Neurosteroid Regulation of Seizures

神经类固醇对癫痫发作的调节

• 批准号: 9094698
• 负责人: Jaideep Kapur
• 金额: $ 34.56万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9094698
• 关键词: AMPA Receptors; Animals; Anticonvulsants; Biochemical; Biological; Brain; Cell membrane; Chronic; Data; Disease; Effectiveness; Electroconvulsive Shock; Electroencephalography; Electrophysiology (science); Epilepsy; Estrogens; Failure; Feedback; Female; Frequencies; GABA-A Receptor; Gene Expression; Glutamates; Goals; Health; Hippocampus (Brain); Injection of therapeutic agent; Knockout Mice; Measures; Mediating; Menstrual cycle; Modeling; Monitor; Multicenter Trials; Neurons; Nuclear Receptors; Ovulation; Patients; Pentylenetetrazole; Phase; Phase III Clinical Trials; Progesterone; Progesterone Receptors; Rattus; Recurrence; Regulation; Resolution; Role; Seizures; Serum; Synapses; Synaptic Transmission; Techniques; Temporal Lobe Epilepsy; Testing; Time; Withdrawal; Woman; corpus luteum; effective therapy; experience; granule cell; hippocampal pyramidal neuron; improved; innovation; insight; neurosteroids; new therapeutic target; novel; patch clamp; placebo controlled study; postsynaptic; protein expression; receptor

DESCRIPTION (provided by applicant): Women constitute a majority of the patients with epilepsy, and many of them experience a cyclical exacerbation of seizures related to periodic changes in serum progesterone and estrogen levels during the menstrual cycle. This condition is called catamenial epilepsy. Currently, there are no scientifically tested effective treatments fr catamenial exacerbation. In a multi-center trial of progesterone therapy for catamenial epilepsy failed to show efficacy. We have developed a model of chronic temporal lobe epilepsy in female rats and will use this model to study the effect of prolonged progesterone exposure on excitatory and inhibitory synaptic transmission and on seizure frequency and intensity. Specifically, we will test our hypothesis that a chronic elevation of progesterone in female animals diminishes the anticonvulsant action of progesterone by enhancing AMPA receptor-mediated glutamatergic synaptic transmission and suppressing GABAA receptor mediated synaptic transmission. In Aim 1, we will determine the impact of progesterone treatment on glutamatergic synaptic transmission on hippocampal principal neurons in naive and epileptic female rats using a combination of patch clamp electrophysiology and analysis of the expression of the AMPA receptor subunits via both biochemical and immunohistochemical techniques. In Aim 2, we will determine the impact of progesterone treatment on GABAergic synaptic transmission on hippocampal principal neurons of naive and epileptic female rats with a similar combination of techniques as in aim 1. In Aim 3, we will determine the role of progesterone receptors in progesterone-induced tolerance during progesterone treatment and withdrawal. These studies will provide novel insights into the mechanisms of catamenial epilepsy. These studies could explain the mechanism of failure progesterone therapy for treatment of catamenial epilepsy and potentially identify novel therapeutic targets for the treatment of catamenial exacerbation of seizures.

描述（由申请人提供）：女性构成大多数癫痫患者，其中许多患者经历了与月经周期中血清孕酮和雌激素水平周期性变化有关的癫痫发作的周期性加剧。这种情况称为死亡癫痫。目前，尚无科学测试的有效治疗方法，可见恶化。在一项对孕酮治疗的多中心试验中，可见癫痫的疗效未能表现出疗效。我们已经开发了雌性大鼠慢性颞叶癫痫的模型，并将使用该模型来研究长时间孕酮对兴奋性和抑制性突触传播以及癫痫发作频率和强度的影响。具体而言，我们将测试我们的假设，即雌性动物中孕酮的慢性升高通过增强AMPA受体介导的谷氨酸能突触传递和抑制GABAA受体介导的突触传播，从而减少了孕酮的抗惊厥作用。在AIM 1中，我们将通过生物学和免疫组织化学技术通过斑块夹夹电生理学的组合来确定孕酮治疗对谷氨酸能突触传播对天真和癫痫雌性大鼠海马主要神经元的影响，并分析AMPA受体亚基的表达。在AIM 2中，我们将确定孕激素治疗对GABA能突触传播的影响对幼稚和癫痫性雌性大鼠的海马主要神经元，其技术与AIM 1相似的技术组合组合。在AIM 3中，我们将确定孕激素受体在孕酮治疗过程中孕酮诱导的耐受性和戒断过程中的作用。这些研究将提供有关癫痫机制的新见解。这些研究可以解释孕激素治疗治疗可见癫痫的机制，并可能识别出新的治疗靶标，以治疗癫痫发作的严重恶化。