Dextromethorphan protects dopaminergic neurons against inflammation-mediated degeneration through inhibition of microglial activation
Dextromethorphan protects dopaminergic neurons against inflammation-mediated degeneration through inhibition of microglial activation
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DOI：
10.1124/jpet.102.043166
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发表时间：
2003-04-01
影响因子：
3.5
通讯作者：
Hong, JS
中科院分区：
文献类型：
--
作者：
Liu, YX;Qin, LY;Hong, JS
人们越来越多地认识到大脑炎症在几种神经退行性疾病的发病机制中起着重要作用，包括帕金森病和阿尔茨海默病。炎症介导的神经退行性变涉及大脑常驻免疫细胞小胶质细胞的激活，小胶质细胞产生促炎和神经毒性因子，包括细胞因子、活性氧中间体、一氧化氮和类二十烷，这些因子影响神经元诱导神经退行性变。因此，在寻找炎症介导的神经退行性疾病的治疗剂时，鉴定防止小胶质细胞活化的化合物可能是非常可取的。在这项研究中，我们报道了右美沙芬（DM），一种广泛用于止咳药物的成分，通过抑制小胶质细胞的激活来减少炎症介导的多巴胺能神经元的变性。用DM （1-10 muM）预处理大鼠中脑神经元-胶质细胞培养物30分钟后，脂多糖（LPS, 10 ng/ml）诱导的小胶质细胞介导的多巴胺能神经元变性呈剂量依赖性。当添加LPS后DM用于培养长达60分钟时，DM的显著神经保护作用也很明显。DM的神经保护作用归因于抑制lps刺激的小胶质细胞活化，因为DM显著抑制lps诱导的肿瘤坏死因子- α、一氧化氮和超氧化物自由基的产生。在富含神经元的培养物中，DM不能阻止1-甲基-4-苯基吡啶或β -淀粉样肽（1-42）诱导的多巴胺能神经毒性，这一发现进一步支持了这一结论。此外，由于LPS并没有显著增加神经胶质细胞培养物中兴奋性氨基酸的释放，n-甲基- d -天冬氨酸拮抗剂马来酸二唑西平也没有显著的神经保护作用，因此DM的神经保护作用不太可能是通过n-甲基- d -天冬氨酸受体介导的。这些结果表明，DM可能是治疗帕金森病的一种有前景的药物。
Inflammation in the brain has increasingly been recognized to play an important role in the pathogenesis of several neurodegenerative disorders, including Parkinson's disease and Alzheimer's disease. Inflammation-mediated neurodegeneration involves activation of the brain's resident immune cells, the microglia, which produce proinflammatory and neurotoxic factors, including cytokines, reactive oxygen intermediates, nitric oxide, and eicosanoids that impact on neurons to induce neurodegeneration. Hence, identification of compounds that prevent microglial activation may be highly desirable in the search for therapeutic agents for inflammation-mediated neurodegenerative diseases. In this study, we report that dextromethorphan (DM), an ingredient widely used in antitussive remedies, reduced the inflammation-mediated degeneration of dopaminergic neurons through inhibition of microglial activation. Pretreatment (30 min) of rat mesencephalic neuron-glia cultures with DM (1-10 muM) reduced, in a dose-dependent manner, the microglia-mediated degeneration of dopaminergic neurons induced by lipopolysaccharide (LPS, 10 ng/ml). Significant neuroprotection by DM was also evident when DM was applied to cultures up to 60 min after the addition of LPS. The neuroprotective effect of DM was attributed to inhibition of LPS-stimulated microglial activation because DM significantly inhibited the LPS-induced production of tumor necrosis factor-alpha, nitric oxide, and superoxide free radicals. This conclusion was further supported by the finding that DM failed to prevent 1-methyl-4-phenylpyridinium- or beta-amyloid peptide ( 1-42)-induced dopaminergic neurotoxicity in neuron-enriched cultures. In addition, because LPS did not produce any significant increase in the release of excitatory amino acids from neuron-glia cultures and N-methyl-D-aspartate antagonist dizocilpine maleate failed to afford significant neuroprotection, it is unlikely that the neuroprotective effect of DM is mediated through N-methyl-D-aspartate receptors. These results suggest that DM may be a promising therapeutic agent for the treatment of Parkinson's disease.