with Alzheimer's disease. J Alzheimers Dis 2014; 39(2): 401-8. Garcia-Mesa Y, Pareja-Galeano H, Bonet-Costa V, et al. Physical exercise neuroprotects ovariectomized 3xTg-AD mice through BDNF mechanisms. Psychoneuroendocrinology 2014; 45: 154-66. Coelho FG, Gobbi S, Andreatto CA, et al. Physical exercise modulates peripheral levels of brain-derived neurotrophic factor (BDNF): A systematic review of experimental studies in the elderly. Arch Gerontol Geriatr 2013; 56(1): 10-5. Rossi C, Angelucci A, Costantin L, et al. Brain-derived neurotrophic factor (BDNF) is required for the enhancement of hippocampal neurogenesis following environmental enrichment. Eur J Neurosci 2006; 24(7): 1850-6. Tomi M, Zhao Y, Thamotharan S, Shin BC, Devaskar SU. Early life nutrient restriction impairs blood-brain metabolic profile and neurobehavior predisposing to Alzheimer's disease with aging. Brain Res 2013; 1495: 61-75. Moy GA, McNay EC. Caffeine prevents weight gain and cognitive impairment caused by a high-fat diet while elevating hippocampal BDNF. Physiol Behav 2013; 109: 69-74.

Current Gene Therapy

Current Gene Therapy

Suggest Documents

Current Gene Therapy - IngentaConnect

Current Gene Therapy - Semantic Scholar

Current Gene Therapy - Semantic Scholar

Current Gene Therapy - Semantic Scholar

Current Status of Cardiovascular Gene Therapy - CyberLeninka

Suicide Gene Therapy Suicide Gene Therapy

Gene therapy: current status and future prospects - CiteSeerX

Gene therapy for Parkinson's disease: current knowledge and future ...

Current standing and frontiers of gene therapy for meningiomas

Current Experimental Studies of Gene Therapy in ...

Polycation-Based Gene Therapy: Current Knowledge and New ...

gene therapy a promising treatment for breast cancer: current scenario ...

Current progress in adenovirus mediated gene therapy for patients ...

Viral Vectors for Gene Therapy: Current State and Clinical Perspectives

Current Status of Gene Therapy Strategies to Treat ... - CyberLeninka

Download Current Surgical Therapy, 12e (Current Therapy) Book ...

Gene Therapy of Cancer Gene Therapy of Cancer

#^XueQ=(( Download 'Current Surgical Therapy- 12e (Current ...

Gene Therapy - InTechOpen

Cancer gene therapy - doiSerbia

Gene Therapy for Hemophilia

GENE THERAPY FOR DIABETES

Germline gene therapy

Gene Therapy and Jurisprudence