(+)-pentazocine(一种sigma受体-1特异性配体)预防初级视网膜神经节细胞兴奋性毒性。

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邓Y, Thangaraju M, Prasad P, Ganapathy V, Smith SB

(+)-pentazocine(一种sigma受体-1特异性配体)预防初级视网膜神经节细胞兴奋性毒性。

《眼科科学》2007 10月;48(10):4785-94。

PubMed ID

17898305 (PubMed视图

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摘要

目的:Sigma受体(sigmaRs)是非阿片类、非苯环利定结合位点，具有强大的神经保护特性。此前，作者使用非常高浓度(1 mM)的兴奋性氨基酸谷氨酸(Glu)和同型半胱氨酸(Hcy)诱导RGC-5细胞系死亡，并证明sigmaR1配体(+)-pentazocine ((+)-PTZ)可以防止细胞死亡。本研究的目的是建立一个生理学相关的范式，以测试(+)-PTZ对视网膜神经节细胞(RGCs)的神经保护作用。方法:用免疫筛分法从1日龄小鼠视网膜中分离出原代神经节细胞(GCs)，培养3天，在(+)-PTZ (0.5, 1,3 microM)存在或不存在的情况下，暴露于10、20、25或50 microM Glu或10、25、50或100 microM Hcy中6或18小时。细胞活力用荧光素原位活力和凋亡检测法测定。通过免疫细胞化学、RT-PCR和Western blotting检测sigmaR1的表达。在(+)-PTZ存在或不存在的兴奋毒素暴露后，用差分干涉对比显微镜(DIC)检查活神经节细胞的形态外观及其过程随时间(0,3,6,18小时)的变化。结果:主要GCs均有稳健的sigmaR1表达。细胞对Glu或Hcy毒性非常敏感(用25或50 microM Glu或50或100 microM Hcy处理6小时后，细胞明显死亡)。用(+)-PTZ预处理1小时后，用25 microM Glu和(+)-PTZ共处理18小时，原发性GCs的细胞死亡显著降低:单独用25 microM Glu, 50%; 25 microM Glu/0.5 microM (+)-PTZ, 38%; 25 microM Glu/1 microM (+)-PTZ, 20%; 25 microM Glu/3 microM (+)-PTZ, 18%. Similar results were obtained with Hcy. sigmaR1 mRNA and protein levels did not change in the presence of the excitotoxins. DIC examination of cells exposed to excitotoxins revealed substantial disruption of neuronal processes; cotreatment with (+)-PTZ revealed marked preservation of these processes. The stereoselective effect of (+)-PTZ for sigmaR1 was established in experiments in which (-)-PTZ, the levo-isomer form of pentazocine, had no neuroprotective effect on excitotoxin-induced ganglion cell death. CONCLUSIONS: Primary GCs express sigmaR1; their marked sensitivity to Glu and Hcy toxicity mimics the sensitivity observed in vivo, making them a highly relevant model for testing neuroprotection. Pretreatment of cells with 1 to 3 microM (+)-PTZ, but not (-)-PTZ, affords significant protection against Glu- and Hcy-induced cell death. sigmaR1 ligands may be useful therapeutic agents in retinal diseases in which ganglion cells die.

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药物靶点

药物	目标	种类	生物	药理作用	行动
镇痛新	Sigma非阿片细胞内受体1	蛋白质	人类	是的	受体激动剂	细节