An update on pharmacological approaches to ...

Review Central & Peripheral Nervous Systems

An update on pharmacological approaches to neurodegenerative diseases

1. Introduction

3. Parkinson’s disease

Roberto Scatena†, Giuseppe E Martorana, Patrizia Bottoni, Giorgia Botta, Paola Pastore & Bruno Giardina

4. Huntington’s disease

00168 Rome, Italy

2. Alzheimer’s disease

†Istituto di Biochimica e Biochimica Clinica, Universita' Cattolica del Sacro Cuore, Largo A. Gemelli 8,

5. Motor neuron diseases 6. Other neurodegenerative diseases 7. Conclusions 8. Expert opinion

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Neurodegenerative diseases are now generally considered as a group of disorders that seriously and progressively impair the functions of the nervous system through selective neuronal vulnerability of specific brain regions. Alzheimer’s disease is the most common neurodegenerative disease, followed in incidence by Parkinson’s disease; much less common are frontotemporal dementia, Huntington’s disease, amyothrophic lateral sclerosis (Lou Gehrig’s disease), progressive supranuclear palsy, spinocerebellar ataxia, Pick’s disease and, lastly, prion disease. In this review, the authors intend to survey new drugs in different clinical phases but not in the preclinical or discovery stages nor already in the market, with new molecules aimed at interrupting or at attenuating different pathogenic pathways of neurodegeneration and/or at ameliorating symptoms. Drugs in different pharmacological phases are under study or are ready to be introduced into therapy for Alzheimer’s disease, which display anti-β-amyloid activity or nerve growth factor-like activity or anti-inflammatory properties. Other drugs possess mixed mechanisms of action, such as acetylcholinesterase inhibition and impairment of β-amyloid formation through inhibition of β-amyloid precursor protein synthesis and/or modulation of secretase activity. Other therapeutic approaches are based on immunotherapy, control of metal ions interactions with β-amyloid and ensuing oxidative reactions as well as metabolic or hormonal regulation. The symptomatic therapy of motor behaviour in Parkinson’s disease, based on L-DOPA, is registering adenosine A2A receptor antagonists, monoamine oxidase B inhibitors and ion channel modulators, as well as dopamine uptake inhibitors and glutamate AMPA receptor antagonists. There are also many other drugs involved, including astrocyte-modulating agents, 5-HT1A agonists and α2-adrenergic receptor antagonists, which are targeted at preventing or ameliorating Parkinson’s disease-related or L-DOPA-induced dyskinesias. Huntington’s disease therapy envisages a Phase III drug, LAX-101, which displays antiapoptotic properties by promoting membrane stabilisation and mitochondrial integrity. Other drugs with antioxidant and antiapoptotic steroid-like and neuroprotective activity are under investigation for the therapy of the less common neurodegenerative diseases.

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Keywords: Alzheimer’s disease, amyothrophic lateral sclerosis, frontotemporal dementia, Huntington’s disease, mitochondria, nitric oxide, Parkinson’s disease, Pick’s disease, prion disease, proteasome, stress proteins Expert Opin. Investig. Drugs (2007) 16(1):xxx-xxx

10.1517/13543784.16.1.xxx © 2007 Informa UK Ltd ISSN 1354-3784

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1. Introduction

Neurodegenerative diseases represent a devastating class of pathological processes that affect nervous tissue and that are characterised by progressive neuronal loss, provoking a serious impairment of mental and physical abilities of the patients and directly or indirectly causing (in due time) their death [1-3]. Neurodegenerative diseases are estimated to affect > 22 million people worldwide and this number could triple by 2050, mainly due to the increase in life expectancy. In fact, age is the most important risk factor for the most common degenerative disorders (i.e., Alzheimer’s disease and Parkinson’s disease) and it is well known that, worldwide, the population of people who are > 60 years of age is expected to double by 2060 [1,4]. Nowadays, there are no drugs that are capable of curing these diseases, mainly because the real aetiopathogenetic mechanisms are not yet fully understood. A recent example of the importance of the understanding of the molecular mechanisms at the basis of neurodegenerative diseases originated from the recent epidemic of mad cow disease and its human counterpart, the new variant Creutzfeldt-Jacob disease [5,6]. Increasing evidence has shown that intra- and/or extracellular accumulation of misfolded proteins; protofibril formation and/or proteasome system dysfunction; altered metal homeostasis; mitochondrial injury and/or oxidative and nitrosative stress; excitotoxic insult; synaptic failure and/or dysfunction of axonal and dendritic transport represent pathogenic events that are present in neurodegenerative disorders [3,4]. It is also clear that progressive neurodegenerative disease is not the result of a single pathogenic event but the consequence of multi-pathogenic insults (such as environmental, genetic and epigenetic), which interact to determine the disease and its particular course. On the one hand, such complex pathophysiology complicates the discovery of drugs that can truly prevent disease but (on the other hand) allows the research on and the adoption of drugs that are capable of interrupting (or at least of attenuating) some of the pathogenic events that determine the neurodegenerative disease [3,4,7]. In particular, pharmacological research has identified the following potential targets for different neurodegenerative diseases. First, inhibition of the production and/or aggregation of pathogenic misfolded proteins wherever present. This class includes: drugs that are capable of acting as modulators of enzymes that produce misfolded proteins or harmful protein fragments (i.e., inhibitors of β- and γ-secretase or activators of α-γ secretase in Alzheimer’s disease); molecules that stimulate synthesis of chaperones (i.e., proteins capable of maintaining a newly synthesised protein in a properly folded state); drugs capable of ameliorating the function of the ubiquitin–proteasome system (thus addressing the misfolded protein to degradation and thereby eliminating or reducing their accumulation) [2,7,8]; and vaccines that should carry on an

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immunological reaction towards pathological peptides, reducing their synthesis and increasing their vaccine-mediated clearance [9,10]. Second, reduction of some processes that precede or ensue from cytoplasmic and extracellular protein aggregation (i.e., inflammatory processes, free radical production, peroxidative damage, altered calcium homeostasis and so on) with a significant role in neuritic/neuronal injury (e.g., anti-inflammatory drugs, metal chelators, antioxidants, PPAR-γ agonists and so on) [2,11]. Third, boost the function of the remaining neurotransmitter systems altered in the specific neurodegenerative process (e.g., old and new cholinesterase inhibitors [donepezil, rivastigmine, galantamine and NMDA antagonists], memantine-like drugs in Alzheimer’s disease; L -DOPA (levodopa) and related new drugs in Parkinson’s disease) [11,12]. Fourth, neuroprotection by molecules that are capable of ameliorating neuron resistance to injury (AL-108 and AL-208 by Allon Therapeutics; AEOL-10113 by Aeolus Pharmaceuticals, Alzheimer’s disease NF-14 by the NIH) in a specific and/or generic way [12-14]. Finally, correction of concomitant dysmetabolism (i.e., classical hyperlipoproteinaemia associated with ApoE 4 genotype of some forms of Alzheimer’s disease) that seems to justify the positive influence of HMG-CoA inhibitors on the course of disease [10,11]. This range of potential therapeutic targets has promoted intense pharmacological research as demonstrated by a 2005 published list of 640 drugs in R&D for neurodegenerative diseases [15]. Considerable data can be cited to give an idea of the scientific and economic burden associated with neurodegeneration; for example, 28% of these developing drugs are focused on Alzheimer’s disease as the main therapeutic indication; 14% are for Parkinson’s disease as first indication; and 29% have a generic clinical indication for neurodegeneration. However, most of these molecules are still in the discovery phase and only a minority are in the pharmacological phase; for example, considering Alzheimer’s disease – the neurodegenerative disease most studied from a pharmacotherapy point of view – out of a total of 177 molecules, there are 106 in discovery phase, 30 in Phase I, 34 in Phase II and 6 in Phase III. On the other hand, for Huntington’s disease – a less studied neurodegenerative disease – there are only eight molecules with this specific indication, six of which are in discovery phase, none in Phase I and II, and two in Phase III. The authors review in more detail the status of drug development for each neurodegenerative disease in Sections 2 – 6. In this survey, the authors focus on drugs that have already entered clinical phases and only briefly mention molecules at earlier preclinical stages of investigation, in discovery phase and drugs that are already in current therapy. In fact, it is well known that there is a strong dissonance between preclinical and clinical studies (i.e., molecules with positive results in various preclinical pharmacological studies too often do not

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Expert Opin. Investig. Drugs (2007) 16(1)

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Scatena, Martorana, Bottoni, Botta, Pastore & Giardina

give an equivalent result in the clinical phase or, worse still, can even present, in a few cases, unexpected toxic effects) in the area of neuroprotection [16]. 2. Alzheimer’s

disease

Alzheimer’s disease is the most common neurodegenerative disorder and the most prevalent cause of dementia with ageing. Classically, treatment of Alzheimer’s disease is based on the use of acetylcholinesterase inhibitors and (recently) of NMDA channel blockers [10,17]; however, new therapeutic approaches that are more closely focused on the pathogenesis (the β-amyloid [Aβ] or τ-protein oligomers and aggregates formation) of the disease are under examination in different pharmacological phases [18,19]. 2.1 Phase

III

In this development stage, there are interesting new molecules such as 3-aminopropanesulfonic acid (3-APS; tramiprosate; Table 1), which is an orally administered, small organic molecule that has been designed to modify the course of Alzheimer’s disease through its anti-β-amyloid activity, thus representing a new therapeutic strategy. 3-APS acts via glycosaminoglycan mimetic activity that should block or reduce the formation of toxic Aβ aggregates by inhibiting the binding of Aβ to glycosaminoglycan. As part of a novel disease-modifying class of product candidates, 3-APS is thought to act at two levels: by preventing and slowing down the formation and deposition of amyloid fibrils in the brain, and by binding to soluble Aβ protein to reduce the amyloid-induced toxicity on neuronal and brain inflammatory cells. An ongoing European Phase III clinical trial (a multi-centre, randomised, double-blind, placebo-controlled and parallel-designed study) is on schedule and will investigate the safety and efficacy of 3-APS in treating Alzheimer’s disease [20-22]. Another drug that seems to prevent the aggregation of β-amyloid peptide is Colostrinin™ (ReGen Therapeutics), a polypeptide complex derived from ovine colostrum. Recent clinical studies have shown that this mixture of proline-rich polypeptides has a stabilising effect on cognitive function in patients with Alzheimer’s disease measured by the Alzheimer’s disease Assessment Scale-Cognitive and in the Instrumental Activities Assessment [23,24]. A different (but equally interesting) new therapeutic approach is represented by xaliproden (SR-57746A), a compound that mimics the effects of nerve growth factor and that is also a 5-HT1A receptor agonist that is orally active and can be dosed once daily. Xaliproden hydrochloride is under development for central and peripheral neurodegenerative disorders and Alzheimer’s disease. Phase III trials have been completed in patients with amyotrophic lateral sclerosis (ALS) in Europe, the US, Canada and Japan where it has orphan drug status for this indication. Xaliproden is also at the Phase III stage of clinical development for Alzheimer’s disease and has orphan drug status for this indication [25,26].

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For the sake of completeness, some old and new NSAID drugs (i.e., celecoxib and flurbiprofen) are included in some Phase III trials, which are essentially used because inflammation is characteristic of a broad spectrum of neurodegenerative diseases in general and of Alzheimer’s disease in particular. Original epidemiological evidence seemed to indicate that anti-inflammatory agents such as NSAIDs have a sparing effect on Alzheimer’s disease, thus confirming the involvement of inflammation in this disease. For these considerations, classical NSAIDs (e.g., flurbiprofen) are still the most logical choice to slow the progression or to delay the onset of Alzheimer’s disease and other neurodegenerative diseases despite the reported failures in Alzheimer’s disease clinical trials adopting naproxen, celecoxib and rofecoxib. Both celecoxib and rofecoxib have recently shown important cardiovascular side effects that contraindicate their use for long-term therapy of neurodegenerative disorders [27-30]. Combination therapy with more anti-inflammatory agents that work through different mechanisms of action may possibly prove to be a superior therapeutic strategy.

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Drugs acting at different levels of the pathogenic mechanisms of Alzheimer’s disease are present in this phase. Clearly, a pharmacological approach to neurotransmission disorders represents the most frequently adopted target. In this respect, phenserine seems to possess two pharmacological activities: acetylcholinesterase inhibition; and inhibition of synthesis of β-amyloid precursor protein (APP). The peculiar dual mode of action of phenserine suggests that it should not only have the potential to improve memory and cognition but to also slow disease progression. Results from the first Phase II clinical trial of phenserine showed consistent and positive trends on all primary and secondary end points in the symptomatic management of Alzheimer’s disease as well as a safety profile in an optimal range for marketability. However, recent data indicate that no statistically significant differences between the efficacy of the active and placebo groups were observed in areas of cognition, global function, behaviour and daily living activities. Because of these data, Axonyx reformulated phenserine to a sustained or extended-release formulation rather than the immediate-release formulation that was used in the recently completed trials [31,32]. The positive isomer of phenserine ([R]-phenserine) appears to decrease the formation of β-amyloid with potential application in the treatment of Alzheimer’s disease progression. The mechanism of action of (R)-phenserine is through RNA translational inhibition as well as β-secretase inhibition. This compound has been shown to lower β-APP and β-amyloid levels in preclinical studies [201]. The primary mechanism of action results in a dose-dependent reduction of β-amyloid, which may result in slowing the progression of Alzheimer’s disease. The initial preclinical side-effect rates potentially allow for higher clinical doses. The first Phase I single ascending-dose clinical study commenced in 2005


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Table 1. Overview of drugs for neurodegenerative disorders in clinical phase . Disease

Drug

Phase

Mechanism of action

Refs

Alzheimer’s disease

3-APS

III

Antiamyloid activity

[21-23]

Colostrinin

III

β-Amyloid protein deposition inhibitor

[24,25]

Xaliproden

III

5-HT1A agonist

[26,27]

Celecoxib

III

Anti-inflammatory activity (COX-2 inhibitor)

[28,29]

Flurbiprofen

III

Anti-inflammatory activity (COX-2 modulator and β-amyloid synthesis [30,31] inhibitor)

Phenserine

II

Acetylcolinesterase inhibition and synthesis inhibition of β-amyloid precursor

(R)-Phenserine

II

β-Amyloid synthesis and secretase inhibitor

ABT-089

II

Nicotinic acetylcholine modulator

CX-516

II

AMPA receptor modulator

[35,36] [37,39]

II

AMPA receptor modulator

Dimebolin

II

Acetylcholinesterase modulator

Ladostigil

II

Acetylcholinesterase inhibitor and monoamine oxidase inhibitor

[41]

SGS742

II

GABAB antagonist

[42,43]

α-5IA

II

GABAA antagonist

SL65.0155

II

5-HT4 antagonist

TC-1734

II

Nicotine acetylcholine receptor agonist

[47]

AN-1792(QS-21)

II

Immunotherapy (amyloid protein deposition inhibitor)

[48]

AAB-001

II

LY-450139

II

PBT-1

II

PBT-2

II

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Rosiglitazone

II

Leuprolide

II

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GT-1061

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[38,39] [40]

[44,45] [46]

Immunotherapy (amyloid protein deposition inhibitor)

[49]

β-Amyloid and γ-secretase inhibitor

[55,56]

Metal chelator

[57,58]

o h Metal chelator

[59]

HMG-CoA reductase inhibitor

[60-62]

PPAR-γ ligand

[63,64]

Gonadotropin-releasing hormone agonist

[65,66]

II

NO modulator

[67]

Nitroflurbiprofen

I

NO donor

[69]

T-817MA

I

Neurotrophic and antioxidant agent

[70,71]

Dexefaroxan

I

α2-Adrenoceptor antagonist

[72,73]

Cerebrolysin

I

Neurotrophic activity

[74]

Neotrofin

I

CNS neurotrophic factor synthesis and release inductor

[75] [80,81]

Istradefylline

III

Adenosine A2A receptor antagonist

Safinamide

III

Monoamine oxidase B inhibitor, ion channel modulator and dopamine [82] uptake inhibitor

Talampanel

II

AMPA receptor antagonist

[79,83]

NS-2330

II

Dopamine agonist, dopamine uptake inhibitor, monoamine uptake inhibitor and acetylcholine agonist

[79,84]

ONO-2506

II

Astrocytic activation modulator and S-100 protein synthesis inhibitor

[85,86]

Sarizotan

II

5-HT1A agonist and D3/D4 ligand

[87]

Fipamezole

II

α2-Adrenergic receptor antagonist

[88]

Besonprodil

I

NMDA receptor antagonist

[85,89]

GDNF: Glial cell-derived neurotrophic factor; PPAR: Peroxisome proliferator-activated receptor.

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[34]

CX-717

Atorvastatin

Parkinson’s disease

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[32,33]



Table 1. Overview of drugs for neurodegenerative disorders in clinical phase (continued). Disease

Drug

Phase

Mechanism of action

Refs

GDNF

I

Growth factor

[90,91]

Huntington’s disease

LAX-101

III

Neuroprotection and neuro-anti-inflammatory effect

[92]

Motor neuron disease

ONO-2506

II

Astrocytic activation modulator and S-100 protein synthesis inhibitor

[93]

Xaliproden

III

5-HT1A agonist

[27]

Talampanel

II

AMPA receptor antagonist

[79]

AEOL-10150

I

Catalytic antioxidant

[94]

NXY-059

III

Free radical scavenger, NO synthesis inhibitor

[95,96]

LY-354740

II

Metabotropic glutamate receptors antagonist

[97,100]

LY-367366

II


[98]

Others

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LY-367385

II


[99]

Semaxanib

II

Adrenocorticotropic hormone agonist

[101]

T-588

II

Neuroprotective activity

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SSR-180575

I

Acetylcholine-release stimulator and

Minocycline

I

Antibiotic activity with neuroprotective effects

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GDNF: Glial cell-derived neurotrophic factor; PPAR: Peroxisome proliferator-activated receptor.

and evaluated the safety of (R)-phenserine in healthy volunteers. In January 2006, a second double-blind, placebo-controlled study of (R)-phenserine in healthy men and women was commenced with the aim of establishing drug tolerability [201]. ABT-089 is a selective neuronal nicotinic receptor modulator that is as potent and effective as nicotine in inducing brain acetylcholine release. By this indirect stimulation, this drug should be effective in improving cognitive functions and should simultaneously have little propensity to induce adverse effects such as ataxia, hypothermia, seizures, and cardiovascular and gastrointestinal side effects [33,34]. Another interesting class of neurotransmission modulators is represented by AMPAkines. The AMPAkines were initially discovered by Cortex Pharmaceuticals, which joined Servier and Organon to develop this class of agents for various CNS disorders. It is thought that AMPA potentiators would stimulate AMPA-type glutamate receptors, thus enhancing excitatory transmission and long-term potentiation and thereby improving cognitive function. An early compound (CX-516) entered the clinic but failed to meet its primary end point. Recently, a more potent compound (CX-717) has come forward to the clinic [35-37]. It is noteworthy to mention dimebolin, a Russian-made drug that can be considered as an anticholinesterase drug albeit at a very high concentration (IC50 = 42 µM) and an antagonist of NMDA receptors. In a pilot clinical study, dimebolin showed an improvement of cognitive and self-service functions of Alzheimer’s disease patients. Interestingly, this drug also reduced the incidence of associated psychotic symptoms [38]. Another novel bifunctional drug is ladostigil

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release inhibitor

[102] [103,104 ] [105,106 ]

(TV-3326), which derives from the combination of the carbamate cholinesterase inhibitor rivastigmine with the pharmacophore of the monoamine oxidase B inhibitor rasagiline. This compound is particularly indicated in Alzheimer’s disease with associated Parkinsonism, but useful pharmacological activities could be further envisioned [39] as monoamine oxidase antagonism seems to also induce a stimulation of the activity of α-secretase and of Bcl-2 (anti-apoptotic oncogene). GABAB receptor antagonism may also enhance cognition and attention, probably by facilitating a secondary release of glutamate, aspartate, glycine and somatostatin. SG-S742, a GABAB receptor antagonist by Saegis and Novartis in Phase II clinical studies, was confirmed to improve attention as well as working memory in patients with mild cognitive impairment. Similar studies are underway for the treatment of Alzheimer’s disease [40,41]. Interestingly, some selective GABAA inverse agonists derived by thiophenes have also shown enhanced cognition. In particular, the authors highlight α-5IA (Merck & Co.) in this group of molecules, which binds with equivalent subnanomolar affinity to the benzodiazepine site of GABAA receptors (particularly to the α-5 subunit). Such a binding enhanced the performance in the hippocampal-dependent test of learning and memory in the rat without convulsive and anxiogenic effects. These data suggest that this particular class of GABAA inverse agonists could be useful in the treatment of cognitive disorders in general and for Alzheimer’s disease in particular [42,43]. SL-650155 is a 5-HT4 partial agonist with significant cognition-enhancing properties that can be associated synergistically with the classical acetylcholine-mediated therapy [44]. In terms of a pharmacological approach to altered


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neurotransmission, drugs that activate nicotine acetylcholine receptors may be a promising therapy in cognitive decline as observed in the elderly, including for Alzheimer’s disease. Ispronicline (TC-1734, a brain-selective α4β2 nicotine acetylcholine receptor partial agonist) has shown memory-enhancing properties in rodents and a good tolerability profile. Moreover, results from Phase I clinical studies confirm a good bioavailability, and pharmacological, pharmacokinetic and safety profiles of the drug [45]. Another interesting and new approach to Alzheimer’s disease therapy is represented by anti-β-amyloid immunotherapy that holds great potential for treating or even preventing Alzheimer’s disease despite some setbacks in initial clinical trials [9,10]. There are three different strategies that have been adopted for exploiting antibodies against β-amyloid. The first approach consists of immunisation with full-length β-amyloid (containing all 42 amino acids); a second approach is active immunisation that involves the administration of small fragments of β-amyloid conjugated to an unrelated carrier protein to enhance T-cell stimulation; and the third approach (passive immunisation) consists of directly administering anti-β-amyloid antibodies to the patients. Different mechanisms of action have been hypothesised for these anti-β-amyloid antibodies [10]: plaque breakdown by induced Fc-mediated phagocytosis; peripheral sink by peripheral formation of antigen–antibody complexes that sequester amyloid protein away from the brain; and aggregation inhibition (antigen–antibody complexes to prevent amyloid aggregation and accumulation). A typical example is represented by A42 (AN-1792) plus QS-21 as an adjuvant (Aquila Biopharmaceuticals, Inc.). This form of active immunisation should facilitate amyloid removal; however, preliminary clinical results have shown that only some parameters related to cognitive functions appear to be modified by this particular therapeutic strategy. Moreover, some episodes of post-vaccination meningoencephalitis occurred in a Phase II multi-centre study that was interrupted [46]. To reduce this important side effect, an alternative strategy can be represented by the use of the humanised monoclonal antibody AAB-001 (passive immunisation; bapineuzumab, Elan Corp. and Wyeth Pharmaceuticals). In fact, this immunoglobulin, which should bind and clear β-amyloid peptide, is designed to provide antibodies against β-amyloid directly to the patient rather than requiring the patient to form his own individual response. Preclinical studies have shown that this approach is equally effective in removing β-amyloid from the brain as traditional active immunisation methods. At present, there is an ongoing multi-centre, double-blind, placebo controlled study with patients who have mild-to-moderate Alzheimer’s disease. Each patient’s participation is expected to last ∼ 2 years [202]. In summary, it could be useful to stress that a number of newer antibodies are ready to enter the clinical phase [47-51]. Reduction of β-amyloid synthesis may be obtained by the γ-secretase inhibitor LY-450139. Preliminary clinical studies

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in healthy volunteers and Alzheimer’s disease patients seem to demonstrate a moderate efficacy:tolerability ratio [52,53]. The pharmacological modulation of β-amyloid by drugs acting on different secretases represents a promising therapeutic approach for the prevention and cure of Alzheimer’s disease. It is important to mention that many of the larger pharmaceutical companies have already advanced projects and patented molecules; therefore, it is likely that γ-secretase as a target for disease modification will be tested in pivotal trials in the next 3 – 5 years [8-10]. Another interesting therapeutic approach derives from the growing body of evidence on the central role of biometals (copper, iron and zinc) in many critical aspects of Alzheimer’s disease and particularly in inducing β-amyloid aggregation and thus facilitating protein precipitation into metal-enriched masses (plaques). Moreover, from a pathogenic point of view, this abnormal combination of β-amyloid with copper or iron can induce the production of hydrogen peroxide, which may cause the conspicuous oxidative damage to the brain in Alzheimer’s disease. In this regard, recent reports have described the exciting development of potential therapeutic agents based on the modulation of metal bioavailability. The metal ligand clioquinol (PBT-1) has demonstrated promising results in animal models and small clinical trials [54]; however, this drug caused a tragic disease (subacute myelo-opticoneuropathy) in the 1960s in Japan and, therefore, it was banned from Japan in 1970 [55] As a consequence, Prana Biotechnology is developing PBT-2, a Prana-original compound, that should be the successor of PBT1 for the treatment of Alzheimer’s disease. PBT-2 is designed to have an improved safety and efficacy profile compared with PBT-1. This compound has demonstrated significantly greater effectiveness in lowering plaque in the transgenic mouse model in both in vitro and in vivo preclinical testing. Moreover, PBT-2 seems to be more efficient than PBT-1 in decreasing the toxicity of plaques through improved peroxide inhibition and appears to have better pharmaceutical characteristics, such as improved solubility [56]. Cholesterol seems to play a significant role in promoting the production of β-amyloid and possibly also the progression of Alzheimer’s disease. Together with epidemiological evidence, this suggests that statin drugs may be of some benefit in the pharmacological treatment of this disorder. A number of clinical studies have been performed to evaluate the effect of atorvastatin on cognitive and behavioural functions in patients with mild-to-moderate Alzheimer’s disease. Results seem to show that this HMG-CoA inhibitor can improve the outcome of mental tests with respect to control tests. The precise mechanism of action still remains undetermined. The options are total cholesterol reduction and HDL cholesterol increment, influence on lipoprotein metabolism, or interaction with ceruloplasmin and copper homeostasis [57-59]. Moreover, the use of insulin sensitisers thiazolidinediones has been also proposed for Alzheimer’s disease therapy as

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insulin resistance has been recently associated with Alzheimer’s disease and memory impairment; however, the actual molecular mechanism of the recorded positive effects of these drugs (e.g., rosiglitazone) on cognitive function, observed in preclinical and clinical studies in Alzheimer’s disease is still unknown [60,61]. Finally, another important approach originates from the use of the gonadotropin-releasing hormone agonist leuprolide (VP-4896). This intriguing strategy derives from experimental and clinical evidence indicating a role for luteinising hormone in promoting neurodegenerative diseases. Interestingly, luteinising hormone can cross the blood–brain barrier and its receptors are more concentrated in the hippocampi, the regions of the brain that are most vulnerable to Alzheimer’s disease. Moreover, luteinising hormone is significantly elevated both in the serum and in the pyramidal neurons of Alzheimer’s disease patients [62,63]. 2.3 Phase

I trials

Drugs at this clinical phase show a variety of mechanisms of action. In particular, there are some so-called nootropic agents that act as NO donors (e.g., GT-1061) [64]. In the brain, NO is a multifunctional messenger molecule that has important roles in learning, memory and the modulation of expression of trophic factors. Small molecules that mimic the biological activity of NO can bypass acetylcholine-mediated receptor activation and thus are foreseen to provide multiple pathways of treating and circumventing dementia in Alzheimer’s disease. Substantial evidence suggests that NO mimetics may display cGMP-dependent and -independent activity and may operate via multiple biochemical signalling pathways, both to ensure the survival of neurons subjected to stress and to provide cognition-enabling pathways to circumvent dementia [65]. Another NO donor in this clinical phase is nitroflurbiprofen, a bifunctional molecule composed of flurbiprofen with its classical anti-inflammatory properties (which can positively influence the neuro-inflammation in Alzheimer’s disease) and of the NO-releasing moiety (which could at least ameliorate the gastric tolerability in long-term treatment) [29]. On the other hand, T-817MA was demonstrated to exert neuroprotective effects and to promote neurite outgrowth in rat primary cultured neurons but the molecular basis of this neuroprotection is not yet known [66,67]. Dexefaroxan is an α2-adrenoceptor antagonist whose basis of therapeutic action in Alzheimer’s disease relies on blocking presynaptic inhibitory autoreceptors, thus stimulating the release of noradrenaline in the hippocampi. The activation of noradrenaline-mediated neurotransmission at this level seems to enhance the generation of new neurons in the hippocampi associated with learning and memory [68,69]. For the sake of completeness, Scatena et al. mention two molecules in advanced clinical phase. Cerebrolysin is a peptide mixture with neurotrophic effects that may reduce the neurodegenerative pathology in Alzheimer’s disease. Data from an APP transgenic mouse model of Alzheimer’s

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disease-like neuropathology showed that cerebrolysin reduced behavioural deficits, that it was neuroprotective and decreased amyloid burden, although the mechanisms involved were not completely established [70]. Neotrofin, a reported inducer of CNS neurotrophic factor synthesis and release, with memory-enhancing activity and demonstrated restoration of age-induced memory deficits, was tested in patients with mild-to-moderate Alzheimer’s disease. Cognitive composite scores indicated improvement in memory (F = 9.6; p = 0.0004), executive functioning (p = 0.004) and attention (p = 0.004). Moreover, PET scanning showed that neotrofin induced metabolic changes in the brain regions that are involved in neural circuits underlying memory, attention and executive functioning [71]. 3. Parkinson’s

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Parkinson’s disease is the most common movement disorder among neurodegenerative diseases. There are ∼ 1% of the population > 65 years of age who suffer from this slowly progressive degenerative disease. Only ∼ 5% of Parkinson’s disease cases are hereditary forms caused by mutations in some genes. It is now known that there are two autosomal dominant disease genes (α-synuclein and dardarin) and three genes that are responsible for autosomal recessive Parkinson’s disease (Parkin, DJ-1 and PINK-1). α-Synuclein (also known as PARK1: its polymerised fibrils constitute the main content of the so-called Lewis bodies), parkin (PARK2), DJ-1 (PARK7) and PTEN-induced kinase 1 (PARK6). Recently, the LRRK2 gene (PARK8) was shown to cause a dominant disease with a broader phenotype. The protein product was named dardarin and contains GTPase and kinase domains. Lewy bodies have been reported in LRRK2 cases, potentially linking this gene with sporadic Parkinson’s disease. One mutation (G2019S) is found in a significant percentage of cases, including sporadic Parkinson’s disease [72,73]. However, most of the cases of Parkinson’s disease are sporadic. Actual therapy is based mainly on the use of L -DOPA in an attempt to compensate for the well-known selective and progressive degeneration of pigmented dopaminergic neurons in the substantia nigra pars compacta [74,75]; however, the efficacy of this symptomatic treatment is far from being considered satisfactory. As happened with Alzheimer’s disease, a better knowledge of the pathogenic mechanisms at the basis of Parkinson’s disease has pushed pharmacological research towards new therapeutic strategies. The introduction on the market of the so-called dopamine agonists, such as bromocriptine, pergolide, cabergoline and, recently, ropinirole and pramipexole, which mimic dopamine and thereby directly stimulate presynaptic (autoreceptors) and postsynaptic DA receptors has (in some way) improved but not revolutionised the pharmacological therapeutic potential to cure Parkinson’s disease. These drugs are in fact often regarded as the first choice in de novo and young Parkinsonian patients to delay the onset of L -DOPA therapy. Moreover,

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they are also used as adjunct therapy together with L -DOPA to retard the development of motor complications in advanced stages of the disease. Interestingly, considering the mode of action, these drugs do not only act as dopamine agonists but also as antioxidant agents. More importantly, they have been shown to possess neuroprotective effects against abnormal dopamine metabolism in excessively L -DOPA-administered Parkinsonian brains and against cytotoxic dopamine quinones generated from excess dopamine, preventing consequential dopamine-mediated neuronal damage induced by excess dopamine or L -DOPA. Last but not least, pramipexole has also shown antidepressant action that appears to be clearly independent from the control of Parkinson’s disease-related dyskinesias. All of these effects support the use of these drugs and of other alternatives to L -DOPA in an attempt to improve the control of the disease and (above all) to delay the dyskinesia related to the disease and/or to L -DOPA treatment. These different therapeutic stategies can be adopted at the same time as always considering the side effects of dopamine agonists that are similar to those of carbidopa and L -DOPA, although they are less likely to cause involuntary movements and are more likely to cause hallucinations or sleepiness. Importantly, these medications seem to increase compulsive behaviours (i.e., hypersexuality and overeating) and may cause hallucinations. Sections 3.1 – 3.3 discuss some of the molecules that are already in clinical phase as potential therapeutic new drugs for the treatment of Parkinson’s disease. 3.1 Phase

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III trials A novel symptomatic treatment targeting nondopaminergic areas in the hope of avoiding the motor complications that are observed with classic dopaminergic therapies is represented by adenosine A2A receptor antagonists such as istradefylline (KW-6002). Adenosine A2A receptors are localised to the indirect striatal output function and control motor behaviour. Results from two studies using istradefylline in patients with Parkinson’s disease were published, both showing a positive benefit from this drug when used as adjunctive therapy to L -DOPA; however, its association with the development of motor complications limits its usefulness in late stages of the disease [76,77]. Another interesting drug is safinamide, a monoamine oxidase B inhibitor, ion channel modulator and dopamine uptake inhibitor. In a Phase II clinical study, safinamide 40 – 90 mg/day significantly improved motor score tests in Parkinsonian patients versus the placebo group after 3 months of therapy. In a subgroup of 101 patients receiving stable treatment with a single dopamine agonist, the addition of safinamide magnified the response [78].

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II trials Talampanel is a glutamate AMPA receptor antagonists that has been found to have anti-Parkinsonian effects when

8

administered as a high-dose monotherapy and antidyskinetic effects on L -DOPA-induced dyskinesias [75,79]. NS-2330 is a triple monoamine reuptake inhibitor that has therapeutic potential in both Parkinson’s disease and Alzheimer’s disease. A Phase II proof-of-concept study is currently underway in early Parkinson’s disease; however, a recently published study in advanced Parkinson’s disease showed no therapeutic benefit from NS-2330 in a Parkinson’s disease patient population [75,80]. ONO-2506 [81] is an astrocyte-modulating agent that protected dopaminergic neurons against MPTP (1-methyl4-phenyl-1,2,3,6-tetrahydropyridine) neurotoxicity in mice and thus reduced neurological deficits. Interestingly, recent data seem to suggest that the neuroprotection is mediated through the modulation of astrocytic activation and the inhibition of S-100 protein synthesis [82]. At this level, there are also other drugs designed to counteract late motor effects of L -DOPA such as sarizotan (a 5-HT1A agonist and D3/D4 ligand) and fipamezole (a potent α2-adrenergic receptor antagonist) that provided a reduction of L -DOPA-induced dyskinesia in the MPTP-induced primate model of Parkinson’s disease [83,84].

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I trials A suggested pathogenetic mechanism at the basis of L -DOPA-induced dyskinesias consists of alterations at the level of striatal glutamate receptors. In this regard, administration of besonprodil (a novel NMDA receptor antagonist) may prevent the appearance of this dramatic side effect. Experimental studies seem to confirm such a hypothesis [81,85] and induced Purdue Neuroscience to enter a clinical phase trial. Finally, it is necessary to mention the question of glial cell-derived neurotrophic factor (GDNF), a biopharmacological approach to Parkinson’s disease that has entered a clinical Phase I trial that is the object of an intense debate at present. In fact, after two open-label studies in which Parkinson’s disease patients experienced a marked and persistent improvement of the symptoms following intraputamenal infusion of GDNF [86], a randomised double-blind study showed no significant improvements of the disease compared with placebo-treated patients. Moreover ∼ 10% of patients in all 3 trials developed neutralising antibodies to the exogenous GDNF that could potentially cross-react with endogenous GDNF; however, a toxicity study on monkeys has shown that high doses of this neurotrophin factor can induce cerebellar damage (loss of Purkinje and granule cells) [87]. These results pushed Amgen (the manufacturer of GDNF) to withdraw the drug from clinical studies. This decision is strongly challenged by patients of the open-label trials who experienced dramatic improvement during GDNF treatment. Some authors suggest that different results in these trials could be due to significant difference in dose, delivery methods, cannula size and (last but not least) in the placebo effect. Considering both previous experiences with other different bio-pharmacological approaches, and the particular anatomical and



pathophysiological status of Parkinson’s disease, a more accurate delivery system at the level of the specific cerebral regions must be accurately evaluated. 4. Huntington’s

development by Aeolus (formerly Incara) as a potential subcutaneous treatment for ALS, stroke, spinal cord injury, lung inflammation and mucositis. This compound is currently undergoing a Phase I clinical trial for ALS [90].

disease 6. Other

Huntington’s disease is a genetic neurodegenerative disease that is characterised by movement disorder, dementia and psychiatric disturbance. Huntington’s disease is believed to be caused by a genetic mutation of the cytosine, adenosine and guanine (CAG) polymorphic trinucleotide repeat. It is believed that there is a direct link between CAG repeat length and age of onset, disease progression and Huntington’s disease clinical symptoms. Huntington’s disease has been diagnosed in ∼ 30,000 patients in the US with a similar number in Europe. At present, there is no effective treatment or cure for Huntington’s disease [1,2]. 4.1 Phase

III trials LAX-101 is a semi-synthetic, highly purified derivative of (all-cis)-5,8,11,14,17-eicosapentaenoic acid. The mechanism of action of LAX-101 and its metabolites is believed to involve stabilisation of cell membranes and of mitochondrial integrity in suffering neurons; thereby preventing or slowing down progression from neuronal dysfunction to apoptosis. LAX-101 is also known to have neurological anti-inflammatory effects [88]. At present, there are two Phase III clinical trials of LAX-101 in Huntington’s disease. The primary end point of the trials will be to determine whether LAX-101 will result in clinically and statistically significant changes in the Total Motor Score-4 subscale of the Unified Huntington's Disease Rating Scale (UHDRS). 5. Motor

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neuron diseases

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neurodegenerative diseases

For other less common neurodegenerative diseases (i.e. progressive supranuclear palsy, spinocerebellar ataxia, Pick’s disease and prion disease) there are at present no specific drugs in clinical phase. However, there are a series of molecules in which the main clinical indication is neurodegeneration that could be useful to delay or slow the progression of degeneration of cells. 6.1 Phase

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Motor neuron diseases are a heterogeneous group of disorders that selectively affect upper and lower motor neurons, or both. The relatively more common acquired motor neuron disease is ALS, which is generally characterised by a dysfunction of both upper and lower motor neurons. It is well known that a defect of cytosolic superoxide dismutase (SOD1) has a significant role in the etiopathogenesis of this disease [1,3]. For this group of neurodegenerative disorders, some drugs that are in clinical Phase II, such as ONO-2506 – which acts by inducing the protection of dopaminergic neurons partially mediated by S-100 inhibition synthesis [89] – and xaliproden, already considered for Alzheimer’s disease (see Section 2.1) and Parkinson’s disease, seems to be useful in motoneuron diseases [26]. Similar conclusions can be drawn for talampanel, a glutamate AMPA receptor antagonist, which has already been considered as a new drug in the therapy of Parkinson’s disease (see Section 3.2). AEOL-10150, a small-molecular antioxidant analogous to the catalytic site of superoxide dismutase, is under

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III trials NXY-059 is an intravenous, nitrone-based, free radical-trapping agent in Phase III trials for the treatment of acute stroke. A recent analysis of one of the Phase III trials showed a statistically significant reduction in the primary outcome of disability after an acute stroke in patients who received NXY-059 compared with placebo. However, other clinical trials did not confirm these results [91,92]. Second-generation nitrones (azulenyl nitrones) with long-lasting antioxidant activity have also been described and have shown to be neuroprotective in animal models [91].

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6.2 Phase

II trials The role of group I metabotropic glutamate (mGlu) receptors in neurodegeneration is controversial because of the contradictory effects of mGlu1/5 agonists in in vitro models of neuronal cell death. Novel and selective antagonists of mGlu1 and mGlu5, LY-354740 and LY-367366, were found to display consistent neuroprotective effects against NMDA-induced excitotoxicity in vitro and in vivo. Furthermore, intraventricular administration of LY-367385 reduced hippocampal cell death in gerbils that were subjected to transient global ischaemia [93-95]. These positive results support the view that antagonists of mGlu1 and mGlu5 and agonists of group II mGlu receptors may be useful in the treatment of neurodegenerative disease. Another interesting drug that reached the clinical phase is semaxanib (Met-Glu-His-Phe-Pro-Gly-Pro; Russian Academy of Sciences), its use springing from the well-known nootropic activity of corticotropin (adrenocorticotropic hormone) and analogues. This corticotropin fragment afforded the improvement of neurochemical parameters of dopamine- and 5-HT-mediated systems, enhancing both the striatal release of dopamine and the locomotor behaviour with positive symptomatic effects in different neurodegenerative processes [96]. However, T-588 is a novel compound that has been shown to exhibit a wide range of neurotrophic effects both in vivo and in vitro in astrocytes, motor neurons, retinal ganglion cells and Purkinjee cells. These neuroprotective effects seem to


9


slow the motor deterioration and to reduce learning and memory deficits in different animal models of dementia. This compound is thought to stimulate acetylcholine release and, above all, to limit intracellular calcium concentration increase by blocking calcium release from intracellular stores [97]. For these mechanisms, this compound could also be used for treatment of other neurodegenerative diseases. 6.3 Phase

I trials SSR-180575 is a novel peripheral benzodiazepine binding site ligand which promotes neuronal survival and repair in axotomy and neuropathy models. This compound has potential for the treatment of neurodegenerative diseases. Interestingly, experimental data seem to suggest that its neuroprotective effects are steroid-mediated [98,99]. Finally, it is worthy mentioning minocycline, a member of the tetracycline class of molecules with broad-spectrum antibiotic activity. Of particular interest is the ability of minocycline to diffuse into the CNS at clinically effective levels. As well as its antimicrobial properties, minocycline has been found to have beneficial effects on inflammation, microglial activation, matrix metalloproteases, NO production and apoptotic cell death. Accordingly, this drug has been found to have neuroprotective effects in animal models of a number of neurodegenerative diseases [100,101]. 7. Conclusions

o h

Scatena et al. would like to make clear that this review can not cover all drugs under investigation for the therapy of neurodegenerative diseases. For a more accurate list of these molecules the reader can refer to reviews on each single neurodegenerative disorder [6,11,12,75,81,100,102-104]. The authors’ aim is to give an idea of the status of current pharmacological research in the field of neurodegeneration. Therefore, the authors have limited the discussion to drugs that have a file of indexed publications and that, at the same time, can represent all of the new pharmacological initiatives that are actually under investigation in this particular field of neurology. It is worth pointing out that, together with the developments in the classical approaches to neurodegeneration (i.e. new activators and/or inhibitors of different neurotransmitters), pharmacological research is devising a series of new molecules with alternative and potentially synergistic therapeutic activities. For example, there are drugs in clinical phase that are better able to moderate the neurotransmission and that could, theoretically, reduce the incidence of well-known dyskinetic side effects. On the other hand, the therapeutic approach towards a reduction in the production of abnormal deposits and/or stimulation of the clearance mechanisms of misfolded proteins represents a real attempt to cure the neurodegeneration or at least to delay the progression of disease. In the next few years, we will certainly see a change in the pharmacological approach to neurodegeneration using

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various, more effective and synergistic tools with hopefully positive outcomes for the patients. 8. Expert

opinion

In the last few years there has been impressive progress in the understanding of the pathogenesis of neurodegeneration but many of the mechanisms still remain confusing. It is evident that a fundamental aid to identifying new disease-modifying therapies in neurodegeneration and to better delineate the real therapeutic index of new molecules depend on an accurate diagnosis and analysis of the specific degenerative disease. In particular, the recent advances in structural and functional brain imaging (i.e., SPECT and PET) could permit the detection and monitoring of signs of presymptomatic lesions. Moreover, measurement of different biomarkers (i.e., for Alzheimer’s disease β-amyloid 42 and tau protein) in the cerebrospinal fluid and, perhaps (for β-amyloid) also in the blood, along with the adoption of new biochemical methodologies (i.e., proteomic studies of CSF) could represent important ways to understand and discriminate the molecular pharmacology of proposed new neuro-drugs, thus complementing the so-called neuropsychological markers for more accurate diagnoses and prognoses. The different methods employed by pharmaceutical companies to approach neurodegenerative diseases have the undeniable advantage of affording a better understanding of the molecular mechanisms at the basis of neuron death as well. Some of these ways have already provided interesting and potentially useful molecules (i.e., secretase activators and inhibitors, Aβ vaccines, new neurotransmission modulators, antioxidant and antiinflammatory agents, and so on) that are now in the clinical phases and that must be already considered as real positive prospects compared with the dramatic courses of neurodegenerative diseases and the low efficacy of the actual pharmacotherapy. The peculiar characteristics of the nervous system require more precise definition of the molecular mechanisms underlying pharmacological activities and the most accurate analysis of the data on distribution, metabolism and elimination of the drugs targeted to neurodegeneration. In fact, all too often we see the failure of drugs in clinical phase that do not fulfill the expectations generated in the pharmacological phases: mostly because of incomplete knowledge of the fundamental biochemical and pharmacological properties of the new compound or because of overlooked interactions with the pathophysiological mechanisms of a disease. As an example, neurodegenerative diseases are generally chronic diseases with a long-lasting preclinical phase that conceals a slowly developing pathogenic mechanism. This particular aspect renders the realisation of good experimental and clinical models extremely difficult for validation of new drugs for the therapy of neurodegeneration. To underestimate this would not only expose patients to dangerous side effects but could also hamper the pharmacological research into an

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otherwise useful drug. However, some intriguing and potentially useful biological activities of a generic drug could be neglected (i.e., thiazolidinediones, which through the interaction with PPAR may be capable of inducing a different family of chaperones or HSPs) [105]. In conclusion, although several of the pathogenic mechanisms of neurodegeneration are not yet fully

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Websites

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http://www.axonyx.com/pipeline/ posiphen.html Axonyx website pipeline (2006).

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Elan website news (2006).

Affiliation

Roberto Scatena†1 MD, Giuseppe E Martorana, Patrizia Bottoni, Giorgia Botta, Paola Pastore & Bruno Giardina †Author for correspondence 1Associate Professor of Biochemistry, Istituto di Biochimica e Biochimica Clinica, Universita' Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy Tel: +39 063 015 4222; Fax: +39 063 550 1918; E-mail: [email protected]