Neuroinflammatory Biomarkers for Nigrostriatal Injury

黑质纹状体损伤的神经炎症生物标志物

• 批准号: 10421066
• 负责人: JOEL Synes PERLMUTTER
• 金额: $ 63.63万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10421066
• 关键词: Address; Animals; Anti-Inflammatory Agents; Area; Attenuated; Biological Markers; Brain; Brain Stem; Cell Nucleus; Clinical Trials; Corpus striatum structure; Data; Deposition; Diffuse; Diffusion Magnetic Resonance Imaging; Dopamine; Drug Targeting; Fiber; Functional disorder; Goals; Histologic; Human; In Vitro; Infusion procedures; Injury; Investigation; Lead; Magnetic Resonance; Magnetic Resonance Imaging; Measures; Medial; Motor; Motor Cortex; Motor Manifestations; Nerve; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurotoxins; Neurotransmitters; Olfactory tubercle; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Peritoneal; Persons; Placebos; Positron-Emission Tomography; Process; Pump; Reactive Oxygen Species; Reporting; Retrograde Degeneration; Testing; Training; alpha synuclein; attenuation; brain tissue; disability; imaging biomarker; implantation; in vivo; kinematics; motor symptom; nerve damage; neuroimaging marker; neuroinflammation; nigrostriatal degeneration; nigrostriatal dopaminergic pathway; nonhuman primate; novel; novel therapeutics; prevent; radiotracer; response

ABSTRACT. Parkinson disease (PD) causes motor and nonmotor manifestations. Underlying pathology includes abnormal deposition of α-synuclein (α-syn) starting in caudal brainstem (as well as olfactory tubercle and medial temporal areas) and then spreads to more rostral brainstem and cortical areas. Initial motor manifestations likely reflect degeneration to the nigrostriatal dopaminergic pathway but cortical dysfunction leading to nonmotor and some motor manifestations may reflect direct α-syn involvement, neurotransmitter deficiencies due to loss of projecting brainstem nuclei or secondary dysfunction of cortical or subcortical networks. Currently, no treatment delays the relentless progression of PD. We have preliminary data (neuroinflammation, increased reactive oxygen species) after nigrostriatal injury in nonhuman primates (NHPs) that suggests that cortical dysfunction may occur from retrograde degeneration along cortico-striatal neurons. Here we will test whether an anti-inflammatory compound, synoxizyme (previously called carboxyfullerene or C3), will reduce the observed neuroinflammation, and prevent retrograde cortical injury as a potential mechanism which could contribute to disability in people with PD. We will confirm this finding and validate in vivo PET measures of neuroinflammation and reactive oxygen species. We also demonstrated that synoxizyme restores nigrostriatal dysfunction after unilateral internal carotid (ic) infusion of the selective neurotoxin MPTP. Synoxizyme may act through attenuation of neuroinflammation and reduce destructive reactive oxygen species. Another goal of this study is to determine whether our new PET radiotracers can act as targets of engagement for synoxizyme. These highly novel studies will determine whether nigrostriatal injury with MPTP in nonhuman primates leads to cortical dysfunction which could provide the basis for investigations into another mechanism of cortical dysfunction that occurs in people with PD. Furthermore, we will validate new PET measures of neuroinflammation and reactive oxygen species that could be key for such studies. We will determine whether diffusion tensor imaging MR measures of mean diffusivity identify cortical striatal tract dysfunction that could support the notion of retrograde degeneration after nigrostriatal injury. We also will determine whether systemically administered synoxizyme will attenuate the effects of MPTP and whether this corresponds with a reduction in MPTP-induced neuroinflammation and increased reactive oxygen species – which may be involved in the pathogenesis of human PD. Finally, we will be able to demonstrate whether the PET measures may provide quantification of targets of engagement for synoxizyme, which would be critical information for a subsequent clinical trial in humans of synoxizyme or any other treatment targeting these pathogenic mechanisms in PD or other neurodegenerative conditions.

抽象的。 帕金森氏病（PD）引起运动和非运动表现。潜在的病理包括异常 从尾脑干开始的α-突触核蛋白（α-Syn）的沉积（以及嗅觉结节和培养基 临时区域），然后扩散到更宽阔的脑干和皮质区域。初始电机表现 可能反映了对黑质纹状体多巴胺能途径的退化，但皮质功能障碍导致 非运动和某些运动表现可能反映直接α-Syn参与，神经递质缺陷 由于脑干核或皮质下网络的次要功能障碍的损失。 目前，没有治疗延迟了PD的不断发展。我们有初步数据（神经炎症， 在非人类隐私（NHP）中骨膜造成损伤后的活性氧增加），这表明 皮质功能障碍可能来自沿皮质 - 纹状体神经元的逆行变性。在这里我们将测试 抗炎化合物，同氧化剂（以前称为羧酸烯还是C3）都会减少 观察到的神经炎症，并防止逆行皮质损伤作为一种潜在机制，可能 有助于PD患者的残疾。我们将确认这一发现并验证体内宠物的测量 神经炎症和活性氧。我们还证明，同步恢复了黑质纹状体 选择性神经毒素MPTP的单侧内颈内（IC）输注后功能障碍。同步可以起作用 通过衰减神经炎症并减少破坏性活性氧。另一个目标 研究是为了确定我们的新宠物放射性示例是否可以充当同步的范围。 这些高度新颖的研究将确定在非人类原发性铅中使用MPTP损伤 为皮质功能障碍，这可以为投资提供基础，以成为另一种皮质机制 PD患者发生功能障碍。此外，我们将验证新的宠物测量 可能是此类研究的关键的神经炎症和活性氧。我们将确定是否 扩散张量化成像的MR测量值是平均可不同性识别皮质纹状体纹状体功能障碍的测量值 支持骨膜损伤后逆行变性的概念。我们还将确定是否 系统施用的同步会减弱MPTP的影响，并且是否与A相对应 MPTP诱导的神经炎症和活性氧的减少 - 可能是 参与人PD的发病机理。最后，我们将能够证明宠物测量是否 可以提供同步的参与目标的量化，这将是至关重要的信息 随后在人类中的临床试验或任何其他针对这些致病性的治疗 PD或其他神经退行性条件的机制。