Mechanisms of Low-Dose Ketamine Treatment for Parkinson's Disease

小剂量氯胺酮治疗帕金森病的机制

• 批准号: 10437941
• 负责人: TORSTEN FALK
• 金额: $ 37.12万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10437941
• 关键词: Action Potentials; Acute; Affect; Anesthetics; Animal Model; Animals; Area; Basal Ganglia; Bradykinesia; Brain; Brain-Derived Neurotrophic Factor; Case Study; Cells; Chemicals; Clinical Data; Clinical Trials; Controlled Clinical Trials; Data; Deep Brain Stimulation; Dendritic Spines; Development; Disease; Disease model; Dopamine; Dopamine Agonists; Dose; Drug Targeting; Dyskinetic syndrome; FRAP1 gene; Foundations; Future; G-Banding; Generations; Gold; Hour; Implanted Electrodes; Infusion procedures; Injections; Interneurons; Involuntary Movements; Ketamine; Knowledge; L-DOPA induced dyskinesia; Levodopa; Locomotion; Long-Term Effects; MK801; Measures; Mental Depression; Migraine; Modeling; Molecular; Morphology; Motor Cortex; Movement; Movement Disorders; N-Methyl-D-Aspartate Receptors; NMDA receptor antagonist; Neurodegenerative Disorders; Neuronal Plasticity; Neurons; Opioid; Opioid Receptor; Opioid agonist; Oxidopamine; Pain; Parkinson Disease; Pathologic; Pathway interactions; Patients; Persons; Phase I Clinical Trials; Post-Traumatic Stress Disorders; Psychiatry; Publications; Rattus; Research Personnel; Science; Severities; Signal Transduction; Symptomatic Parkinsonism; Symptoms; Synapses; System; Testing; Therapeutic; Therapeutic Effect; Time; Tremor; United States; Vertebral column; Walking; Work; abnormal involuntary movement; antagonist; awake; base; behavior measurement; bench to bedside; bench-to-bedside translation; chronic pain; common treatment; comorbid depression; density; dopamine replacement therapy; drug candidate; interest; meetings; multidisciplinary; novel; pain reduction; pre-clinical; receptor; relating to nervous system; sex; 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).

摘要 帕金森氏病(PD)是第二大最常见的神经退行性疾病，在美国有100多万人受到影响 美国。帕金森病会导致行走和说话等动作困难，原因是 大脑化学物质多巴胺的丧失。目前对帕金森病的对症治疗主要基于多巴胺。 L多巴的替代疗法；然而，这些疗法有许多长期副作用，导致 对非多巴胺能疗法感兴趣。最严重的副作用是L-多达诱发的 运动障碍(LID)，不自主运动，可能与疾病本身一样，甚至更虚弱。任何 辅助治疗延长L多巴可以无盖使用的时间框架将是一个重大进展。 最近的出版物显示，小剂量氯胺酮输注范例是安全和耐受性良好的 疼痛状态(包括偏头痛)、难治性抑郁和创伤后的临床试验 应激障碍(PTSD)。小剂量的氯胺酮导致疼痛状态的长期减少，治疗耐药 除了抑郁，它还降低了创伤后应激障碍症状的严重程度和共病抑郁。它们之间有一个共同点 偏头痛、抑郁、创伤后应激障碍、帕金森病和LID是大脑中的电活动过度同步 而不适应的可塑性变化发生在大脑中，包括在PD和LID感兴趣的区域，称为 基底节(BG)。因此，我们研究了小剂量亚麻药氯胺酮在治疗中的应用。 警局和LID的。我们从临床前数据中有证据表明小剂量氯胺酮输注的治疗效果 LID大鼠模型(剂量依赖的异常非自主运动减少； 来自5个帕金森病患者的病例研究(减少运动障碍和减少抑郁)。 在大鼠眼睑模型中，这种效应仅在给予小剂量氯胺酮10小时时才能看到，而不是仅仅 一次急性小剂量氯胺酮注射。建议研究的前提是确定 新型小剂量氯胺酮的使用是‘真正的卧床到床边’的科学，将为控制提供基础 小剂量氯胺酮治疗眼睑脱垂的临床试验，并可寻找更具特异性的新治疗药物 目标是治疗LID和抑郁症，这是许多PD患者面临的两个关键问题。我们的主要假设是 小剂量亚麻药氯胺酮输注使神经细胞过度同步振荡活动去同步化 充分参与LID，以诱导持久的抗运动障碍效果，起到“化学脑深部刺激”的作用 (星展银行)“。我们推测氯胺酮通过BG中的两种受体分子在分子水平发挥作用。 以及皮质、NMDA受体和阿片受体，长期影响包括神经细胞的变化 被称为树突的连接。一个由多学科研究人员组成的团队和一名临床医生 专业知识将通过研究低剂量这种长期影响的机制来填补知识的关键空白 氯胺酮输注在分子和细胞水平。他们将研究对受体的影响和脊椎的变化。 大小和密度(目标1)，并在系统层面上，研究振荡神经活动的同步性(目标2)。