Cannabinoid control of epilepsy

大麻素控制癫痫

• 批准号: 10115138
• 负责人: IVAN SOLTESZ
• 金额: $ 35.08万
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10115138
• 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，因为太多患者患有不受控制的癫痫发作和副作用 治疗。内源性大麻素信号传导已被认为是突触前的主要有效调节因子 大脑中神经递质的释放，最近人们对使用外源性神经递质的兴趣激增 从大麻植物中提取的大麻素化合物，用于控制顽固性癫痫。然而， 大麻素控制神经元兴奋性的机制尚不清楚。最近，我们 发现了一种全新的、具有重要功能的突触后机制，大麻素通过该机制 控制海马锥体细胞的兴奋性。该途径涉及有效的 1 型大麻素 受体 (CB1) 介导的 h 电流 (Ih) 调节，h 电流 (Ih) 是树突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假设 医学上相关的大麻素在慢性 TLE 中发挥抗惊厥作用的部分原因是 整个皮质套主细胞和中间神经元中 Ih 的调节。假设将被检验 在 TLE 实验小鼠模型中进行，评估将在体外和体内进行 电生理学、特定亚细胞中的细胞类型特异性纳米级超分辨率分子成像 高通量和数据驱动的超级计算下已识别的锥体细胞和中间神经元的概况 网络建模。我们预计，定义一种新型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取得重大进展 慢性癫痫的机制，并将有助于开发基于大麻的抗癫痫治疗 策略。

项目成果

Neural stem cell lineage-specific cannabinoid type-1 receptor regulates neurogenesis and plasticity in the adult mouse hippocampus.

神经干细胞谱系特异性 1 型大麻素受体调节成年小鼠海马的神经发生和可塑性。

• 发表时间: 2018
• 作者: Zimmermann, Tina;Maroso, Mattia;Beer, Annika;Baddenhausen, Sarah;Ludewig, Susann;Fan, Wenqiang;Vennin, Constance;Loch, Sebastian;Berninger, Benedikt;Hofmann, Clementine;Korte, Martin;Soltesz, Ivan;Lutz, Beat;Leschik, Julia
• 通讯作者: Leschik, Julia

PharmacoSTORM nanoscale pharmacology reveals cariprazine binding on Islands of Calleja granule cells.

PharmacoSTORM 纳米级药理学揭示了卡利拉嗪与 Calleja 颗粒细胞岛的结合。

• 发表时间: 2021
• 影响因子: 16.6
• 作者: Prokop, Susanne;Ábrányi;Barti, Benjámin;Vámosi, Márton;Zöldi, Miklós;Barna, László;Urbán, Gabriella M;Tóth, András Dávid;Dudok, Barna;Egyed, Attila;Deng, Hui;Leggio, Gian Marco;Hunyady, László;van der Stelt, Mario;Keserű, Györg
• 通讯作者: Keserű, Györg

Proceedings of the Epilepsy Foundation's 2017 Cannabinoids in Epilepsy Therapy Workshop.

癫痫基金会 2017 年癫痫治疗大麻素研讨会论文集。

• 发表时间: 2018-08
• 作者: Huizenga, Megan N;Fureman, Brandy E;Soltesz, Ivan;Stella, Nephi
• 通讯作者: Stella, Nephi

ABHD4-dependent developmental anoikis safeguards the embryonic brain.

ABHD4 依赖性发育失巢凋亡保护胚胎大脑。

• 发表时间: 2020
• 影响因子: 16.6
• 作者: László, Zsófia I;Lele, Zsolt;Zöldi, Miklós;Miczán, Vivien;Mógor, Fruzsina;Simon, Gabriel M;Mackie, Ken;Kacskovics, Imre;Cravatt, Benjamin F;Katona, István
• 通讯作者: Katona, István

Plants come to mind: phytocannabinoids, endocannabinoids and the control of seizures.

我想到了植物：植物大麻素、内源性大麻素和控制癫痫发作。

• 发表时间: 2019
• 作者: Farrell, Jordan S;Soltesz, Ivan
• 通讯作者: Soltesz, Ivan