Cannabinoid control of epilepsy

大麻素控制癫痫

基本信息

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
项目类别：
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

项目摘要

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）是成年人中最常见的癫痫综合征。当前的治疗选择 TLE不足，因为太多的患者患有不受控制的癫痫发作，并且由于治疗。内源性大麻素信号已被认为是主要的，有效的调节剂神经递质在大脑中释放，最近人们对使用外源的兴趣激增从大麻植物获得的大麻素化合物控制着顽固性癫痫。然而，大麻素对神经元兴奋性的控制的机制尚不清楚。最近，我们发现了一种从根本上新的，功能上重要的突触后机制，大麻素通过控制海马锥体细胞中的兴奋性。该途径涉及有效的大麻素类型1 受体（CB1）H-电流（IH）的介导的调节，这是树突状兴奋性的关键调节剂，由树突状兴奋性。超极化激活，环状核苷酸门控通道（HCN）。在这里，我们建议检验假设那种与医学相关的大麻素在慢性TLE中施加了反对术的作用整个皮质地幔中的主要细胞和中间神经元中IH的调节。该假设将进行检验在实验的小鼠模型中，将在体外和体内进行评估电生理学，细胞类型特异性纳米级超分辨率分子成像中的特定亚细胞成像在高通量和数据驱动的超级计算中鉴定的锥体细胞和中间神经元的概况网络建模。我们预计定义了新型大麻素调节剂的功能后果慢性癫痫中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，将有助于基于大麻的抗癫痫治疗的发展策略。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

NECAB1 and NECAB2 are Prevalent Calcium-Binding Proteins of CB1/CCK-Positive GABAergic Interneurons.

DOI：
10.1093/cercor/bhaa326
发表时间：
2021-02-05
期刊：
Cerebral cortex (New York, N.Y. : 1991)
影响因子：
0
作者：
Miczán V;Kelemen K;Glavinics JR;László ZI;Barti B;Kenesei K;Kisfali M;Katona I
通讯作者：
Katona I

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

DOI：
10.1093/cercor/bhy258
发表时间：
2018-12-01
期刊：
Cerebral cortex (New York, N.Y. : 1991)
影响因子：
0
作者：
Zimmermann T;Maroso M;Beer A;Baddenhausen S;Ludewig S;Fan W;Vennin C;Loch S;Berninger B;Hofmann C;Korte M;Soltesz I;Lutz B;Leschik J
通讯作者：
Leschik J

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。

DOI：
10.1016/j.yebeh.2018.05.016
发表时间：
2018
期刊：
Epilepsy & behavior : E&B
影响因子：
0
作者：
Huizenga,MeganN;Fureman,BrandyE;Soltesz,Ivan;Stella,Nephi
通讯作者：
Stella,Nephi

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

DOI：
10.1038/s41467-021-26757-z
发表时间：
2021-11-11
期刊：
Nature communications
影响因子：
16.6
作者：
Prokop S;Ábrányi-Balogh P;Barti B;Vámosi M;Zöldi M;Barna L;Urbán GM;Tóth AD;Dudok B;Egyed A;Deng H;Leggio GM;Hunyady L;van der Stelt M;Keserű GM;Katona I
通讯作者：
Katona I

STORM Super-Resolution Imaging of CB1 Receptors in Tissue Preparations.

组织制剂中 CB1 受体的 STORM 超分辨率成像。