EARLY GENES AND KINDLING DEVELOPMENT

早期基因和点燃发育

• 批准号: 3084673
• 负责人: JAMES R BURKE
• 金额: $ 7.68万
• 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/3084673
• 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，困扰着超过 200 万人 在美国的人。 超过25%的患者患有癫痫 尽管采用常规治疗进行了最佳治疗，但仍继续癫痫发作 药物。 Kindling是复杂部分性癫痫（CPE）的动物模型， 最常见且通常难治的成人癫痫类型 治疗。 点燃是指重复、集中应用 最初对大脑进行亚惊厥性电刺激，最终 结果导致癫痫发作。 每次刺激都必须引起电描记 癫痫发作（出院后（AD））。 此外，激活一个亚型 兴奋性氨基酸受体，N-甲基-D-天冬氨酸（NMDA）受体， AD期间需要火种的发展。 这些瞬态如何 事件不会产生持久的神经元兴奋性增强 已知。 最近发现AD和NMDA受体激活可以触发 c-fos（一种即早基因（IEG））的增加已被证明可以 通过充当 转录调节因子。 推测 c-fos 表达 激活持久状态所必需的目标基因 神经元的兴奋性称为点燃。 为了方便测试这个 假设，我们已经开始研究点燃中最早的事件 发展。 我们发现 AD 持续时间会持续增加 仅在 2 个短暂的刺激诱发 AD 后。 我们还展示了 AD 诱发的 c-fos 表达以高度特异性的模式发生 一致涉及内侧杏仁核。 检验这一假设的初步尝试将通过分块进行 AD 后 c-fos 的转录和翻译。 额外的 实验将专门干扰第二信使系统 参与c-fos诱导。 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进行测试 源自大鼠齿状回。 那些被发现有效的将被 检查它们对 c-fos 表达和 AD 持续时间增加的影响 体内。 这些实验的结果应该会增加我们的 了解引火物发展的机制。 这一调查的最终目标是扩大 人类 CPE 的预期发现，从而促进更好 了解和治疗人类癫痫发作。