MOBILIZATION OF DANTROLENE-SENSITIVE INTRACELLULAR CALCIUM POOLS IS INVOLVED IN THE CYTOTOXICITY INDUCED BY QUISQUALATE AND N-METHYL-D-ASPARTATE BUT NOT BY 2-AMINO-3-(3-HYDROXY-5-METHYLISOXAZOL-4-YL)PROPIONATE AND KAINATE IN CULTURED CEREBRAL CORTICAL-NEURONS
MOBILIZATION OF DANTROLENE-SENSITIVE INTRACELLULAR CALCIUM POOLS IS INVOLVED IN THE CYTOTOXICITY INDUCED BY QUISQUALATE AND N-METHYL-D-ASPARTATE BUT NOT BY 2-AMINO-3-(3-HYDROXY-5-METHYLISOXAZOL-4-YL)PROPIONATE AND KAINATE IN CULTURED CEREBRAL CORTICAL-NEURONS
复制标题
DOI：
10.1073/pnas.89.7.2590
复制
发表时间：
1992-04-01
影响因子：
11.1
通讯作者：
SCHOUSBOE, A
中科院分区：
文献类型：
--
作者：
FRANDSEN, A;SCHOUSBOE, A
通过对大脑皮层神经元的原代培养，已经证明了抗高温药物丹曲lene对兴奋性氨基酸半qualate （QA）和n -甲基- d -天冬氨酸（NMDA）诱导的细胞毒性有保护作用，而对kainate （KA）或2-氨基-3-（3-羟基-5-甲基异恶唑-4-酰基）丙酸盐（AMPA）介导的细胞损伤没有影响。同时，研究表明，KA和AMPA主要通过内流增加细胞内游离钙（[Ca2+]i）的浓度，而NMDA和QA刺激的[Ca2+]i的增加主要是由细胞内储存的Ca2+释放引起的，对NMDA来说，这似乎至少部分是由Ca2+内流介导的。根据对细胞毒性的影响，丹曲林阻断了QA和NMDA诱导的[Ca2+]i的增加，而KA和AMPA诱导的增加不受影响。2-氨基-3-[3-（羧基甲氧基）-5-甲基异恶唑-4-基]丙酸盐，在毒性方面是一种选择性KA拮抗剂，仅将KA刺激的[Ca2+]i的增加降低了30%，这可能表明[Ca2+]i的升高并不是KA诱导细胞毒性的唯一因素。另一方面，本研究强调了Ca2+对一些兴奋性氨基酸（谷氨酸、NMDA和QA）诱导的细胞毒性的重要性，并支持了目前的建议，即多种机制在起作用，甚至涉及钙稳态。由于兴奋性氨基酸诱导的细胞毒性被认为与神经病理状况（如缺血）有关，因此丹曲林可能具有治疗意义。
By using primary cultures of cerebral cortical neurons, it has been demonstrated that the antihyperthermia drug dantrolene protects against cytotoxicity induced by the excitatory amino acids quisqualate (QA) and N-methyl-D-aspartate (NMDA), whereas no effect was observed on cell damage mediated by kainate (KA) or 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionate (AMPA). In parallel it was shown that KA and AMPA increased the concentration of intracellular free calcium ([Ca2+]i) mainly by influx, whereas the increase in [Ca2+]i stimulated by NMDA and QA predominantly was caused by release of Ca2+ from intracellular stores, which for NMDA seemed to be mediated at least partly by Ca2+ influx. In accordance with the effects on cytotoxicity, dantrolene blocked the increase in [Ca2+]i elicited by QA and NMDA leaving the increase induced by KA and AMPA unaffected. The finding that 2-amino-3-[3-(carboxymethoxy)-5-methylisoxazol-4-yl]propionate, which regarding toxicity is a selective KA antagonist, only reduced the KA-stimulated increase in [Ca2+]i by 30% may suggest that the elevation of [Ca2+]i is not the only element in KA-induced cytotoxicity. On the other hand, the present study underlines the importance of Ca2+ for cytotoxicity induced by some excitatory amino acids (glutamate, NMDA, and QA) and supports the current proposal that multiple mechanisms are operating, even concerning calcium homeostasis. Because excitatory amino acid-induced cytotoxicity is thought to be involved in neuropathological conditions such as ischemia, it is possible that dantrolene might be of therapeutic interest.