New Therapies for Essential Tremor from Cannabidiols Mechanisms

大麻二酚机制治疗特发性震颤的新疗法

• 批准号: 10478737
• 负责人: Charles Adrian Handforth
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10478737
• 关键词: AMPA Receptors; Adverse effects; Advisory Committees; Affect; Age; Agonist; Anatomy; Animal Model; Antidepressive Agents; Anxiety; Autoreceptors; Behavior; Brain; CNR1 gene; CNR2 gene; Cannabidiol; Cannabinoids; Cannabis; Cells; Cerebellum; Cerebral cortex; Clinical; Clinical Trials; Complex; Data; Development; Dose; Drug Utilization; Drug usage; Effectiveness; Endocannabinoids; Enzyme Inhibition; Enzyme Inhibitor Drugs; Enzymes; Epilepsy; Essential Drugs; Essential Tremor; FAAH inhibitor; GABA-A Receptor; Gap Junctions; General Population; Goals; Harmaline; Hepatic; Human; Impairment; Inferior; Intention Tremor; Knock-out; Knockout Mice; Laboratory Research; Lead; Mediating; Mental Depression; Modeling; Molecular Target; Mus; Neurons; Occupational; Olives - dietary; Pain; Patients; Persons; Pharmaceutical Preparations; Pharmacology; Pilot Projects; Play; Prevalence; Publishing; Purkinje Cells; Receptor Activation; Reporting; Retirement; Role; Serotonin; Serotonin Agonists; Serotonin Receptor 5-HT1A; Serotonin Receptor 5-HT2A; Synapses; T-Type Calcium Channels; Testing; Thalamic structure; Therapeutic; Therapeutic Uses; Tremor; Vanilloid; Veterans; Withdrawal; Work; anandamide; antagonist; base; clinical efficacy; comorbid depression; disability; experimental study; fatty acid amide hydrolase; interest; mouse model; nervous system disorder; novel therapeutics; postsynaptic; pre-clinical; programs; receptor; research clinical testing; response; serotonin receptor; social; stem; therapy development; vanilloid receptor subtype 1

Project Summary/Abstract Essential tremor affects 0.5-0.9% of the general population and about 4.5% above age 65. Medications for tremor are re-purposed drugs found empirically, often lack potency, and are often not well tolerated. In our program we study how drugs that suppress tremor work and through what molecular targets. Many patients report that cannabidiol suppresses tremor. Cannabidiol is non-psychotropic and has shown clinical efficacy for epilepsy, but may cause adverse effects, and induces hepatic enzymes. More effective and well-tolerated medications for tremor, based on cannabidiol’s mechanism, are desirable. To assess tremor in mice, we use the harmaline tremor model, which has many similarities to essential tremor. Our pilot data indicate that cannabidiol robustly suppresses harmaline-induced tremor, consistent with clinical observations. Cannabidiol has many actions, but the main receptors activated by it directly or indirectly are cannabinoid receptors type 1 and 2, the type 1 vanilloid receptor, and the serotonin type 1a receptor. By co-administering specific receptor antagonists along with cannabidiol, it is possible to determine the mechanism of action. In pilot experiments we found that activation of vanilloid 1 and serotonin 1a receptors both mediate cannabidiol's anti-tremor effect. As a vanilloid 1 agonist suppresses tremor, an effect blocked by a serotonin 1a receptor antagonist, it appears that vanilloid 1 receptor activation by cannabidiol is upstream to serotonin 1a receptor-mediated tremor suppression. In Aim 1 we will seek to replicate these findings and, also find out whether mice lacking the serotonin 1a receptor (knockouts) fail to show tremor suppression by cannabidiol or the vanilloid 1 receptor agonist. Much of cannabidiol's mechanism is due to inhibition of fatty acid amide hydrolase, leading to elevation of the endogenous cannabinoid anandamide, which then activates several receptors. We found in pilot experiments that a drug that inhibits this enzyme also suppresses tremor, an effect that requires both vanilloid 1 and serotonin 1a receptor activation. This suggests that inhibitors of fatty acid amide hydrolase could be used clinically to treat tremor. In Aim 2 we will seek to replicate these findings, using drugs and knockout mice to explore the role of vanilloid 1 and serotonin1a receptors in tremor suppression through inhibition of this enzyme and also assess whether anandamide administration suppresses tremor through the same mechanisms. An important potential tremor therapy stemming from cannabidiol's mechanisms is the administration of drugs that activate serotonin 1a receptors, which generally inhibit neuronal firing. When located on serotonin cell bodies, serotonin 1a autoreceptor activation reduces cell firing and serotonin release, thereby reducing activation of excitatory post-synaptic serotonin 2a receptors. Post-synaptic serotonin 1a receptors play a role in antidepressant and other actions. In pilot studies we found that both autoreceptor- and postsynaptic- preferring serotonin 1a agonists suppress tremor, while a drug that stimulates both receptors was even more effective. In Aim 3 we shall replicate these experiments and, also determine whether repeated dosing causes any of these serotonin agonists to lose their ability to suppress tremor. We will test them in serotonin 1a knockout mice to confirm that they are in fact suppressing tremor by activating the serotonin 1a receptor. This program is expected to lead to the identification of new therapies for essential tremor: inhibitors of fatty acid amide hydrolase, anandamide-like drugs, and serotonin 1a receptor agonists. These therapies are anticipated to be potent and well tolerated, should be available soon for clinical trials, and may also be beneficial for anxiety and depression, conditions that are common in Veterans with essential tremor.

项目摘要/摘要 必需树影响总数的0.5-0.9％，大约4.5％高于65岁。 Treers的药物是经验发现的重新选择的药物，通常缺乏效力，并且通常不好 容忍。在我们的计划中，我们研究抑制树木的药物如何工作以及通过哪种分子 目标。许多患者报告说大麻二酚会抑制震颤。大麻二醇是非精神型的， 已经显示出对癫痫的临床有效性，但可能会引起不良反应，并诱导肝酶。 基于大麻二酚的机制，对震颤的更有效且耐受性良好的药物是 理想。 要评估小鼠树，我们使用Harmaline树模型，该模型与必不可少的相似之处 震颤。我们的试验数据表明大麻二醇可靠地抑制Harmaline引起的震颤，与 临床观察。大麻二醇具有许多动作，但是直接或间接激活的主要接收器 是1型和2型大麻素受体，1型香草素受体和5-羟色胺1A受体。经过 共同管理特定的接收器拮抗剂以及大麻二酚，可以确定 作用机理。在试验实验中，我们发现香草素1和5-羟色胺1A受体的激活 两者都介导大麻二醇的抗晶状体效应。当一只香草素1激动剂抑制震颤时，这种效果被阻止 5-羟色胺1A受体拮抗剂，看来大麻二酚的香草素1受体激活在上游 5-羟色胺1A受体介导的震颤抑制。在AIM 1中，我们将寻求复制这些发现，也将 找出缺乏血清素1a受体（淘汰）的小鼠是否无法通过 大麻二酚或香草素1受体激动剂。 大麻二酚的大部分机制是由于抑制脂肪酸酰胺水解酶，导致升高 内源性大麻蛋白枪，然后激活多个接收器。我们在飞行员中发现 一种抑制这种酶的药物的实验也抑制了震颤 1和5-羟色胺1A受体激活。这表明脂肪酸酰胺水解酶的抑制剂可能是 在临床上用于治疗震颤。在AIM 2中，我们将寻求使用药物和淘汰小鼠复制这些发现 通过抑制这一点，探索香草素1和5-羟色胺1a受体在震颤中的作用 酶，还评估Anandamide给药是否通过相同的震颤抑制震颤 机制。 由大麻二醇的机制引起的重要潜在树治疗是给予 激活5-羟色胺1A受体的药物，通常会抑制神经元触发。当位于5-羟色胺 细胞体，5-羟色胺1A自身受体激活可减少细胞发射和5-羟色胺释放，从而减少 激活后突触后血清素2a受体的激活。突触后血清素1a受体起作用 在抗抑郁药和其他动作中。在试点研究中，我们发现自动受体和突触后 - 偏爱5-羟色胺1A激动剂抑制树，而刺激两种受体的药物甚至更多 有效的。在AIM 3中，我们将复制这些实验，还确定是否重复给药原因 这些5-羟色胺激动剂失去抑制震颤的能力。我们将在5-羟色胺1a中测试它们 敲除小鼠以确认它们实际上是通过激活塞列辛1A受体来抑制树的。 预计该程序将导致确定基本树的新疗法： 脂肪酸酰胺水解酶，anandamide样药物和5-羟色胺1A受体激动剂。这些疗法 预计可能会有潜力且容忍良好，应尽快用于临床试验，也可能是 对动画和抑郁症有益，在具有必要震颤的退伍军人中常见的情况。