Valproate pretreatment protects dopaminergic neurons from LPS-induced neurotoxicity in rat primary midbrain cultures: role of microglia
Valproate pretreatment protects dopaminergic neurons from LPS-induced neurotoxicity in rat primary midbrain cultures: role of microglia
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DOI：
10.1016/j.molbrainres.2004.10.021
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发表时间：
2005-03-24
期刊：
影响因子：
--
通讯作者：
Hong, JS
中科院分区：
文献类型：
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作者：
Peng, GS;Li, GR;Hong, JS
帕金森病是一种神经退行性疾病，其特征是黑质中的多巴胺能 (DA) 神经元进行性变性。越来越多的证据支持神经炎症参与这种疾病的发病机制的观点。丙戊酸（VPA）长期以来一直用于治疗癫痫和双相情感障碍。体内和体外研究表明，VPA 具有神经保护和神经营养作用。在这项研究中，我们利用大鼠中脑的原代神经元神经胶质细胞培养物，证明了 VPA 是一种有效的神经保护剂，可对抗脂多糖 (LPS) 诱导的神经毒性。结果显示，根据 [H-3] 多巴胺摄取和 TH-ir 神经元数量计数确定，用 0.6 MM VPA 预处理 48 小时可显着减弱 LPS 诱导的多巴胺能神经元变性。 VPA 的神经保护作用是浓度依赖性的，并且至少部分是通过降低激活的小胶质细胞释放的促炎因子水平来介导的。具体而言，在用 VPA 预处理的培养物中，LPS 诱导的 TNFa、NO 和细胞内活性氧释放的增加显着减少。 VPA 的这些抗炎作用具有时间和浓度依赖性，并与小胶质细胞数量的减少相关。因此，我们的结果表明，长期 VPA 预处理可通过降低释放的促炎因子水平来保护多巴胺能神经元免受 LPS 诱导的神经毒性，并进一步表明这些抗炎作用可能是由 VPA 诱导的小胶质细胞数量减少所致。综上所述，我们的研究强化了 VPA 可能有助于治疗帕金森病的观点。 (C) 2004 Elsevier B.V. 保留所有权利。
Parkinson's disease is a neurodegenerative disorder characterized by progressive degeneration of dopaminergic (DA) neurons in the substantia nigra. Accumulating evidence supports the notion that neuroinflamniation is involved in the pathogenesis of this disease. Valproate (VPA) has long been used for the treatment of seizures and bipolar mood disorder. In vivo and in vitro studies have demonstrated that VPA has neuroprotective and neurotrophic actions. In this study, using primary neuron-glia cultures from rat midbrain, we demonstrated that VPA is a potent neuroprotective agent against lipopolysaccharide (LPS)-induced neurotoxicity. Results showed that pretreatment with 0.6 MM VPA for 48 h robustly attenuated LPS-induced degeneration of dopaminergic neurons as determined by [H-3] dopamine uptake and counting of the number of TH-ir neurons. The neuroprotective effect of VPA was concentration-dependent and was mediated, at least in part, through a decrease in levels of pro-inflammatory factors released from activated microglia. Specifically, LPS-induced increase in the release of TNFa, NO, and intracellular reactive oxygen species was markedly reduced in cultures pretreated with VPA. These anti-inflammatory effects of VPA were time and concentration-dependent correlated with a decrease in the number of microglia. Thus, our results demonstrate that protracted VPA pretreatment protects dopaminergic neurons from LPS-induced neurotoxicity through a reduction in levels of released proinflammatory factors, and further suggest that these anti-inflammatory effects may be contributed by VPA-induced reduction of microglia cell number. Taken together, our study reinforces the view that VPA may have utility in treating Parkinson's disease. (C) 2004 Elsevier B.V. All rights reserved.