Tropisetron as a neuroprotective agent against glutamate-induced excitotoxicity and mechanisms of action.
Tropisetron as a neuroprotective agent against glutamate-induced excitotoxicity and mechanisms of action.
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DOI：
10.1016/j.neuropharm.2013.05.020
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发表时间：
2013-10
影响因子：
4.7
通讯作者：
Linn CL
中科院分区：
文献类型：
--
作者：
Swartz MM;Linn DM;Linn CL
本研究的目的是确定托烷司琼对视网膜神经节细胞（RGCs）的神经保护作用，以及探讨与α 7 nAChR诱导的神经保护相关的可能机制。使用两步淘选技术从所有其他视网膜组织中分离成年猪RGC。分离后，将RGCs在对照未处理条件下培养3天，在500 μM谷氨酸存在下诱导兴奋性毒性，并在谷氨酸之前应用托烷司琼诱导神经保护。与对照条件相比，500 μM谷氨酸盐使RGC存活率平均降低62%。然而，与对照组相比，在谷氨酸盐之前用100 nM托烷司琼预处理的RGC使细胞存活率平均增加至105%。使用α 7 nAChR拮抗剂MLA（10 nM）进行的抑制研究支持以下假设：托烷司琼是一种有效的神经保护剂，可对抗谷氨酸诱导的兴奋性毒性;由α7 nAChR激活介导。进行ELISA研究以确定在托烷司琼治疗后，通常与兴奋性毒性和神经保护相关的信号级联是否上调或下调。托烷司琼对pAkt水平没有明显影响，但显著降低了与兴奋性毒性相关的p38 MAPK水平，从平均15 ng/ml降至6 ng/ml。另一种与神经保护相关的机制涉及NMDA受体的内化。双标记免疫细胞化学和电生理研究提供了进一步的证据，托烷司琼引起的NMDA受体亚单位的内化。这项研究的结果表明，托烷司琼可能是一种有效的治疗药物，用于治疗中枢神经系统退行性疾病，涉及兴奋性毒性。
The objective of this study was to determine the neuroprotective role of tropisetron on retinal ganglion cells (RGCs) as well as to explore the possible mechanisms associated with alpha7 nAChR-induced neuroprotection. Adult pig RGCs were isolated from all other retinal tissue using a two-step panning technique. Once isolated, RGCs were cultured for 3 days under control untreated conditions, in the presence of 500 μM glutamate to induce excitotoxicity, and when tropisetron was applied before glutamate to induce neuroprotection. 500 μM glutamate decreased RGC survival by an average of 62% compared to control conditions. However, RGCs pretreated with 100 nM tropisetron before glutamate increased cell survival to an average of 105% compared to controls. Inhibition studies using the alpha7 nAChR antagonist, MLA (10 nM), support the hypothesis that tropisetron is an effective neuroprotective agent against glutamate-induced excitotoxicity; mediated by α7 nAChR activation. ELISA studies were performed to determine if signaling cascades normally associated with excitotoxicity and neuroprotection were up- or down-regulated after tropisetron treatment. Tropisetron had no discernible effects on pAkt levels but significantly decreased p38 MAPK levels associated with excitotoxicity from an average of 15 ng/ml to 6 ng/ml. Another mechanism shown to be associated with neuroprotection involves internalization of NMDA receptors. Double-labeled immunocytochemistry and electrophysiology studies provided further evidence that tropisetron caused internalization of NMDA receptor subunits. The findings of this study suggest that tropisetron could be an effective therapeutic agent for the treatment of degenerative disorders of the central nervous system that involves excitotoxicity.
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影响因子：
4.7
作者：
Cook DR;Gleichman AJ;Cross SA;Doshi S;Ho W;Jordan-Sciutto KL;Lynch DR;Kolson DL
通讯作者：
Kolson DL
影响因子：
2.5
作者：
COHEN, ED;ZHOU, ZJ;FAIN, GL
通讯作者：
FAIN, GL
影响因子：
5.5
作者：
Davis, SF;Linn, CL
通讯作者：
Linn, CL
影响因子：
2.9
作者：
Kaneko, S;Maeda, T;Kimura, J
通讯作者：
Kimura, J
影响因子：
4.8
作者：
Kihara, T;Shimohama, S;Akaike, A
通讯作者：
Akaike, A