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。的当前治疗选择 TLE是不够的，因为太多的患者患有不受控制的癫痫发作和不良副作用， 治疗内源性大麻素信号传导已被认为是突触前神经元的主要的、有效的调节剂。 神经递质释放的大脑，最近有兴趣使用外源性 从大麻植物中获得的大麻素化合物，用于控制顽固性癫痫。然而，在这方面， 大麻素控制神经元兴奋性的潜在机制还不清楚。最近我们 发现了一种全新的、功能重要的突触后机制， 控制海马锥体细胞的兴奋性。这一途径涉及强效大麻素1型 受体（CB1）介导的h电流（Ih）调节，是由 超极化激活的环核苷酸门控通道（HCN）。在这里，我们提出测试的假设 医学上相关大麻素在慢性TLE中发挥其抗惊厥作用部分是通过 整个皮质套的主细胞和中间神经元中的Ih调节。假设将被检验 在TLE的实验小鼠模型中，评估将在体外和体内进行 电生理学，特定亚细胞中细胞类型特定的纳米级超分辨率分子成像 以高通量和数据驱动的超级计算能力识别出的锥体细胞和中间神经元的轮廓 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认识的重大进展 慢性癫痫的机制，并将有助于开发基于大麻的抗癫痫治疗 战略布局