Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes
Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes
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DOI：
10.1038/sj.mp.4001893
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发表时间：
2006-12-01
影响因子：
11
通讯作者：
Hong, J-S
中科院分区：
文献类型：
--
作者：
Chen, P-S;Peng, G-S;Hong, J-S
丙戊酸盐（VPA）是一种情绪稳定剂和抗癫痫药物，最近发现其可抑制组蛋白去乙酰化酶（HDAC）。越来越多的研究表明，丙戊酸钠对包括中脑多巴胺能神经元在内的多种细胞具有神经营养作用。然而，神经营养作用的介质的起源和性质尚不清楚。我们以前已经证明，VPA通过抑制小胶质细胞释放促炎因子，抑制脂多糖（LPS）处理的神经胶质细胞培养中脑DA神经元的存活。在这项研究中，我们报告，VPA上调神经营养因子的表达，包括胶质细胞源性神经营养因子（GDNF）和脑源性神经营养因子（BDNF）的星形胶质细胞和这些影响可能在介导VPA诱导的DA神经元的神经营养效应中发挥重要作用。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（MPP+）诱导的神经毒性。我们的研究确定星形胶质细胞作为一个新的目标VPA诱导大鼠中脑的神经营养和神经保护作用，并显示了潜在的新的DA神经元和星形胶质细胞之间的细胞相互作用的作用。VPA的神经营养和神经保护作用也表明这种药物可用于治疗神经退行性疾病，包括帕金森病。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，该双相情感障碍涉及离散脑区的神经元和神经胶质的损失。
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.