NEUROPROTECTIVE ANTAGONISTS OF KAINATE NEUROTOXICITY

描述：(改编自申请人的摘要)。病理性的 神经递质L-谷氨酸受体过度兴奋 被认为是导致神经细胞死亡或退化的原因 出现在许多急性和慢性神经疾病中。这样做的目的是 该项目是开发一种限制神经元损伤的药物治疗方法 在兴奋毒性刺激谷氨酸的红藻氨酸亚类之后 感受器。来自动物研究的证据表明，这种制剂可能是 在预防延迟性神经元变性方面非常有效 发生在全脑缺血之后。 其目的是测试大量化合物的能力 抑制红藻氨酸刺激的培养大鼠摄取45-钙离子 皮质神经元。放射性配基结合和电生理研究 将被用来定义活性化合物的作用机理。 有希望的分子将在红藻氨酸的体外模型中进行测试 神经毒性和全脑缺血的活体模型。这个 该方法旨在识别通过多个 红藻氨酸受体竞争抑制之外的机制 谷氨酸识别位点。重点将放在可能通过以下途径发挥作用的分子上 阻断与海人藻酸受体相关的离子通道； 构成了一类全新的药理制剂。

DESCRIPTION: (Adapted from the Applicant's Abstract). Pathological overstimulation of receptors for the neurotransmitter L-glutamate is believed to contribute to the death or degeneration of nerve cells that occurs in many acute and chronic neurological disorders. The goal of this project is to develop a drug treatment which will limit neuronal damage subsequent to excitotoxic stimulation of the kainate subclass of glutamate receptors. Evidence from animal studies suggests that such agents may be singularly effective in preventing the delayed neuronal degeneration that occurs following global cerebral ischemia. The intent is to test a large number of compounds for their ability to inhibit specific kainate-stimulated 45-Ca++ uptake into cultured rat cortical neurons. Radioligand binding and electrophysiological studies will be used to define the mechanism of action of active compounds. Promising molecules will be tested in an in vitro model of kainate neurotoxicity and an in vivo model of global cerebral ischemia. The approach is designed to identify compounds that act through a number of mechanisms in addition to competitive inhibition at the kainate receptor's glutamate recognition site. The focus will be on molecules that may act by blocking the ion channel associated with the kainate receptor; these would constitute a completely novel class of pharmacological agents.