Cannabinoid control of epilepsy

大麻素控制癫痫

• 批准号: 9899338
• 负责人: IVAN SOLTESZ
• 金额: $ 35.04万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899338
• 关键词: 2-arachidonylglycerol; Adult; Agonist; Anticonvulsants; Antiepileptic Agents; Area; Attenuated; Brain; CNR1 gene; Cannabidiol; Cannabinoids; Cannabis; Cells; Chronic; Computer Models; Data; Development; Disease; Electroencephalography; Electrophysiology (science); Endocannabinoids; Epilepsy; Frequencies; Glutamates; Hippocampus (Brain); Image; Imaging Techniques; In Vitro; Injections; Interneurons; Intervention; Intractable Epilepsy; Ion Channel; Marijuana; Mediating; Medical; Modeling; Monitor; Mus; Nature; Neocortex; Neurons; Pathway interactions; Patients; Pattern; Pharmacotherapy; Phytochemical; Pilocarpine; Plants; Population; Pyramidal Cells; Receptor Signaling; Regulation; Resistance; Resolution; Seizures; Signal Transduction; Synapses; Syndrome; Temporal Lobe Epilepsy; Testing; Tetrahydrocannabinol; Treatment Side Effects; base; cannabinoid drug; cell type; cyclic-nucleotide gated ion channels; entorhinal cortex; exogenous cannabinoid; gamma-Aminobutyric Acid; in vivo; interest; kainate; molecular imaging; mouse model; nanoscale; network models; neuronal excitability; neurotransmission; neurotransmitter release; novel; patch clamp; postsynaptic; presynaptic; restoration; treatment strategy

Temporal lobe epilepsy (TLE) is the most common epilepsy syndrome in adults. Current treatment options for TLE are inadequate, as too many patients suffer from uncontrolled seizures and from negative side effects of treatment. Endogenous cannabinoid signaling has been recognized as a major, potent regulator of presynaptic neurotransmitter release in the brain, and there has been a recent surge of interest in using exogenous cannabinoid compounds obtained from the marijuana plant for the control of intractable epilepsy. However, mechanisms underlying cannabinoid control of neuronal excitability are not well understood. Recently, we discovered a fundamentally new, functionally significant, postsynaptic mechanism by which cannabinoids control excitability in hippocampal pyramidal cells. This pathway involves the potent, cannabinoid type 1 receptor- (CB1) mediated modulation of the h-current (Ih), a key regulator of dendritic excitability generated by hyperpolarization-activated, cyclic nucleotide-gated channels (HCNs). Here we propose to test the hypothesis that that medically relevant cannabinoids exert their anti-convulsant actions in chronic TLE partly through the regulation of Ih in principal cells and interneurons throughout the cortical mantle. The hypothesis will be tested in experimental mouse models of TLE, and the assessment will be carried out with in vitro and in vivo electrophysiology, cell-type-specific nanoscale super-resolution molecular imaging in specific subcellular profiles of identified pyramidal cells and interneurons at a high throughput, and data-driven supercomputational network modeling. We anticipate that defining the functional consequences of a novel cannabinoid regulator of neuronal excitability in chronic epilepsy will lead to significant advances in the understanding of disease mechanisms in chronic epilepsy, and will aid the development of cannabis-based anti-epileptic treatment strategies.

颞叶癫痫(TLE)是成人最常见的癫痫综合征。目前的治疗方案 TLE是不够的，因为太多的患者患有失控的癫痫发作和 治疗。内源性大麻素信号被认为是突触前的主要、有效的调节因素 大脑中神经递质的释放，最近人们对使用外源激素的兴趣激增 从大麻植物中获得的用于控制顽固性癫痫的大麻类化合物。然而， 大麻素控制神经元兴奋性的机制还不是很清楚。最近，我们 发现了一种全新的、具有重要功能的突触后机制，通过这种机制，大麻类物质 控制海马区锥体细胞兴奋性。这一途径涉及强效的大麻素1型 受体(CB1)介导的H-电流(Ih)的调制，h-电流是树突状细胞兴奋性的关键调节因子 超极化激活的环核苷酸门控通道(HCN)。在这里，我们建议检验这一假设 与医学相关大麻类物质在慢性TLE中发挥抗惊厥作用的部分原因是通过 Ih在整个皮质外套膜的主细胞和中间神经元中的调节。这一假设将得到检验。 在实验性小鼠TLE模型中，将进行体外和体内的评估 电生理学、特定细胞类型的纳米级超分辨分子成像 高通量识别的锥体细胞和中间神经元的轮廓，以及数据驱动的超级计算 网络建模。我们预计，定义一种新的大麻素调节剂的功能后果 慢性癫痫的神经元兴奋性将导致对疾病的理解的重大进步 慢性癫痫的机制，并将有助于开发以大麻为基础的抗癫痫治疗 战略。