Histone Deacetylase (HDAC) Inhibitors as Potential Drugs to Target Memory and Adult Hippocampal Neurogenesis

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, neuropsychiatric disorders, phenotypical, HISTONE DEACETYLASE, basolateral amygdala, hippocampus-dependent, ameliorated, kinase, astrocytes