STATUS EPILEPTICUS REORGANIZES CANNABINOID RECEPTORS

癫痫持续状态重组大麻素受体

• 批准号: 7342830
• 负责人: ROBERT John DELORENZO
• 金额: $ 32.59万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-24 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7342830
• 关键词: Acute; Agonist; Animal Behavior; Animals; Antibodies; Anticonvulsants; Brain; Cannabinoids; Clinical; Condition; DNA Sequence Rearrangement; Development; Endocannabinoids; Epilepsy; Event; Figs - dietary; Frequencies; G-Protein-Coupled Receptors; GTP-Binding Proteins; Glutamates; Goals; Hippocampus (Brain); Hour; Immunohistochemistry; Injury; Label; Laboratories; Lead; Life; Long-Term Effects; Mediating; Memory; Memory Loss; Memory impairment; Modeling; Morbidity - disease rate; Nature; Nerve; Neuraxis; Neurological emergencies; Neurons; Pilocarpine; Proteins; Rattus; Receptor Activation; Recurrence; Regulation; Research; Research Personnel; Role; Seizures; Status Epilepticus; System; Testing; Therapeutic Intervention; Time; Week; Western Blotting; cannabinoid receptor; gamma-Aminobutyric Acid; immunoreactivity; insight; long term memory; man; mind control; mortality; neuronal excitability; neurotransmitter release; novel; novel therapeutics; programs; protein activation; receptor; receptor binding; receptor coupling; receptor expression; receptor function; research study

The central nervous system cannabinoid receptor (CB1) is one of the most abundant G-Protein coupled receptors in brain and mediates many of the effects of cannabinoid substances on neuronal function. Our laboratory has demonstrated that one hour of prolonged seizures (status epilepticus, SE) in the pilocarpine model of SE produces a long-term reorganization in the expression of the CB1 receptor ahd that these changes in CB1 expression persist for essentially the life of the animal. SE is a major neurological emergency that has a high mortality and morbidity, including acquired epilepsy (AE) and memory deficits. Our preliminary results suggest that the SE induced persistent changes in expression and function of the CB1 receptor are reorganized to be decreased on inhibitory and increased on excitatory nerve terminals, indicating that this long-term plasticity change may represent a significant modulator of neuronal function. This research effort will test the Central Hypothesis that SE (acute event) causes long lasting reorganization in the expression of the CB1 that results in persistent changes in the overall function of the endocannabinoid system, causing a greater inhibition of glutamate release and a smaller inhibition of GABA release in epileptic compared to control brain and ultimately in changes in the behavior of the animal, as manifested by memory deficits. To test this hypothesis we will conduct the following specific aims: Aim 1. Evaluate whether SE alone or with the development of AE causes persistent rearrangements in the immunoreactivity and expression of the CB1 receptor in brain and evaluate the time course of these changes; Aim 2. Determine if the SE induced changes in CB1 receptor expression are associated with corresponding changes in CB1 function as determined by G-protein activation, receptor binding and regulation of neurotransmiter release; Aim 3. Determine the association of SE induced CB1 receptor reorganization on excitatory and inhibitory nerve terminals; Aim 4. Determine the effects of long-term plasticity changes in CB1 expression and function on the long-term memory effects observed after SE. The goal of this research is to determine if changes in the expression of the CB1 system following SE contribute to altered neuronal excitability and memory deficits produced by SE. These studies may lead to the development of novel therapeutic interventions to reverse the effects of SE on AE and memory loss by pharmacologically regulating the endogenous CB1system.

中枢神经系统大麻素受体(CB1)是最丰富的G蛋白偶联蛋白之一 大脑中的受体，并介导大麻素类物质对神经元功能的许多影响。我们的 实验室已经证明，长达一小时的癫痫发作(癫痫持续状态，SE)在匹罗卡品中 SE模型对CB1受体的表达产生长期的重组，这些 CB1表达的变化基本上会持续到动物的一生。SE是一种主要的神经学疾病 具有高死亡率和高发病率的紧急情况，包括获得性癫痫(AE)和记忆障碍。 我们的初步结果表明，SE诱导了持续的表达和功能变化 在兴奋性神经末梢上，CB1受体重组为抑制减少而增加， 这表明这种长期的可塑性变化可能代表了神经元功能的一个重要调节器。 这项研究工作将检验中心假说，即SE(急性事件)会导致长期重组 在CB1的表达中导致内源性大麻素整体功能的持续变化 对谷氨酸释放的抑制作用较强，对GABA释放的抑制作用较小。 癫痫与对照大脑相比，最终改变了动物的行为，表现为 记忆缺陷。为了验证这一假设，我们将进行以下具体目标：目标1.评估 Se单独或与AE的发展一起导致免疫反应的持续性重排和 CB1受体在脑内的表达，并评估这些变化的时间进程；目的2.确定 SE诱导的CB1受体表达的变化与CB1的相应变化有关 功能由G蛋白激活、受体结合和神经递质释放调节决定； 目的3.确定SE诱导的CB1受体重组与兴奋性和抑制性的关系 神经末梢；目的4.确定CB1表达和功能的长期可塑性变化的影响 关于SE后观察到的长期记忆效应。这项研究的目标是确定是否发生了 癫痫发作后CB1系统的表达有助于神经元兴奋性和记忆障碍的改变 由SE生产。这些研究可能导致开发新的治疗干预措施来逆转 SE通过对内源性CB1系统的药理调节对AE和记忆丧失的影响