BackgroundExtensive loss of donor neural stem cell (NSCs) due to ischemic stress and low rate of differentiation at the site of cell graft are two of the major issues that hamper optimal outcome in NSCs transplantation studies. Given that histone deacetylases (HDACs) modulate various cellular processes by deacetylating histones and non-histone proteins, we hypothesized that combined treatment with small molecules, sodium butyrate (NaB; a known HDAC inhibitor) and nicorandil, will enhance the rate neuronal differentiation of NSCs besides their preconditioning to resist oxidative stress.MethodsNSCs derived from 14-day old Sprague Dawley rat ganglion eminence were characterized for tri-lineage differentiation. Treatment with 1 mM NaB significantly changed their culture characteristics while continuous treatment for 10 days enhanced their neural differentiation. NaB treatment also preconditioned the cells for their resistance to oxidative stress.ResultsThe highest rate of neural differentiation and preconditioning effect was achieved when the NSCs were treated concomitantly with NaB and nicorandil. Cell proliferation assay showed that concomitant treatment with NaB and nicorandil retarded their rate of proliferation.ConclusionThese data conclude that preconditioning of NSCs with NaB and nicorandil effectively enhances their differentiation capacity besides preconditioning the cells to support their survival under ischemic conditions.Electronic supplementary materialThe online version of this article (10.1186/s40035-017-0097-1) contains supplementary material, which is available to authorized users.