New Therapies for Essential Tremor from Cannabidiols Mechanisms

项目摘要/摘要 特发性震颤影响0.5-0.9%的总人口和约4.5%的65岁以上人群。 治疗震颤的药物是根据经验发现的重复使用的药物，通常缺乏效力，而且往往不太好。 被容忍了。在我们的项目中，我们研究了抑制震颤的药物是如何起作用的，以及通过什么分子 目标。许多患者报告说，大麻二醇可以抑制震颤。大麻二酚是非精神药物， 已经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。 根据大麻二醇的作用机制，更有效和耐受性更好的震颤药物是 令人向往。 为了评估小鼠的震颤，我们使用了骆驼蓬震颤模型，它与Essential有许多相似之处。 震颤。我们的试验数据表明，大麻二醇有力地抑制了骆驼蓬碱诱发的震颤，这与 临床观察。大麻二酚具有多种作用，但其直接或间接激活的主要受体 它们是大麻素受体1和2、香草素受体1和5羟色胺1a受体。通过 联合应用特定受体拮抗剂和大麻二酚，有可能确定 作用机制。在初步实验中，我们发现香草素1和5-羟色胺1a受体的激活 两者都与大麻二酚的抗震颤作用有关。当香草素1激动剂抑制震颤时，这种作用被 作为一种5-羟色胺1a受体拮抗剂，似乎大麻二醇激活香草素1受体的上游是 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，并且 找出缺乏5-羟色胺1a受体(基因敲除)的小鼠是否未能通过以下方式表现出震颤抑制 大麻二醇或香草素1受体激动剂。 大麻二醇的作用机制很大程度上是由于抑制脂肪酸酰胺水解酶，导致血浆中 内源性大麻素脱氧核糖核酸，然后激活几个受体。我们在Pilot中发现的 实验表明，一种抑制这种酶的药物也可以抑制震颤，这是一种需要两种香草素的效果 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 临床上用来治疗震颤。在目标2中，我们将使用药物和基因敲除小鼠来复制这些发现 探讨香草素-1和5-羟色胺1a受体在震颤抑制中的作用 酶，并评估阿南达胺是否通过同样的方式抑制震颤 机械装置。 一种重要的潜在震颤疗法源于大麻二醇的机制是给药 激活5-羟色胺1a受体的药物，这种受体通常会抑制神经元的放电。当定位于5-羟色胺时 在细胞体内，5-羟色胺1a自身受体的激活减少了细胞的激活和5-羟色胺的释放，从而减少了 兴奋性突触后5-羟色胺2a受体的激活。突触后5-羟色胺1a受体发挥作用 在抗抑郁剂和其他作用中。在先导研究中，我们发现自体受体和突触后 偏爱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能抑制震颤。 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 任何这些5-羟色胺激动剂都会失去抑制震颤的能力。我们将测试它们的5-羟色胺1a 以证实它们实际上是通过激活5-羟色胺1a受体来抑制震颤的。 这一计划有望导致发现治疗特发性震颤的新疗法： 脂肪酸酰胺水解酶、烷胺类药物和5-羟色胺1a受体激动剂。这些疗法 预计是有效的和良好的耐受性，应该很快就可以用于临床试验，也可能 有益于焦虑和抑郁，这种情况在有特发性震颤的退伍军人中很常见。

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.