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ARS Home » Southeast Area » Oxford, Mississippi » Natural Products Utilization Research » Research » Publications at this Location » Publication #309926
Title: Mechanism for neurotropic action of vorinostat, a pan histone deacetylase inhibitor

Author
item SHUKLA, SURABHI - University Of Mississippi
item SHARIAT-MADAR, ZIA - University Of Mississippi
item WALKER, LARRY - University Of Mississippi
item TEKWANI, BABU - University Of Mississippi

Submitted to: Molecular and Cellular Neuroscience
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/23/2016
Publication Date: 9/1/2016
Citation: Shukla, S., Shariat-Madar, Z., Walker, L.A., Tekwani, B.L. 2016. Mechanism for neurotropic action of vorinostat, a pan histone deacetylase inhibitor. Molecular and Cellular Neuroscience. 77:11-20.

Interpretive Summary: We investigated the effect of vorinostat (suberanilohydroxamic acid, SAHA), a known inhibitor of histone deacetylase class I & II and an anticancer drug, on the differentiation of rat adrenal medulla pheochromocytoma cells. Our results suggests (1) that neurite outgrowth mediated by both nerve growth factor (NGF) and vorinostat were blocked by these inhibitors and (2) that vorinostat exerts a positive effect on neuritogenesis via activation of MAP kinase and Phosphatidyl Inositol Kinase pathways. Bioactive small molecules with neurotrophic and neuritogenic actions, like vorinostat identified in the present study, hold great promise as therapeutic agents for treatment of neurodegenerative diseases and neuronal injuries by virtue of their ability to stimulate neuritic outgrowth.

Technical Abstract: In this study we investigated the effect of vorinostat (suberanilohydroxamic acid, SAHA), a class I and class II HDAC inhibitor, on the differentiation of Neuroscreen-1 (NS-1) cells. NS-1 cell is a subclone of the rat pheochromocytoma cell line (PC 12). PC12 cells on treatment with nerve growth factor can be induced to differentiate into neuron-like cells having elongated neurites. We found vorinostat independently induces neurite outgrowth in NS-1 cells. To further understand mechanism for SAHA-induced differentiation of NS1 cell, the effect of this HDAC inhibitor on intracellular signaling was investigated using MEK1/2 inhibitors (PD98059 and U0126) and PI3K inhibitor (LY294002). Our results suggests that neurite outgrowth mediated by both nerve growth factor (NGF) and vorinostat were blocked by inhibitors of MEK1/2 & PI3K. Vorinostat induced the phosphorylation of ERK1/2 at 2 hrs; this phosphorylation of ERK was abolished in presence of U0126 confirming role of ERK pathway in differentiation of NS-1 cells. However, phosphorylation of ERK induced by vorinostat was not rapid as it for NGF mediated neuritogenesis. Our result suggests that vorinostat exerts a positive effect on neuritogenesis via activation of MEK1/2 & PI3K pathways. Bioactive small molecules with neurotrophic and neuritogenic actions, like vorinostat identified in the present study, hold great promise as therapeutic agents for treatment of neurodegenerative diseases and neuronal injuries by virtue of their ability to stimulate neuritic outgrowth.