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: 10654668
• 负责人: TORSTEN FALK
• 金额: $ 37.01万
• 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/10654668
• 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; Corpus striatum structure; Data; Deep Brain Stimulation; Dendritic Spines; Development; Disease; Disease Progression; Disease model; Dopamine; Dopamine Agonists; Dose; Drug Targeting; Dyskinetic syndrome; FRAP1 gene; Foundations; Future; Generations; 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; 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; behavior measurement; bench to bedside; bench-to-bedside translation; chronic pain; common treatment; comorbid depression; density; dopamine replacement therapy; drug candidate; interest; meetings; multidisciplinary; neural; neuroprotection; novel; pain reduction; pre-clinical; receptor; 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).

抽象的 帕金森氏病（PD）是第二个最常见的神经退行性疾病，影响了100万以上的人 美国。 PD在行走和说话之类的动作上造成困难，因为 脑化学多巴胺的丧失。当前有症状的PD治疗主要基于多巴胺 用L-DOPA替代疗法；但是，这些处理具有许多长期副作用，导致 对非多巴胺能疗法的兴趣。最严重的副作用是LDODA诱导的 运动障碍（盖子），比疾病本身可能更像或更使人衰弱的非自愿运动。任何 辅助疗法延长了可以在没有盖子的情况下使用L-DOPA的时间范围，这将是一个重大进展。 最近的出版物表明，低剂量氯胺酮输注范式是安全的，并且容忍了 疼痛状态（包括偏头痛头）的临床试验，耐药后抑郁症和创伤后的临床试验 应激障碍（PTSD）。低剂量氯胺酮导致疼痛状态的长期减少，耐药性 抑郁症，还减少了PTSD症状严重程度和合并症。彼此之间的一个共同点 偏头痛，抑郁症，PTSD，PD和盖子是大脑中的电活动过于同步 大脑中发生不良适应性塑料变化，包括在PD和盖子中感兴趣的区域 基底神经节（BG）。因此，我们研究了在治疗中使用低剂量亚手提感觉氯胺酮 PD和盖子。我们有证据表明，低剂量氯胺酮在临床前数据中的治疗作用 大鼠模型的盖子（剂量依赖性降低异常非自愿运动； 单个“输注治疗”）和5个PD患者病例研究（减少运动障碍和减少抑郁症）。 在大鼠盖模型中，只有在给出低剂量氯胺酮10小时而不仅仅是仅用的情况下才能看到这种作用 一次急性低剂量氯胺酮注射。拟议研究的前提是定义 低剂量氯胺酮的新颖使用是“真正的长凳”科学，将为受控的基础提供基础 低剂量氯胺酮治疗盖的临床试验，可以鉴定出更特殊的治疗药物 治疗盖子和抑郁症的靶标，这是许多PD患者的两个关键问题。我们的主要假设是 低剂量的亚麻省氯胺酮输注对神经细胞中的过度同步振荡活性 足够参与盖子以诱导持久的抗脱染色效应，作为“化学深脑刺激 （DBS）”。我们假设氯胺酮通过BG中的两种受体分子在分子水平上起作用 和皮质，NMDA受体和阿片类药物受体，并且长期效应包括神经细胞的变化 连接称为树突状刺。一个多学科的研究人员和一个必要的临床团队 专业知识将通过研究低剂量的长期影响的机制来填补一个关键的空白 分子和细胞水平上的氯胺酮输注。他们将研究对受体和脊柱变化的影响 大小和密度（AIM 1），在系统级别上，研究振荡性神经活动的同步（AIM 2）。