Mechanisms of Low-Dose Ketamine Treatment for Parkinson's Disease [Diversity Supplement for Raveena Parmar]

低剂量氯胺酮治疗帕金森病的机制 [Raveena Parmar 的多样性补充]

• 批准号: 10740600
• 负责人: TORSTEN FALK
• 金额: $ 2.21万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740600
• 关键词: Acute; Affect; Anesthetics; Area; Basal Ganglia; Bradykinesia; Brain; Case Study; Chemicals; Clinical Trials; Controlled Clinical Trials; Data; Deep Brain Stimulation; Dendritic Spines; Development; Disease; Disease Progression; Dopamine; Dopamine Agonists; Dose; Drug Targeting; Dyskinetic syndrome; Foundations; Hour; Infusion procedures; Injections; Involuntary Movements; Ketamine; Knowledge; L-DOPA induced dyskinesia; Levodopa; Long-Term Effects; Mental Depression; Migraine; Modeling; Molecular; Movement; Movement Disorders; N-Methyl-D-Aspartate Receptors; Neurodegenerative Disorders; Neurons; Opioid Receptor; Pain; Parkinson Disease; Patients; Persons; Post-Traumatic Stress Disorders; Publications; Rattus; Research Personnel; Science; Severities; Symptomatic Parkinsonism; Symptoms; System; Therapeutic; Therapeutic Effect; Time; Tremor; United States; Vertebral column; Walking; Work; abnormal involuntary movement; bench to bedside; common treatment; comorbid depression; density; dopamine replacement therapy; interest; multidisciplinary; neural; novel; pain reduction; pre-clinical; receptor; side effect; treatment-resistant depression

ABSTRACT Parkinson's disease (PD) is the 2nd most common neurodegenerative disorder, affecting over 1 million people in the United States. PD causes difficulties with movements such as walking and speaking that occur because of loss of the brain chemical dopamine. Current symptomatic PD treatments are based largely on dopamine replacement therapies with L-DOPA; however, these treatments have many long-term side effects which led to interest in non-dopaminergic therapies. The most severe side effect is the development of L-DODA-induced dyskinesia (LID), involuntary movements that can be as or even more debilitating than the disease itself. Any adjunct therapy extending the time frame where L-DOPA can be used without LID would be a major advance. Recent publications showed that low-dose ketamine infusion paradigms were safe and well tolerated in clinical trials for pain states (including migraine headaches), treatment-resistant depression and posttraumatic stress disorder (PTSD). Low-dose ketamine has led to a long-term reduction of pain states, treatment-resistant depression, it also reduced PTSD symptom severity and comorbid depression. One commonality between migraine headaches, depression, PTSD, PD and LID is that electric activity in the brain is overly synchronized and maladaptive plastic changes occur in the brain, including in an area that is of interest in PD and LID called the basal ganglia (BG). Therefore, we investigated the use of low-dose sub-anesthetic ketamine in the treatment of PD and LID. We have evidence of a therapeutic effect of low-dose ketamine infusion from preclinical data in a rat model of LID (dose-dependent reduction of abnormal involuntary movements; long-term effects after a single ‘infusion-treatment’) and from 5 PD patient case studies (reduced dyskinesia and reduced depression). In the rat LID model this effect was only seen when low-dose ketamine was given for 10 hours and not with just a single acute low-dose ketamine injection. The premise of the proposed studies to define mechanisms of the novel use of low-dose ketamine is ‘true bench to bedside’ science, will provide the foundation for controlled clinical trials of low-dose ketamine treatment for LID, and could identify new more specific therapeutic drug targets to treat LID and depression, two critical problems for many PD patients. Our main hypothesis is that a low-dose sub-anesthetic ketamine infusion desynchronizes overly synchronous oscillatory activity in nerve cells involved in LID sufficiently to induce a lasting anti-dyskinetic effect, working as a “chemical deep brain stimulation (DBS)”. We hypothesize that ketamine works on the molecular level via 2 types of receptor molecules in the BG and cortex, NMDA receptors and opioid receptors, and that the long-term effect includes changes in nerve cell connections called dendritic spines. A multidisciplinary team of researchers and a clinician with the necessary expertise will fill a critical gap in knowledge by investigating the mechanisms of this long-term effect of low-dose ketamine infusion on the molecular and cellular level. They will study effects on receptors and changes in spine size and density (Aim 1), and on the systems level, investigate synchrony of oscillatory neural activity (Aim 2).

抽象的 帕金森病 (PD) 是第二大常见的神经退行性疾病，影响着超过 100 万人 在美国，帕金森病会导致行走和说话等动作出现困难。 大脑化学物质多巴胺的丧失 目前的对症 PD 治疗主要基于多巴胺。 左旋多巴替代疗法；然而，这些疗法有许多长期副作用，导致 对非多巴胺能疗法的兴趣最严重的副作用是 L-DODA 诱导的发展。 运动障碍（LID），一种不自主的运动，可能与疾病本身一样甚至更严重。 延长 L-DOPA 可以在没有 LID 的情况下使用的时间范围的辅助治疗将是一个重大进步。 最近的出版物表明，低剂量氯胺酮输注范例在患者中是安全且耐受性良好的 针对疼痛状态（包括偏头痛）、难治性抑郁症和创伤后的临床试验 应激障碍 (PTSD) 低剂量氯胺酮可导致疼痛状态长期减轻，且难以治疗。 抑郁症，它还降低了 PTSD 症状的严重程度和共病抑郁症之间的一个共同点。 偏头痛、抑郁症、创伤后应激障碍 (PTSD)、PD 和 LID 是大脑电活动过度同步造成的 大脑中会发生适应不良的可塑性变化，包括与 PD 和 LID 相关的区域（称为 PD 和 LID） 因此，我们研究了在治疗中使用低剂量亚麻醉氯胺酮。 我们的临床前数据显示低剂量氯胺酮输注具有治疗作用。 LID 大鼠模型（异常不自主运动的剂量依赖性减少；治疗后的长期影响） 单次“输注治疗”）和 5 个 PD 患者案例研究（减少运动障碍和减少抑郁）。 在大鼠 LID 模型中，只有在给予低剂量氯胺酮 10 小时时才能观察到这种效应，而不是仅仅给予氯胺酮。 单次急性低剂量氯胺酮注射的前提是确定该研究的机制。 低剂量氯胺酮的新用途是“真正的实验室到临床”科学，将为受控 低剂量氯胺酮治疗 LID 的临床试验，可以确定新的更具特异性的治疗药物 治疗 LID 和抑郁症是许多 PD 患者面临的两个关键问题。 低剂量亚麻醉氯胺酮输注可消除神经细胞中过度同步的振荡活动 充分参与 LID 以诱导持久的抗运动障碍作用，作为“化学深部脑刺激” (DBS)”。我们研究氯胺酮通过 BG 中的 2 种受体分子在分子水平上发挥作用。 和皮质、NMDA 受体和阿片受体，长期影响包括神经细胞的变化 称为树突棘的连接由多学科研究人员和临床医生组成，具有必要的能力。 专业知识将通过研究低剂量长期影响的机制来填补知识上的一个关键空白 他们将在分子和细胞水平上研究氯胺酮输注对受体的影响和脊柱的变化。 大小和密度（目标 1），并在系统水平上研究振荡神经活动的同步性（目标 2）。