EFFECTS OF ANTICONVULSANTS ON GLIAL ION TRANSPORT

抗惊厥药对胶质离子运输的影响

基本信息

批准号：
3404324
负责人：
H Steve WHITE
金额：
$ 11.6万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
1985
资助国家：
美国
起止时间：
1985-04-01 至 1993-11-30
项目状态：
已结题

项目摘要

The six specific aims of this competing renewal are designed to determine the effects of anticonvulsant and convulsant drugs on ion-transport processes, acid-base homeostasis and electrophysiology of astrocytes in tissue culture. These studies are designed to test the hypothesis that anticonvulsants in addition to their effects on neurons and synapses also stimulate astrocytic regulatory processes, and in so doing provide the CNS with an enhanced ability to regulate electrolyte, acid-base and neurotransmitter homeostasis within the CNS, thereby limiting seizure activity. Specifically, primary cultures of mouse cerebral cortical astrocytes will be acutely and chronically exposed to therapeutic concentrations of the prototype anticonvulsants phenytoin, carbamazepine, valproate, diazepam, ethosuximide, acetazolamide, and to the calcium channel blocker flunarizine. The effects of the above treatments on; the uptake, steady-state distribution and release of 22 Na+, 42 K+, 36 Cl- and 45 Ca++; the intracellular concentration of Na+, K+, Cl- and H+; the transport enzymes Na+/K+, Ca++/Mg++ -ATPase and the glial specific enzyme carbonic anhydrase; the electrophysiology (membrane potential, resistance and conductance); and the uptake of the neurotransmitter substance glutamate will be assessed. In addition, studies to characterize the effect of the receptor specific convulsants N-methyl-d-aspartate, and entylenetetrazol on the above parameters in untreated and anticonvulsant-treated (acute and chronic) astrocytes will also be conducted. The focus of this application does not differ significantly from that of the initial grant. Such an analysis is important for if a thorough understanding of the mechanisms of these drugs is to be obtained, a comprehensive examination of their effects on astrocytes as well as neurons must be undertaken. These studies will also enhance our understanding of the seizure process. Thus, through an increased understanding of the mechanisms of the currently available anticonvulsant drugs and the processes underlying seizure disorders, drugs with greater selectively and fewer adverse effects can be developed.

该竞争更新的六个具体目标旨在确定抗惊厥药和抽搐药物对离子传输的影响过程，酸碱稳态和星形胶质细胞的电生理学组织培养。这些研究旨在检验以下假设除了对神经元和突触的影响外，抗惊厥药还刺激星形胶质细胞调节过程，因此进行中枢神经系统具有增强的调节电解质，酸碱和中枢神经系统内的神经递质稳态，从而限制了癫痫发作活动。具体而言，小鼠脑皮质的一级培养物星形胶质细胞将急性和长期暴露于治疗中原型抗惊厥药的浓度，卡马西平，卡马西平，丙丙酸酯，地西ep，乙糖酰亚胺，乙唑胺和钙通道阻滞剂氟纳嗪。上述治疗的影响；这吸收，稳态分布和22 Na+，42 K+，36 Cl-和36 Cl-和 45 Ca ++; Na+，K+，Cl-和H+的细胞内浓度；这转运酶Na+/K+，Ca ++/mg ++ -ATPase和Glial特异性酶碳酸酐酶；电生理学（膜电位，电阻和电导）；和神经递质物质的摄取将评估谷氨酸。此外，研究效果的研究受体特异性抽搐剂N-甲基-D-天冬氨酸和在未处理和抗惊厥药治疗（急性和慢性）星形胶质细胞也将是实施。该应用程序的重点与最初的赠款。这样的分析对于彻底的了解这些药物的机制将得到获得全面检查其对星形胶质细胞和神经元的影响必须进行。这些研究还将增强我们对癫痫发作过程。因此，通过对当前可用的抗惊厥药的机制和癫痫发作疾病的基础过程，有选择性更大的药物以及可以开发出更少的不良影响。