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

摘要 帕金森氏病（PD）是第二大最常见的神经退行性疾病，影响超过100万人， 美国的PD导致运动困难，如行走和说话，这是因为 大脑化学物质多巴胺的流失。目前的症状性PD治疗主要基于多巴胺 L-DOPA替代疗法;然而，这些治疗具有许多长期副作用，导致 对非多巴胺能疗法感兴趣。最严重的副作用是L-DODA诱导的 运动障碍（LID），不自主运动，可以作为或甚至比疾病本身更衰弱。任何 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的进步。 最近的出版物表明，低剂量氯胺酮输注模式是安全的，耐受性良好， 疼痛状态（包括偏头痛）、难治性抑郁症和创伤后 应激障碍（PTSD）。低剂量氯胺酮导致疼痛状态的长期减轻， 它还降低了PTSD症状的严重程度和共病抑郁症。一个共同点是， 偏头痛、抑郁症、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 和适应不良的可塑性变化发生在大脑中，包括在PD和LID中感兴趣的区域，称为 基底神经节（BG）。因此，我们研究了在治疗中使用低剂量亚麻醉剂氯胺酮 PD和LID。我们从临床前数据中获得了低剂量氯胺酮输注的治疗效果的证据， LID大鼠模型（异常不自主运动的剂量依赖性减少; 单次“输注-治疗”）和5例PD患者病例研究（运动障碍减少和抑郁减少）。 在大鼠LID模型中，仅当给予低剂量氯胺酮10小时时才观察到这种效应，而不是仅仅给予氯胺酮。 一次急性低剂量氯胺酮注射提出研究的前提是确定 低剂量氯胺酮的新用途是“真正的实验室到床边”的科学，将为控制 低剂量氯胺酮治疗LID的临床试验，并可确定新的更特异性的治疗药物 目标是治疗LID和抑郁症，这是许多PD患者的两个关键问题。我们的主要假设是， 低剂量亚麻醉剂氯胺酮输注抑制神经细胞过度同步振荡活动 参与LID足以诱导持久的抗运动障碍效应，作为“化学脑深部刺激” (DBS)".我们假设氯胺酮通过BG中的2种受体分子在分子水平上起作用 和皮层，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。一个多学科的研究人员和一个临床医生团队， 专家将通过调查这种低剂量长期影响的机制来填补知识的关键空白。 分子和细胞水平的氯胺酮注射他们将研究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）。

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).