3-hydroxymorphinan, a metabolite of dextromethorphan, protects nigrostriatal pathway against MPTP-elicited damage both in vivo and in vitro
3-hydroxymorphinan, a metabolite of dextromethorphan, protects nigrostriatal pathway against MPTP-elicited damage both in vivo and in vitro
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DOI：
10.1096/fj.06-6006com
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发表时间：
2006-12-01
期刊：
影响因子：
4.8
通讯作者：
Kim, Hyoung-Chun
中科院分区：
文献类型：
--
作者：
Zhang, Wei;Shin, Eun-Joo;Kim, Hyoung-Chun
我们研究了右美沙芬 (DM) 类似物在脂多糖 (LPS) 和 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 模型中的神经保护特性，以确定帕金森病 (PD) 的神经保护药物。体内研究表明，使用两种不同的 PD 模型，每天注射 DM 类似物可以保护黑质致密部的多巴胺 (DA) 神经元，并恢复纹状体中的 DA 水平。在研究的五种类似物中，DM 的一种代谢物 3-羟基吗啡喃 (3-HM) 是最有效的，它可以恢复 DA 神经元损失和 DA 耗竭，高达 90% 的对照组。行为研究表明，在所研究的 DM 类似物中，预防毒素引起的运动活动减少的功效与神经保护作用之间存在极好的相关性，其中 3-HM 在减轻行为损伤方面最有效。体外研究揭示了 3-HM 的神经保护作用有两种神经胶质依赖性机制。首先，星形胶质细胞通过增加神经营养因子的基因表达来介导 3-HM 诱导的神经营养效应，这与组蛋白 H3 乙酰化的增加有关。其次，小胶质细胞通过减少 MPTP 引发的反应性小胶质细胞增生参与 3-HM 介导的神经保护，这一点可以通过活性氧产生的减少来证明。总之，我们在所研究的 LPS 和 MPTP PD 模型中展示了 3-HM 的有效神经保护作用。凭借其高效低毒的特点，3-HM 可能成为 PD 的一种新疗法。-Zhang, W., Shin, E-J., Wang, T., Lee, P. H., Pang, H., Wie, M-B., Kim, W-K., Kim, S-J., Huang, W-H., Wang, Y., Zhuang, W., Hong, J-S., Kim, H-C.。 3-Hydroxymorphinan 是右美沙芬的代谢产物，可保护黑质纹状体通路免受 MPTP 引起的体内和体外损伤。
We investigated the neuroprotective property of analogs of dextromethorphan (DM) in lipopolysaccharide (LPS) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) models to identify neuroprotective drugs for Parkinson's disease (PD). In vivo studies showed that daily injections with DM analogs protected dopamine (DA) neurons in substantia nigra pars compacta and restored DA levels in striatum using two different models for PD. Of the five analogs studied, 3-hydroxymorphinan (3-HM), a metabolite of DM, was the most potent, and restored DA neuronal loss and DA depletion up to 90% of the controls. Behavioral studies showed an excellent correlation between potency for preventing toxin-induced decrease in motor activities and neuroprotective effects among the DM analogs studied, of which 3-HM was the most potent in attenuating behavioral damage. In vitro studies revealed two glia-dependent mechanisms for the neuroprotection by 3-HM. First, astroglia mediated the 3-HM-induced neurotrophic effect by increasing the gene expression of neurotrophic factors, which was associated with the increased acetylation of histone H3. Second, microglia participated in 3-HM-mediated neuroprotection by reducing MPTP-elicited reactive microgliosis as evidenced by the decreased production of reactive oxygen species. In summary, we show the potent neuroprotection by 3-HM in LPS and MPTP PD models investigated. With its high efficacy and low toxicity, 3-HM may be a novel therapy for PD.-Zhang, W., Shin, E-J., Wang, T., Lee, P. H., Pang, H., Wie, M-B., Kim, W-K., Kim, S-J., Huang, W-H., Wang, Y., Zhang, W., Hong, J-S., Kim, H-C. 3-Hydroxymorphinan, a metabolite of dextromethorphan, protects nigrostriatal pathway against MPTP-elicited damage both in vivo and in vitro.