STN DBS Effects on Neuroinflammation and Degeneration Induced by Alpha-Synuclein Inclusions

STN DBS 对 α-突触核蛋白包涵体诱导的神经炎症和变性的影响

• 批准号: 10355915
• 负责人: Caryl E Sortwell
• 金额: $ 49.13万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10355915
• 关键词: Brain-Derived Neurotrophic Factor; Cells; Clinical Research; Clinical Trials Design; Corpus striatum structure; Deep Brain Stimulation; Denervation; Diagnosis; Disease; Disease Progression; Dopamine; Electrical Engineering; Enrollment; Exhibits; FDA approved; Female; Functional disorder; Idiopathic Parkinson Disease; Immunohistochemistry; Injections; Laboratories; Link; Maintenance; Mediating; Medical; Modeling; Modification; Motor Cortex; Nerve Degeneration; Neurons; Neurotoxins; Outcome Measure; Parkinson Disease; Patients; Phenotype; Phosphotransferases; Rattus; Reporting; Research Personnel; Resort; Rest Tremor; Rice; Role; STN stimulation; Signal Transduction; Single Nucleotide Polymorphism; Structure of subthalamic nucleus; Substantia nigra structure; Synapses; System; Testing; Time; Transcript; Tropomyosin; Universities; alpha synuclein; density; disease diagnosis; dopaminergic neuron; effective therapy; illness length; male; motor symptom; neuroinflammation; neuronal survival; neuroprotection; neurosurgery; nigrostriatal system; nonhuman primate; novel; overexpression; pars compacta; pilot trial; preclinical study; prevent; putamen; receptor; release factor; synaptic function; synucleinopathy; transcriptome sequencing

Project Summary Subthalamic nucleus deep brain stimulation (STN DBS) to treat the cardinal motor symptoms of Parkinson’s disease (PD) has increased dramatically since its first use was reported in 1994. DBS is a vetted, safe and efficacious neurosurgical therapy for PD. Once considered a treatment of last-resort with patients undergoing neurosurgery approximately 10-16 years post diagnosis, STN DBS now is FDA approved for use as early as four years after diagnosis and symptomatic efficacy may be superior to medical therapy at that time. Questions remain as to whom will best benefit from additional and earlier years of stimulation treatment. Specifically, the question of whether early STN DBS can modify the progression of PD has yet to be examined in an appropriately designed clinical trial. Dopaminergic denervation of the putamen is nearly complete within four years of PD diagnosis and precedes loss of nigral neurons. Thus, neuroprotective therapies that seek to protect the nigrostriatal system cannot be adequately evaluated in subjects with disease duration longer than this four-year timeframe. Several clinical studies have investigated whether STN DBS has the ability to slow or halt the progression of PD. However, the common thread in all of these studies is that the subjects enrolled were mid to late-stage PD when STN DBS was initiated. Most recently, a pilot trial has shown that STN DBS was applied within 2 years of PD diagnosis is safe and efficacious with subjects receiving STN DBS exhibiting a slower worsening of rest tremor. This suggests that early DBS may slow some aspects of PD progression. Preclinical studies by our group and others have demonstrated that STN DBS can protect against degeneration of nigrostriatal dopamine (DA) neurons induced by neurotoxicant insult in both rats and nonhuman primates. In our laboratory we have previously shown that STN DBS significantly increases brain- derived neurotrophic factor (BDNF) in the nigrostriatal system and the primary motor cortex (M1). Further, we have directly linked the neuroprotective effect of STN DBS to BDNF-tropomyosin receptor kinase type B (trkB) signaling in substantia nigra pars compacta (SNpc) neurons as trkB blockade prevents this neuroprotection. In contrast to results in neurotoxicant models, STN DBS applied in the alpha-synuclein (α-syn) overexpression models has yielded mixed neuroprotection results. Whether STN DBS can protect the nigrostriatal system in the context of synucleinopathy therefore remains an open question. In the present proposal we employ an alternative synucleinopathy model: the α-syn preformed fibril (PFF) model. The α-syn PFF model shares key features of idiopathic PD and may be more disease-relevant to idiopathic PD than α-syn overexpression models, potentially providing greater predictive validity. Using the α-syn PFF model we will determine whether STN DBS can provide neuroprotection of SNpc cell bodies, SNpc nigrostriatal terminals and M1 corticostriatal neurons. We will further investigate the impact of long-term STN DBS on potential arbiters of neuroprotection and disease-modification: neuroinflammation and BDNF.

项目概要 丘脑底核深部脑刺激（STN DBS）治疗帕金森病的主要运动症状 自 1994 年首次使用以来，PD 疾病 (PD) 急剧增加。DBS 是一种经过审查、安全且可靠的药物。 有效的神经外科治疗曾被认为是接受治疗的患者的最后手段。 诊断后大约 10-16 年进行神经外科手术，STN DBS 现已获得 FDA 批准，最早可以使用 诊断后四年，对症疗效可能优于当时的药物治疗。 仍然存在哪些人将从额外的和早期的刺激治疗中受益最多的问题。 早期 STN DBS 是否可以改变 PD 的进展这一问题尚未在一项研究中得到检验。 适当设计的临床试验在四年内几乎完成了壳核的多巴胺能去神经术。 多年的帕金森病诊断和黑质神经元损失之前，神经保护疗法寻求解决这一问题。 对于病程长于以下的受试者，无法充分评估对黑质纹状体系统的保护作用 在这四年的时间范围内，多项临床研究调查了 STN DBS 是否有能力减缓或缓解。 然而，所有这些研究的共同点是受试者入组。 STN DBS 启动时已处于中晚期 PD 最近，一项试点试验表明 STN DBS。 在 PD 诊断后 2 年内应用是安全有效的，接受 STN DBS 的受试者表现出 静止性震颤恶化速度较慢，这表明早期 DBS 可能会减缓 PD 进展的某些方面。 我们小组和其他人的临床前研究表明 STN DBS 可以预防 大鼠和大鼠中神经毒物损伤引起的黑质纹状体多巴胺（DA）神经元变性 在我们的实验室中，我们之前已经证明 STN DBS 显着增加了非人类灵长类动物的大脑功能。 黑质纹状体系统和初级运动皮层（M1）中的衍生神经营养因子（BDNF）。 STN DBS 的神经保护作用与 BDNF 原肌球蛋白受体激酶 B 型 (trkB) 直接相关 黑质致密部 (SNpc) 神经元中的信号传导，因为 trkB 阻断可防止这种神经保护作用。 与神经毒物模型的结果相反，STN DBS 应用于 α-突触核蛋白 (α-syn) 过度表达 STN DBS 是否可以保护黑质纹状体系统，模型得出了不同的神经保护结果。 因此，突触核蛋白病的背景仍然是一个悬而未决的问题，在本提案中，我们采用了一个概念。 另一种突触核蛋白病模型：α-syn 预形成纤维 (PFF) 模型 α-syn PFF 模型共享关键。 特发性 PD 的特征，并且可能比 α-syn 过度表达与特发性 PD 的疾病相关性更大 模型，可能提供更大的预测有效性，我们将使用 α-syn PFF 模型来确定是否 STN DBS 可以为 SNpc 细胞体、SNpc 黑质纹状体末梢和 M1 皮质纹状体提供神经保护 我们将进一步研究长期 STN DBS 对神经保护潜在仲裁者的影响。 和疾病缓解：神经炎症和 BDNF。