Therapeutic Potential of Isoform Selective Hdac Inhibitors for the Treatment of Schizophrenia

Abstract

Increasing evidence supports a role for epigenetic involvement in some of the neurobiological alterations observed in neurodegenerative and psychiatric disorders including schizophrenia. In particular, there is mounting evidence implicating dysfunction in acetylation status, a chromatin modification mediated in part by HDACs, as a possible contributing factor to certain facets of this debilitating disease. Additional data support the notion that small molecule inhibition of HDACs may provide therapeutic alternatives to treating many of the symptoms associated with schizophrenia, particularly cognitive deficits. However, the development of highly potent and selective inhibitors of the individual HDAC isoforms will be necessary to delineate the associated biological effects and test the feasibility of such an approach for this complex and chronically treated disease. Here, we summarize current evidence for the role of HDAC isoforms in schizophrenia and highlight the state of the art in developing selective inhibitors of these isoforms as a potential treatment for schizophrenia.

Possible contribution of epigenetic changes in the development of schizophrenia-like behavior in vasopressin-deficient Brattleboro rats

“…We can propose that the AVP deficient Brattleboro rat strain is a valuable model (i) to study the development of SCZ-like behavior, to establish new test battery for SCZ, (ii) follow the changes in epigenetic state of affected genes, and (iii) test newly discovered antipsychotics. This is hotspot as influencing HDACs may provide therapeutic alternatives for treating many of the symptoms associated with SCZ, particularly cognitive deficits [107]. Our studies confirmed that no single gene, more probably fine changes in an array of molecules are responsible for the majority of SCZ cases.…”

Genomics and epigenomics in novel schizophrenia drug discovery: translating animal models to clinical research and back

“…Epigenetic evidences also highlight the potential role of DNMT and HDAC inhibitors in the treatment of schizophrenia [103], as summarized in Table 4 [89,99,[104][105][106][107][108][109]. So far both in vitro and animal studies showed that DNMT and HDAC inhibitors reduce DNA methylation of RELN and Table 3.…”

“…It can thus be hypothesized that antipsychotic drugs, blocking D2-like signaling, induce H3 phosphoacetylation, a dual H3 modification associated with transcriptional activation and epigenetic regulation of gene expression [94]. Distinct antipsychotic classes and subtypes can be differentiated based on their ability to stimulate epigenetic modifications, as summarized in Table 2 [86,90,[94][95][96][97][98][99][100][101][102][103]. Not surprisingly clozapine, the gold standard of treatment-resistant schizophrenia, shows a peculiar profile, compared to other antipsychotics, both typical and atypical.…”

Synthesis of hybrid anticancer agents based on kinase and histone deacetylase inhibitors

“…Its promising preliminary data, notably in biochemical and in vitro assays as well as in the NIH cell line, render it an effective potential chemical probe for angiogenisis. 35,36 Current studies are aimed at exploring further SAR in these hybrids with regard to HDAC isoform 37,38 and kinase selectivity 39 as well as improving their physiochemical properties, 40 and will be reported in due course.…”