Evaluation of selective inhibitors of histone deacetylases as potential neurotrophic agents

Neurodegeneration is characterized by progressive loss of structure and functions of neurons. Neurotrophic actions and neuroprotection leading to neuroplasticity and neuritogenesis are important markers for neuroregeneration. Neurotrophins activate complex signal transduction pathways for regulating neuritogenesis. Recent reports have indicated neuroprotective potential of inhibitors of histone deacetylases (HDAC). A set of selective HDAC inhibitors was tested as potential neurotrophic agents in NS-1 cells, a sub clone of PC12 cells. PCI-34051 (a HDAC8 inhibitor) and tubastatin (a HDAC6 inhibitor) induced significant neuritic outgrowth in NS-1 cells. Belinostat (a class I and II HDAC inhibitor) and tenovin (a sirtuin inhibitor) alone did not show any effect on neurite outgrowth. Interestingly, they significantly reduced neurite outgrowth induced by NGF in combination. Attenuation of NGF-induced neurite outgrowth by belinostat and tenovin did not affect the activation of ERK phosphorylation pathway. Bioactive small molecules with neurotrophic and neuritogenic actions, like PCI-34051 and tubastatin identified in the present study, hold great promise as therapeutic agents for treatment of neurodegenerative diseases and repair of neuronal injuries by virtue of their ability to stimulate neuritic outgrowth. Contrasting actions of different HDAC inhibitors raise interesting questions regarding distinctive roles of individual HDAC isoforms in neurotropic functions, which require further investigations.