Valproate is protective against 6-OHDA-induced dopaminergic neurodegeneration in rodent midbrain: A potential role of BDNF up-regulation

Abstract

Background/purpose: The main purpose of this study was to extend previously reported showing potent neuroprotective effect of valproic acid (VPA) in primary midbrain neuro-glial cultures to investigate whether VPA could protect dopamine (DA) neurons in vivo against 6-hydroxydopamine (6-OHDA)-induced neurodegeneration and to determine the underlying mechanism. Methods: Male adult rats received a daily intraperitoneal injection of VPA or saline for two weeks before and after injection of 5, 10, or 15 μg of 6-OHDA into the brain. All rats were evaluated for motor function by rotarod performance. Brain samples were prepared for immunohistochemical staining and for determination of levels of dopamine, dopamine metabolites, and neurotrophic factors. Results: 6-OHDA injection showed significant and dose-dependent damage of dopaminergic neurons and decrease of striatal dopamine content. Rats in the VPA-treated group were markedly protected from the loss of dopaminergic neurons and showed improvements in motor performance, compared to the control group at the moderate 6-OHDA dose (10 μg). VPA-treated rats also showed significantly increased brain-derived neurotrophic factor (BDNF) levels in the striatum and substantia nigra compared to the levels in control animals. Conclusion: Our studies demonstrate that VPA exerts neuroprotective effects in a rat model of 6-OHDA-induced Parkinson's disease (PD), likely in part by up-regulation BDNF. Keywords: Brain-derived neurotrophic factor, 6-Hydroxydopamine, Parkinson disease, Substantia nigra, Valproic acid