14 Current Psychopharmacology, 2012, 1, 14-28 Histone Deacetylase (HDAC) Inhibitors as Potential Drugs to Target Memory and Adult Hippocampal Neurogenesis Antonio Contestabile * , Silvia Sintoni and Barbara Monti Department of Biology, University of Bologna, Italy Abstract: Epigenetic mechanisms have been recognized to be important for the physiologic regulation of cognitive functions and their pathologic alterations contribute to many neurologic and neuropsychiatric diseases. We survey here an important mechanism of epigenetic regulation of brain function, the histone acetylation state modulated by histone deacetylases (HDACs), and its impact on cognitive behaviour as well as on hippocampal adult neurogenesis, which is presently recognized as an essential process for learning and memory. A potent way to modulate histone acetylation state is through HDAC inhibitors, which are currently tested as potential drugs for treatment of major diseases including cancer and neurologic/neuropsychiatric disorders. Various HDAC inhibitor molecules and their impact on brain function are examined with particular reference to neuroprotective action of some of these substances. The core of the review deals with the current status of the literature on the use of some of these inhibitors as memory enhancers and dementia-fighting agents as well as on their possible role in regulation of adult neurogenesis in the hippocampal dentate gyrus, a process linked to the ability of acquiring new memories. Possible reasons for the many controversial results arising from the literature are discussed in view of establishing a more reliable ground for the future use of HDAC inhibitors to improve memory process in brain health and disease. Keywords: Epigenetics, histone acetylation state, transcription regulation, memory, hippocampus, dentate gyrus, adult neurogenesis. EPIGENETIC MECHANISMS AND DISEASES Epigenetics refer to a complex interplay of mechanisms allowing self-perpetuation of gene expression modifications in the absence of DNA sequence alterations and of the original signal that triggered them [1, 2]. Epigenetic mechanisms play an important role in defining phenotypic variability both in physiologic and pathologic conditions [3, 4]. Current understanding of epigenetic mechanisms focuses on DNA methylation and various modifications of histonic proteins that may affect chromatin structure and expression of specific genes. DNA methylation occurs at cytosine nucleotides mainly localized in the promoter CpG regions of genes and affects gene expression by recruiting histone modifying complexes [5, 6]. Regarding the histonic component of chromatin, several chemical modifications, including acetylation, phosphorylation ubiquitination, sumoilation and methylation, may affect gene expression [7- 9]. Histones are the essential proteic component of the nucleosomes, the 147 base pairs of DNA wrapped around an octamer made of 2 copies of each of the histones 2A, 2B, 3 and 4 (H2A, H2B, H3, H4), which constitutes the discrete elementary unit of chromatin structure [10]. The N-terminal regions of histones escape nucleosome core and may interact with other proteins mediating their chemical modifications. These highly dynamic and reversible modifications are carried on by antagonistic enzymes, which attach or remove a given chemical group to a histone residue. A good example is the acetylation of lysine residues, which is promoted by histone acetyltransferases (HATs) and reverted by histone deacetylases (HDACs) [10, 11]. High levels of histone *Address correspondence to this author at the Department of Biology, University of Bologna, Via Selmi 3, 40126 Bologna, Italy; Tel. +39 051 2094134; Fax: +39 051 2094286; E-mail: antonio.contestabile@unibo.it acetylation confer an “open” configuration to chromatin favoring accessibility of transcription factors while low levels of acetylation compact chromatin structure, thus contrasting binding of transcription factor [10] (Fig. 1). Targeting the histone acetylation state aims to counteract diseases with a clear epigenetic component, from cancer to neurological disorders [12-16]. Three main HAT families acetylate lysine residues at both histones and non-histonic proteins and act as co- activators of transcription factors promoting gene expression [17-19]. HDACs oppose the role of HATs, deacetylating lysine residues at histone tails and catalyzing the same reaction on several non-histonic proteins [20, 21]. HDACs are a complex family of at least 11 proteins plus sirtuins, grouped into four classes and localized either in the nucleus and/or in the cytosol [20, 22]. Class I HDACs are mainly involved in cell proliferation and apoptosis, while class II enzymes mediate cell migration and angiogenesis. Class III HDACs consist of the specific sub-group of sirtuins and class IV comprises HDAC 11 with characteristics in between Class I and II [20-22]. Deregulation of HDACs activity results in aberrant gene silencing and favors tumorigenesis [23]. Sirtuins were originally studied for their role in regulating caloric restriction and organism lifespan [24]. By now, it is clear that they intervene in all relevant cellular processes putatively involved in cancer and are overexpressed in a variety of tumors [25, 26]. In recent years, HDACs have been extensively studied in order to find inhibitory agents to be used for cancer therapy [27]. The existence of a histone code that regulates gene expression by acting on chromatin [28] has attracted attention of researchers in different fields from developmental biology to neurobiology of learning and memory. Mutations in genes that interfere with epigenetic mechanisms result in 2211-55 /12 $58.00+.00 © 2012 Bentham Science Publishers