EFFECTS OF SODIUM PYRITHIONE ON SPINAL MOTONEURONS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 目的：研究吡嘧磺隆对猴细胞内钙离子浓度的影响。 检测了以吡嘧磺啶钠形式给药的吡嘧磺啶（PT）和终末血清代谢产物2-甲磺酰基吡啶（2-MSP）诱导猴运动神经元细胞内钙升高的潜力。PT在猴运动神经元中产生细胞内钙的持续增加。 这种增加的EC 50为10 μ M。 这种作用被SKF 96365阻断，SKF 96365是钙释放激活钙通道的拮抗剂。 这些数据表明，PT通过打开非电压门控钙离子通道来增加膜对钙的渗透性。先前的研究表明，PT也会导致大鼠运动神经元细胞内钙的增加，但EC 50为0.31 μ M。 2-MSP在两种动物中均不诱导细胞内神经元钙的增加。 PT对大鼠产生神经毒性。 在猴中未观察到该效应，即使给药剂量显著高于在大鼠中引起该效应的剂量水平。 本研究为可能的生化机制提供了证据，该机制可以解释PT给药后大鼠与猴相比的选择性神经毒性。这项研究使用WNPRC动物服务。 这项工作得到了耶鲁大学的一个研究项目的支持，该项目得到了OLIN公司的支持（1999-2000年），并在本报告所述期间出版了一份出版物。

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.