Chen P-S, Peng G-S, Li G, Yang S, Wu X, Wang C-C, Wilson B, Lu R-B, Gean P-W, Chuang D-M, Hong J-S
Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
Mol Psychiatry. 2006 Dec;11(12):1116-25. doi: 10.1038/sj.mp.4001893. Epub 2006 Sep 12.
Valproate (VPA), one of the mood stabilizers and antiepileptic drugs, was recently found to inhibit histone deacetylases (HDAC). Increasing reports demonstrate that VPA has neurotrophic effects in diverse cell types including midbrain dopaminergic (DA) neurons. However, the origin and nature of the mediator of the neurotrophic effects are unclear. We have previously demonstrated that VPA prolongs the survival of midbrain DA neurons in lipopolysaccharide (LPS)-treated neuron-glia cultures through the inhibition of the release of pro-inflammatory factors from microglia. In this study, we report that VPA upregulates the expression of neurotrophic factors, including glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) from astrocytes and these effects may play a major role in mediating VPA-induced neurotrophic effects on DA neurons. Moreover, VPA pretreatment protects midbrain DA neurons from LPS or 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity. Our study identifies astrocyte as a novel target for VPA to induce neurotrophic and neuroprotective actions in rat midbrain and shows a potential new role of cellular interactions between DA neurons and astrocytes. The neurotrophic and neuroprotective effects of VPA also suggest a utility of this drug for treating neurodegenerative disorders including Parkinson's disease. Moreover, the neurotrophic effects of VPA may contribute to the therapeutic action of this drug in treating bipolar mood disorder that involves a loss of neurons and glia in discrete brain areas.
丙戊酸盐（VPA）是一种心境稳定剂和抗癫痫药物，最近被发现可抑制组蛋白脱乙酰酶（HDAC）。越来越多的报道表明，VPA在包括中脑多巴胺能（DA）神经元在内的多种细胞类型中具有神经营养作用。然而，神经营养作用的介质的来源和性质尚不清楚。我们之前已经证明，VPA通过抑制小胶质细胞释放促炎因子，延长了脂多糖（LPS）处理的神经元-胶质细胞培养物中脑DA神经元的存活时间。在本研究中，我们报告VPA上调了神经营养因子的表达，包括星形胶质细胞分泌的胶质细胞源性神经营养因子（GDNF）和脑源性神经营养因子（BDNF），这些作用可能在介导VPA对DA神经元的神经营养作用中起主要作用。此外，VPA预处理可保护中脑DA神经元免受LPS或1-甲基-4-苯基吡啶鎓（MPP+）诱导的神经毒性。我们的研究确定星形胶质细胞是VPA在大鼠中脑诱导神经营养和神经保护作用的新靶点，并显示了DA神经元与星形胶质细胞之间细胞相互作用的潜在新作用。VPA的神经营养和神经保护作用也表明该药物可用于治疗包括帕金森病在内的神经退行性疾病。此外，VPA的神经营养作用可能有助于该药物在治疗双相情感障碍中的治疗作用，双相情感障碍涉及离散脑区神经元和胶质细胞的丢失。
