EFFECTS OF SODIUM PYRITHIONE ON SPINAL MOTONEURONS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 目的：研究吡硫酮对猕猴细胞内钙离子浓度的影响。 以吡硫酮钠的形式给予吡硫酮(PT)和终末血清代谢物2-甲磺酰基吡啶(2-MSP)，观察它们对猴运动神经元细胞内钙离子浓度的影响。PT使猴运动神经元细胞内钙离子持续增加。这种增加的EC_(50)为10M，这种作用被钙释放激活的钙通道拮抗剂SKF 96365所阻断。这些数据表明，PT通过开放非电压门控钙离子通道来增加膜对钙的通透性。先前的研究表明，PT也能引起大鼠运动神经元细胞内钙的增加，但EC50为0.31M。2-MSP对这两种动物的细胞内钙离子都没有诱导增加的作用。 PT对大鼠有神经毒性作用。在猴子身上没有观察到这种效应，即使在剂量水平上明显高于在老鼠身上引起这种效应的剂量。这项研究为一种可能的生化机制提供了证据，该机制可以解释给予PT后大鼠与猴子相比的选择性神经毒性。这项研究使用了WNPRC动物服务中心。 这项工作得到了耶鲁大学的分包合同的支持，得到了Olin公司的支持(1999-2000年)，并在本报告所述期间出版了一本出版物。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Objective: To examine the effects of pyrithione on intracellular calcium concentrations in monkeys. Pyrithione (PT), administered as sodium pyrithione, and the terminal serum metabolite, 2-methylsulfonyl pyridine (2-MSP), were tested for their potential to induce an increase in intracellular calcium in motor neurons from the monkey. PT produces a sustained increase in intracellular calcium in monkey motor neurons. The EC50 for this increase is 10 ¿M. This effect is blocked by SKF 96365, an antagonist of calcium-release-activated calcium channels. The data suggest that PT increases membrane permeability to calcium by opening a non-voltage-gated calcium ion channel. Previous investigation showed that PT also produces an increase in intracellular calcium in motor neurons from the rat, but the EC50 is 0.31 ¿M. 2-MSP is without effect on inducing an increase in intracellular neuronal calcium in either species. PT produces neurotoxicity to the rat. This effect has not been observed in the monkey even when administered at dose levels significantly higher than that which causes the effect in rats. This investigation provides evidence for a probable biochemical mechanism that could explain the selective neurotoxicity in rats compared to monkeys following administration of PT. This research used WNPRC Animal Services. This work was supported by a subcontract from Yale University supported by OLIN Corporation (1999-2000), and a publication has resulted during this reporting period.