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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要特发性震颤影响普通人群的 0.5-0.9%，其中 65 岁以上的人约占 4.5%。治疗震颤的药物是根据经验发现的药物的重新用途，通常缺乏效力，并且通常效果不佳在我们的项目中，我们研究了抑制震颤的药物如何发挥作用以及通过什么分子发挥作用。许多患者报告大麻二酚可抑制震颤。已显示出对癫痫的临床疗效，但可能会引起不良反应，并诱导肝酶。基于大麻二酚的机制，更有效且耐受性良好的震颤药物是理想的。为了评估小鼠的震颤，我们使用骆驼蓬碱震颤模型，该模型与原发性震颤模型有许多相似之处我们的试验数据表明，大麻二酚可有效抑制骆驼蓬碱引起的震颤，这与以下结果一致：临床观察大麻二酚具有多种作用，但主要是由其直接或间接激活的受体。是 1 型和 2 型大麻素受体、1 型香草素受体和 1a 型血清素受体。将特定受体拮抗剂与大麻二酚共同给药，可以确定在初步实验中，我们发现香草酸 1 和血清素 1a 受体的激活。两者均介导大麻二酚的抗震颤作用，因为香草酸 1 激动剂可抑制震颤，而这种作用可被阻断。一种血清素 1a 受体拮抗剂，看来大麻二酚激活香草酸 1 受体是上游 5-羟色胺 1a 受体介导的震颤抑制在目标 1 中，我们将寻求复制这些发现。找出缺乏 5-羟色胺 1a 受体（敲除）的小鼠是否无法通过以下方法表现出震颤抑制：大麻二酚或香草酸 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，导致内源性大麻素 anandamide，然后激活我们在飞行员中发现的几种受体。实验表明，抑制这种酶的药物也能抑制震颤，这种效果需要香草醛和 1 和血清素 1a 受体激活，这表明脂肪酸酰胺水解酶的抑制剂可能是。在目标 2 中，我们将寻求使用药物和基因敲除小鼠来复制这些发现。通过抑制香草酸 1 和血清素 1a 受体来探索香草酸 1 和血清素 1a 受体在震颤抑制中的作用酶并评估 anandamide 给药是否通过相同的方法抑制震颤机制。来自大麻二酚机制的一种重要的潜在震颤疗法是施用激活血清素 1a 受体的血清素药物，当位于血清素上时，通常会抑制神经元放电。细胞体中，血清素 1a 自身受体激活会减少细胞放电和血清素释放，从而减少兴奋性突触后血清素 2a 受体的激活发挥作用。在抗抑郁药和其他作用中，我们发现自身受体和突触后。首选 5-羟色胺 1a 激动剂可以抑制震颤，而刺激两种受体的药物则更有效在目标 3 中，我们将重复这些实验，并确定重复给药是否会导致。这些血清素激动剂中的任何一种都会失去抑制震颤的能力，我们将在血清素 1a 中测试它们。基因敲除小鼠证实它们实际上是通过激活血清素 1a 受体来抑制震颤。该计划预计将导致特发性震颤新疗法的确定：脂肪酸酰胺水解酶、anandamide 类药物和 5-羟色胺 1a 受体激动剂这些疗法。预计有效且耐受性良好，应该很快可用于临床试验，并且也可能对焦虑和抑郁有益，这些症状在患有特发性震颤的退伍军人中很常见。