Targeting toll like receptor 4 (TLR4) and TLR2 to resolve EAE-associated paralysis, pain and cognitive deficits: efficacy of a clinically-relevant blood brain barrier permeable TLR4/TLR2 antagonist

靶向 Toll 样受体 4 (TLR4) 和 TLR2 以解决 EAE 相关的麻痹、疼痛和认知缺陷：临床相关血脑屏障可渗透性 TLR4/TLR2 拮抗剂的功效

• 批准号: 9153350
• 负责人: LINDA WATKINS
• 金额: $ 33.68万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9153350
• 关键词: Address; Anti-Inflammatory Agents; Anti-inflammatory; Behavioral; Binding; Blood - brain barrier anatomy; Brain; Cell Death; Cells; Cerebrospinal Fluid; Characteristics; Chronic; Clinical; Clinical Trials; Cognitive deficits; Demyelinations; Department of Defense; Development; Disease; Disease Progression; Dose; Drug abuse; Encephalitis; Experimental Autoimmune Encephalomyelitis; Female; Functional disorder; Funding; Goals; Grant; Height; Human; Immune; Immunohistochemistry; Immunologic Receptors; Impaired cognition; Impairment; Inflammation; Inflammatory; Investigation; Investigational Drugs; Investigational New Drug Application; Isomerism; Life; Literature; Lysophosphatidylcholines; Maps; Modeling; Motor; Multiple Sclerosis; Naltrexone; Opioid; Opioid Receptor; Pain; Pain management; Paralysed; Paresis; Pathology; Population; Process; Rattus; Recruitment Activity; Research; Rodent; Role; Series; Site; Social Interaction; Specificity; Spinal; Spinal Cord; Symptoms; System; TLR2 gene; TLR4 gene; Testing; Therapeutic; Tissues; Translations; Work; behavioral study; chronic demyelination; clinically relevant; cytokine; glial activation; improved; male; motor disorder; multiple sclerosis treatment; neuroinflammation; neuron loss; non-drug; novel; painful neuropathy; pre-clinical; receptor; remyelination; small molecule; social cognition; symptomatic improvement

PROJECT SUMMARY Multiple sclerosis (MS) is a life-long, debilitating disease in both males and females. Symptoms include loss of motor function, neuropathic pain, cognitive impairments, and impaired social interaction. MS is furthermore associated with elevations in circulating and central (spinal cord and brain) levels of pro- inflammatory cytokines and decreased levels of anti-inflammatory cytokines, suggesting a dysregulation of immune and glial processes resulting in chronic inflammation. This ongoing inflammation is important in demyelination, chronic glial activation, and neuronal death characteristic of the disease. Targeted suppression of spinal cord neuroinflammation using anti-inflammatory strategies dramatically improves symptoms of experimental autoimmune encephalomyelitis (EAE), a rat model of MS. Looking forward toward translation, what is needed is not our current approaches that are injected intrathecally, but rather a means to effectively treat EAE/MS via a clinically relevant, orally available, blood-brain barrier permeable small molecule that targets EAE/MS pathology driven by neuroinflammation. We have discovered, and extensively characterized, such a small molecule. This drug (the non-opioid (+)-isomer of naltrexone; (+)-naltrexone) is rapidly moving toward FDA application for Investigational New Drug status. This is a selective antagonist at toll-like receptor 4 (TLR4) and TLR2. As it fails to bind classical opioid receptors, (+)-naltrexone does not interfere with the efficacy of opioids for pain control or normal functioning of opioid receptor systems. Targeting TLR2 and TLR4 arises from an extensive literature demonstrating the importance of these receptors in the neuroinflammatory processes and EAE/MS symptoms to be studied here. A complimentary series of behavioral and immunohistochemistry studies are proposed in males and females which will explore the ability of (+)-naltrexone to suppress EAE-induced (a) paresis/paralysis, (b) neuropathic pain, (c) cognitive impairment, and (d) social interaction impairment, as well as (e) improve survival, when (+)-naltrexone is systemically administered across days, comparing dosing early vs. late in the EAE timecourse. The IHC studies will analyze brain and spinal cord tissues collected after early vs. late (+)- naltrexone treatment (mapping onto the behavioral studies) to define whether (+)-naltrexone suppresses glial activation, neuronal cell death, and demyelination, as well as stimulates remyelination, as predicted. These studies create two complimentary Aims. Aim 1 explores a novel means of positively intervening in EAE-induced motor dysfunction, neuropathic pain, deficits in social interaction and cognition, and loss of life by targeting TLR4/TLR2 by systemic administration of (+)-naltrexone. Aim 2 transitions to an initial exploration of potential mechanisms underlying pathophysiology, focusing on the impact of TLR4/TLR2 blockade on demyelination and remyelination, neuronal cell death, and neuroinflammation. These studies provide a thorough investigation of the role of TLR4/TLR2 in major MS-relevant symptoms of EAE.

项目摘要 多发性硬化症（MS）是男性和女性的终身疾病。症状包括 运动功能，神经性疼痛，认知障碍和社交互动障碍的丧失。 MS是 此外，与循环和中央（脊髓和脑）升高有关 炎性细胞因子和抗炎细胞因子水平降低，表明失调的失调 免疫和神经胶质过程导致慢性炎症。这种持续的炎症在 该疾病的脱髓鞘，慢性神经胶质激活和神经元死亡的特征。 使用抗炎策略对脊髓神经炎症的有针对性抑制 改善实验性自身免疫性脑脊髓炎（EAE）的症状，MS的大鼠模型。期待 要翻译，需要的不是我们目前的智能注射的方法，而是一个 通过临床相关的，口服的，血脑屏障可渗透的方法有效治疗EAE/MS 靶向由神经炎症驱动的EAE/MS病理学的分子。 我们已经发现并广泛地表征了如此小的分子。这种药物（非阿片类药物 （+） - 纳曲酮的异构体； （+） - 纳曲酮）正在迅速朝着FDA申请研究新药 地位。这是Toll样受体4（TLR4）和TLR2的选择性拮抗剂。由于无法约束古典阿片类药物 受体，（+） - 纳曲酮不会干扰阿片类药物对疼痛控制或正常功能的功效 阿片受体系统。靶向TLR2和TLR4是由广泛的文献引起的 这些受体在神经炎症过程中的重要性以及在此要研究的EAE/MS症状。 在男性和 女性将探索（+） - 纳曲酮抑制EAE诱导的（a）麻痹/麻痹的能力，（b） 神经性疼痛，（c）认知障碍和（d）社会互动障碍以及（e）改善 生存时，当（+） - 纳曲酮在整个几天内全身给药时，比较早期给药 EAE时期。 IHC研究将分析早期后与晚期（+） - 纳曲酮处理（映射到行为研究）以定义（+） - 纳曲酮是否抑制神经胶质 正如预测的那样，激活，神经元细胞死亡和脱髓鞘以及刺激透明膜。 这些研究创造了两个免费目标。 AIM 1探讨了一种新颖的积极介入的手段 EAE引起的运动功能障碍，神经性疼痛，社交互动和认知的缺陷以及通过 通过（+） - 纳曲酮的全身给药靶向TLR4/TLR2。目标2过渡到初始探索 病理生理学的潜在机制，重点是TLR4/TLR2阻碍的影响 脱髓鞘和再髓，神经元细胞死亡和神经炎症。这些研究提供了 对TLR4/TLR2在EAE的主要MS相关症状中的作用进行了详尽的研究。