EARLY GENES AND KINDLING DEVELOPMENT

早期基因和点燃发育

• 批准号: 3084675
• 负责人: JAMES R BURKE
• 金额: $ 8.78万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-01 至 1996-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3084675
• 关键词: NMDA receptors; antibiotics; cycloheximide; dantrolene; dentate gyrus; electrostimulus; gene expression; genetic transcription; genetic translation; immunocytochemistry; in situ hybridization; kindling; laboratory rat; messenger RNA; neurons; protooncogene; second messengers

Epilepsy is a common neurologic disorder afflicting over two million people in the United States. More than 25% of patients with epilepsy continue to have seizures despite optimal therapy with conventional drugs. Kindling is an animal model of complex partial epilepsy (CPE), the adult seizure type that is most common and often refractory to treatment. Kindling refers to a phenomenon in which repeated, focal application of initially subconvulsive electrical stimulations to the brain eventually results in seizure. Each stimulation must evoke an electrographic seizure (afterdischarge (AD)). Moreover, activation of a subtype of excitatory amino acid receptor, the N-methyl-D-aspartate (NMDA) receptor, during AD is required for kindling to develop. How these transient events generate the long lasting enhanced neuronal excitability is not known. The recent discovery that AD and NMDA receptor activation can trigger increases in c-fos, an immediate early gene (IEG), has been shown to alter the expression of other genes (target genes) by acting as a transcriptional regulator. It is hypothesized that c-fos expression activates target genes which are necessary for the persistent state of neuronal excitability known as kindling. To facilitate testing this hypothesis, we have begun to study the earliest events in kindling development. We showed that a lasting increase in AD duration occurs after only 2 brief stimulation-evoked ADs. We have also demonstrated that AD-evoked c-fos expression occurs in a highly specific pattern uniformly involving the medial amygdaloid nucleus. Initial attempts to test this hypothesis will be performed by blocking transcription and translation of c-fos following AD. Additional experiments will specifically interfere with second messenger systems involved in c-fos induction. Candidate compounds for blocking NMDA- induced c-fos expression will be tested in primary neuronal culture derived from rat dentate gyrus. Those found effective will then be examined for their effect on c-fos expression and increase in AD duration in vivo. The results of these experiments should increase our understanding of the mechanism underlying the development of kindling. The ultimate goal of this line of investigation is to extend the anticipated findings to human CPE, thereby facilitating better understanding and treatment of seizures in humans.

癫痫是一种常见的神经系统疾病， 在美国的人。 超过25%的癫痫患者 尽管采用常规药物进行了最佳治疗， 毒品 Kindling是复杂部分性癫痫（CPE）的动物模型， 成人癫痫发作类型是最常见的，往往难治性 治疗 点燃是指一种现象，其中重复，重点应用的 最初是对大脑的亚惊厥性电刺激， 导致癫痫发作 每次刺激必须引起电图 癫痫发作（出院后（AD））。 此外，激活一种亚型的 兴奋性氨基酸受体，N-甲基-D-天冬氨酸（NMDA）受体， 在AD期间，需要点燃发展。 这些短暂的 事件产生的持久增强的神经元兴奋性不是 知道的 最近发现AD和NMDA受体激活可以触发 c-fos（即早基因）的增加已被证明， 改变其他基因（靶基因）的表达， 转录调节因子 推测c-fos的表达可能与 激活靶基因，这是必要的持续状态， 神经元兴奋性被称为点燃。 为了便于测试， 假设，我们已经开始研究点燃的最早期事件 发展 我们发现AD持续时间的持续增加 两次短暂刺激诱发的AD后 我们还证明 AD诱发的c-fos表达以高度特异的模式发生， 均累及内侧杏仁核 最初尝试检验这一假设将通过区组 AD后c-fos的转录和翻译。 额外 实验将专门干扰第二信使系统 参与c-fos诱导。 用于阻断NMDA的候选化合物 诱导的c-fos表达将在原代神经元培养物中测试 来源于大鼠齿状回。 那些被发现有效的， 检测它们对c-fos表达和AD持续时间增加的影响 in vivo. 这些实验的结果应该会增加我们的 理解点燃发展的潜在机制。 这条调查路线的最终目标是扩大 人类CPE的预期结果，从而促进更好地 了解和治疗人类癫痫发作。