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。 帕金森病 (PD) 会导致运动和非运动表现。潜在病理包括异常 α-突触核蛋白（α-syn）从尾部脑干（以及嗅结节和内侧脑干）开始沉积 颞区），然后扩散到更多的脑干和皮质区域。初始运动表现 可能反映了黑质纹状体多巴胺能通路的退化，但皮质功能障碍导致 非运动和一些运动表现可能反映直接 α-syn 参与、神经递质缺乏 由于突出的脑干核团丧失或皮质或皮质下网络的继发性功能障碍。 目前，没有任何治疗方法可以延缓帕金森病的持续进展。我们有初步数据（神经炎症， 非人灵长类动物 (NHP) 黑质纹状体损伤后活性氧含量增加，这表明 皮质纹状体神经元逆行变性可能会导致皮质功能障碍。这里我们将测试 抗炎化合物 Synoxizyme（以前称为羧基富勒烯或 C3）是否会减少 观察到的神经炎症，并防止逆行性皮质损伤作为一种潜在机制，可以 导致帕金森病患者残疾。我们将证实这一发现并验证体内 PET 测量 神经炎症和活性氧。我们还证明了 synoxizyme 可恢复黑质纹状体 单侧颈内动脉 (ic) 输注选择性神经毒素 MPTP 后功能障碍。合酶可能起作用 通过减弱神经炎症并减少破坏性活性氧。这次的另一个目标 研究的目的是确定我们的新型 PET 放射性示踪剂是否可以作为 synoxizyme 的参与靶标。 这些高度新颖的研究将确定 MPTP 对非人类灵长类动物的黑质纹状体损伤是否会导致 皮质功能障碍，这可以为研究皮质功能障碍的另一种机制提供基础 PD 患者出现的功能障碍。此外，我们将验证新的 PET 措施 神经炎症和活性氧可能是此类研究的关键。我们将确定是否 扩散张量成像 MR 测量平均扩散率可识别皮质纹状体束功能障碍 支持黑质纹状体损伤后逆行性变的概念。我们还将确定是否 全身施用 Synoxizyme 会减弱 MPTP 的作用，这是否与 减少 MPTP 诱导的神经炎症并增加活性氧 - 这可能是 参与人类PD的发病机制。最后，我们将能够证明 PET 是否可以测量 可以提供共酶参与目标的量化，这对于 Synoxizyme 或任何其他针对这些致病菌的治疗方法的后续临床试验 PD 或其他神经退行性疾病的机制。