STATUS EPILEPTICUS REORGANIZES CANNABINOID RECEPTORS

癫痫持续状态重组大麻素受体

基本信息

批准号：
7994399
负责人：
ROBERT John DELORENZO
金额：
$ 32.27万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-01-24 至 2011-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7994399
关键词：
Acute Agonist Animal Behavior Animals Antibodies Anticonvulsants Brain Cannabinoids Clinical 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 Time Western Blotting cannabinoid receptor gamma-Aminobutyric Acid immunoreactivity insight long term memory man mind control mortality neuronal excitability neurotransmitter release novel novel therapeutic intervention programs protein activation receptor receptor binding receptor coupling receptor expression receptor function research study

项目摘要

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蛋白之一大脑中的受体并介导大麻素物质对神经元功能的许多影响。我们的实验室表明，毛果石中的长时间癫痫发作（癫痫持续状态，SE） SE模型在CB1受体AHD的表达中产生了长期的重组 CB1表达的变化基本上是动物的生命。 SE是主要神经系统紧急死亡率和发病率很高，包括获得的癫痫（AE）和记忆缺陷。我们的初步结果表明，SE诱导了持续的表达和功能变化重新组织CB1受体以减少抑制性，并在兴奋性神经末端增加，表明这种长期可塑性变化可能代表神经元功能的重要调节剂。这项研究工作将检验中心假设，即SE（急性事件）会导致持久的重组在CB1的表达中，导致内源性大麻素的整体功能持续变化系统，导致更大的抑制谷氨酸释放和较小的GABA释放抑制与对照大脑相比，癫痫症以及最终在动物行为的变化中，这表明内存不足。为了检验这一假设，我们将执行以下特定目的：目标1。单独或随着AE的发展会导致免疫反应性的持续重排和 CB1受体在大脑中的表达并评估这些变化的时间过程；目标2。确定是否 SE诱导的CB1受体表达的变化与CB1的相应变化有关通过G蛋白激活，受体结合和神经传递释放的调节确定的功能； AIM 3。确定SE诱导的CB1受体在兴奋性和抑制性上的关联神经末端；目标4。确定CB1表达和功能长期可塑性变化的影响在SE之后观察到的长期记忆效应。这项研究的目的是确定 SE后CB1系统的表达有助于改变神经元兴奋性和记忆缺陷由se产生。这些研究可能导致新的治疗干预措施的发展通过药理调节内源性CB1SYSTEM，SE对AE和记忆丧失的影响。