British Journal of Clinical Pharmacology
DOI:10.1111/j.1365-2125.2012.04443.x
Letter to the Editors
Epigenetic drugs for Alzheimer’s disease: hopes and challenges Filippo Caraci,1,2 Gian Marco Leggio,1 Filippo Drago1 & Salvatore Salomone1 1
Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, University of Catania, Viale A. Doria 6, 95125 Catania and 2Department of Educational Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
In his letter Peedicayil [1] suggests that epigenetic mechanisms, in particular histone deacetylases (HDACs) and gene methylation, might represent a promising target for drug discovery in Alzheimer’s disease (AD). In our recent review [2] we focused on disease modifying drugs in advanced clinical development (Phase II/III). Therefore we did not discuss drugs that specifically exert epigenetic effects, because none of them so far has reached advanced clinical development for AD. However, as suggested by Peedicayil, epigenetic mechanisms in neurodegenerative diseases have been the object of intensive research in recent years and deserve attention because they might soon constitute a novel paradigm in AD arena. Histone acetylation is dynamically regulated by histone acetyltransferases (HATs) and HDACs. HATs neutralize the positive charge on lysine residues allowing chromatin to adopt a more relaxed structure and to recruit the transcriptional machinery. HDACs reverse lysine acetylation, restore histone positive charge and locally stabilize chromatin architecture [3]. Thus, the level of histone acetylation dramatically affects chromatin condensation and gene transcription. DNA methylation is also involved in histone modification. Methylation of CpG islands in promoter regions is associated with gene silencing and is highly interactive with histone acetylation and the other histonemodifying mechanisms [3]. Studies of late-onset AD in twins support the notion that risk factors may affect AD pathophysiology through epigenetic mechanisms [4]. On the other hand, some AD risk factors, such as chronic stress [5], induce strong epigenetic modifications in animal models [6]. Alteration of physiological stress responses, such as those affecting the hypothalamic-pituitary-adrenal axis, may further increase the epigenetic impact of chronic adverse stress in AD [7]. Filippo Caraci is assistant professor of pharmacology (ricercatore), Gian Marco Leggio is instructor/researcher in pharmacology (assegnista di ricerca), Filippo Drago is full professor of pharmacology (professore ordinario), Salvatore Salomone is associate professor of pharmacology (professore associato) 1154
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Chronic psychological distress has been also associated with late-life non-AD dementia [8], but the role of epigenetic mechanisms in this condition has not been investigated so far. HDAC2, but not HDAC1, is known as a negative regulator of memory [9]. Cognitive function in AD may be affected by an epigenetic blockade of gene transcription.A recent study suggests that this blockade is mediated by HDAC2 in patients with AD and shows that it is potentially reversible in mouse models of neurodegeneration [10]. Non-specific pan-HDAC inhibitors include valproic acid, trichostatin A, sodium 4-phenylbutyrate and vorinostat. All these drugs, however, have been shown to affect, by different mechanisms, Ab plaque deposition and/or tau hyperphosphorylation [11]. It remains unclear, therefore, whether or not these drugs, endowed with neuroprotective action in vitro, re-instate memory and reverse learning deficits in AD mouse models through Ab clearance, rather than primarily through HDAC inhibition. The causal involvement of epigenetic mechanisms in AD, if confirmed, may help in understanding failure of clinical trials with disease modifying drugs despite their proven efficacy in Ab clearing. According to this view, if the epigenetic blockade starts before the clinical onset of AD, then reducing Ab generation and deposition alone may not be sufficient to rescue cognitive functions. Finally, as with any novel drug treatment, epigenetic modifiers must be carefully considered in terms of safety and tolerability, particularly considering the fundamental role of epigenetics in the regulation of global gene expression patterns. HDAC inhibitors have been initially studied and used in neoplastic diseases, such as haematological malignancies [3]. Vorinostat and romidepsin were first approved for the treatment of cutaneous T cell lymphoma, but the potential therapeutic utility of HDAC inhibitors for non-oncology indications requires more stringent safety profiles. Key safety issues include the long term effects on stem cells and germ cells. Potential effects on human reproduction are not relevant in AD patients (generally beyond the reproductive age), © 2012 The Authors British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society
Letter to the Editors
but other effects involving immune function [12, 13] might prevent the use of HDAC inhibitors in AD patients. Furthermore it should be considered that HDAC inhibitors developed for cancer may poorly permeate the blood–brain barrier [14]. Recently a CNS-penetrant HDAC (Class I) inhibitor, EVP-0334, has been developed and studied in a phase I clinical trial for the treatment of AD [3], but further detailed information has not yet been disclosed. Identification of subtype- or target-selective HDAC inhibitors, such as for HDAC2 will hopefully provide, in the near future, transcriptional and synaptic effects in neurons, with fewer off target effects, making possible the clinical development of these drugs for AD.
Competing Interests None of the authors has any competing interests to declare. All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from any organization for the submitted work, no financial relationships with any organization that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.
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7 Rothman SM, Mattson MP. Adverse stress, hippocampal networks, and Alzheimer’s disease. Neuromolecular Med 2010; 12: 56–70. 8 Wilson RS, Arnold SE, Schneider JA, Li Y, Bennett DA. Chronic distress, age-related neuropathology, and late-life dementia. Psychosom Med 2007; 69: 47–53. 9 Guan JS, Haggarty SJ, Giacometti E, Dannenberg JH, Joseph N, Gao J, Nieland TJ, Zhou Y, Wang X, Mazitschek R, Bradner JE, DePinho RA, Jaenisch R, Tsai LH. HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 2009; 459: 55–60. 10 Graff J, Rei D, Guan JS, Wang WY, Seo J, Hennig KM, Nieland TJ, Fass DM, Kao PF, Kahn M, Su SC, Samiei A, Joseph N, Haggarty SJ, Delalle I, Tsai LH. An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature 2012; 483: 222–6. 11 Fischer A, Sananbenesi F, Mungenast A, Tsai LH. Targeting the correct HDAC(s) to treat cognitive disorders. Trends Pharmacol Sci 2010; 31: 605–17. 12 Kelly-Sell MJ, Kim YH, Straus S, Benoit B, Harrison C, Sutherland K, Armstrong R, Weng WK, Showe LC, Wysocka M, Rook AH. The histone deacetylase inhibitor, romidepsin, suppresses cellular immune functions of cutaneous T-cell lymphoma patients. Am J Hematol 2012; 87: 354–60. 13 Rossi LE, Avila DE, Spallanzani RG, Ziblat A, Fuertes MB, Lapyckyj L, Croci DO, Rabinovich GA, Domaica CI, Zwirner NW. Histone deacetylase inhibitors impair NK cell viability and effector functions through inhibition of activation and receptor expression. J Leukoc Biol 2012; 91: 321–31. 14 Hooker JM, Kim SW, Alexoff D, Xu Y, Shea C, Reid A, Volkow N, Fowler JS. Histone deacetylase inhibitor, MS-275, exhibits poor brain penetration: PK studies of [C]MS-275 using Positron Emission Tomography. ACS Chem Neurosci 2010; 1: 65–73.
RECEIVED 24 July 2012
3 Arrowsmith CH, Bountra C, Fish PV, Lee K, Schapira M. Epigenetic protein families: a new frontier for drug discovery. Nat Rev Drug Discov 2012; 11: 384–400.
ACCEPTED
4 Mastroeni D, Grover A, Delvaux E, Whiteside C, Coleman PD, Rogers J. Epigenetic mechanisms in Alzheimer’s disease. Neurobiol Aging 2011; 32: 1161–80.
ACCEPTED ARTICLE PUBLISHED ONLINE
5 Cuadrado-Tejedor M, Ricobaraza A, Frechilla D, Franco R, Perez-Mediavilla A, Garcia-Osta A. Chronic mild stress accelerates the onset and progression of the Alzheimer’s disease phenotype in Tg2576 mice. J Alzheimers Dis 2012; 28: 567–78. 6 Wilkinson MB, Xiao G, Kumar A, LaPlant Q, Renthal W, Sikder D, Kodadek TJ, Nestler EJ. Imipramine treatment and resiliency exhibit similar chromatin regulation in the mouse nucleus accumbens in depression models. J Neurosci 2009; 29: 7820–32.
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CORRESPONDENCE Dr Salvatore Salomone MD PhD, Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, University of Catania, Viale Andrea Doria 6, 95125 Catania, Italy. Tel.: +3909 5738 4085 Fax: +3909 5738 4238 E-mail:
[email protected]
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