Pharmacological Properties Role in Chromatin Remodeling

Chromatin architecture consists of DNA, histones, and nonhistone proteins. The nucleosome represents the basic repeating unit of chromatin and consists of DNA wrapped around a histone octamer that contains H2A, H2B, H3, and H4 histones. ► Chromatin remodeling occurs due to covalent histone modifications (acetylation, methylation, phosphorylation, ubiquitination, and sumoylation) and ► DNA methylation (Tsankova et al. 2007). Two major enzymes, ► histone acetyltransferases (HATs) and HDACs, regulate histone acetylation and deacetylation, respectively. The acetylation of histones leads to a relaxed chromatin state, which allows the DNA to interact more easily with various components of transcriptional machinery, such as transcription factors, transcriptional regulatory protein complexes, and RNA polymerases, resulting in increased gene transcription (Renthal and Nestler 2008). The removal of acetyl groups from histones (deacetylation) by the activation of HDACs condenses the chromatin structure, causing a decrease in gene transcription. HDAC inhibitors can increase overall gene expression by inhibiting HDAC activity, thus preventing the condensation of the chromatin structure (see Fig. 1). Therefore, HDAC-induced chromatin remodeling plays

Condensed chromatin Relaxed chromatin

Condensed chromatin Relaxed chromatin

Psychiatric disorders Neurodegenerative Addictive behaviors diseases

Psychiatric disorders Neurodegenerative Addictive behaviors diseases

Histone Deacetylase Inhibitors. Fig. 1. Hypothetical model of histone deacetylases (HDACs)-induced chromatin remodeling via histone deacetylation (condensed chromatin). HDAC inhibitors cause the opening of the chromatin structure (relaxed chromatin) due to its ability to increase histone acetylation (A). HDAC inhibition may serve as a potential therapeutic remedy for the treatment of brain disorders.

a fundamental role in regulating gene expression (► Epi-genetics; ► Gene expression and transcription).

HDAC Inhibitors and Therapeutic Implications

Mammalian HDACs have been classified into four classes based on their homology to yeast HDACs and subcellular localization (Xu et al. 2007; Kazantsev and Thompson 2008). Class I HDACs are mostly nuclear and include HDAC 1, 2, 3, and 8. Class II HDACs can be either cytosolic and/or nuclear and include HDAC 4, 5, 6, 7, 9, and 10. Class IV HDACs include only HDAC 11, which display properties that are closely related to class I HDACs and are mainly localized in the nucleus. Class I, II, and IV HDACs require Zn2+ for activation and are therefore referred to as Zn2+-dependent HDACs. On the other hand, class III HDACs are NAD+ -dependent enzymes that are collectively called sirtuins. Sirtuins are not structurally related to either class I, II, or IV HDACs. HDAC inhibitors that are specific to the Zn2+-dependent class I and II HDACs and their clinical implications are described below.

A number of HDAC inhibitors belonging to different classes (hydroxamates, aliphatic acids, benzamides, and cyclic peptides) have been developed during the last decade and are currently in phase I and II clinical trials for the treatment of various cancers. Recently, the HDAC inhibitor Vorinostat (SAHA suberoylanilide hydroxamic acid), has been approved by the US Food and Drug

Administration to be used for the treatment of cutaneous T-cell lymphoma (Xu et al. 2007; Lee et al. 2008). Despite the tremendous amount of progress regarding the clinical use of HDAC inhibitors to treat cancers, these compounds can display some forms of toxicity. These include fatigue, nausea, vomiting, thrombocytopenia, neutrope-nia, and cardiac irregularities (Balasubramanian et al. 2009). Drug development efforts have been diverted to synthesize HDAC isoform-specific inhibitory compounds with some success in the cancer field (Lee et al. 2008) and this approach may overcome the problems associated with drug toxicity (Balasubramanian et al. 2009). The HDAC inhibitors: ► Trichostatin A (TSA), sodium butyrate, SAHA, and ► valproic acid have been used in animal models to treat neurodegenerative (► Neurodegeneration and its prevention; ► Learning & Memory: Molecular Mechanisms) and psychiatric disorders (► Schizophrenia;

► Generalized Anxiety Disorder; ► Anxiety: animal models; ► Depression: animal models) (Tsankova et al. 2007; Kazantsev and Thompson 2008; Abel and Zukin 2008; Guidotti et al. 2009). Using an animal model for depression, it has been suggested that hippocampal chromatin remodeling may play a role in the pathophysiology of depression (► Animal models for psychiatric states;

► Antidepressants), and HDAC inhibitors may be beneficial in treating depression (Tsankova et al. 2006). Genetic and pharmacological manipulations of HDACs in the ► nucleus accumbens (NAc) brain region have been shown to modify the behavioral sensitivity to ► cocaine, and TSA treatment can decrease cocaine self-administration (► Cocaine; ► Cocaine dependence) in rats (Renthal and Nestler 2008; Romieu et al. 2008). Acute ethanol has been shown to inhibit HDAC activity, and ethanol withdrawal after chronic ethanol exposure has been shown to increase HDAC activity in the ► amygdala of rats. Blocking HDAC activity by TSA treatment during ethanol withdrawal has prevented the development of anxiety-like behaviors (► Alcohol; ► Alcohol abuse and dependence) and has also corrected deficits in histone acetylation in amygdaloid brain regions of rats (Pandey et al. 2008). Collectively, these results suggest that HDAC inhibitors may represent potential therapeutic agents for the treatment of various brain disorders. Given that several HDAC isoforms exist and previous studies have used pan-HDAC inhibitors, it is important to investigate the role of specific HDAC isoforms in different brain disorders using both pharmacological and genetic approaches to block the action of specific HDACs that may lead to development of HDAC isoform-specific pharmacotherapy of brain diseases.

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