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

项目摘要 丘脑底核深部电刺激治疗帕金森病的主要运动症状 自1994年首次使用以来，疾病(PD)已急剧增加。星展银行是一家经过审查、安全和 帕金森病的有效神经外科治疗。曾被认为是对正在接受治疗的患者的最后手段 神经外科诊断后大约10-16年，STN DBS现在最早被FDA批准使用 四年后诊断和对症疗效可能优于当时的药物治疗。问题 至于谁将从额外的和更早的刺激治疗中受益最大，这一点仍然存在。具体地说， 关于早期STN DBS是否可以改变PD的进展的问题还有待于 设计得当的临床试验。壳核的多巴胺能神经支配在4小时内几乎完成。 多年的帕金森病诊断，并在黑质神经元丧失之前。因此，寻求神经保护疗法的 对于病程超过30天的受试者，不能充分评估黑质纹状体系统的保护 这四年的时间框架。几项临床研究已经调查了STN DBS是否有能力减缓或 阻止帕金森病的进展。然而，所有这些研究的共同主线是，受试者 STN DBS启动时均为中晚期PD。最近，一项试点试验表明，STN DBS 在帕金森病诊断后2年内应用是安全有效的，接受STN DBS的受试者表现为 静止性震颤的缓慢恶化。这表明，早期DBS可能会减缓PD进展的某些方面。 我们团队和其他人进行的临床前研究表明，STN DBS可以预防 神经毒物致大鼠和大鼠黑质纹状体多巴胺神经元变性 非人灵长类动物。在我们的实验室中，我们之前已经证明STN DBS显著增加了大脑- 黑质纹状体系统和初级运动皮质中的衍生神经营养因子(BDNF)。此外，我们 已将STN DBS的神经保护作用与BDNF-原肌球蛋白受体B型(TrkB)直接联系起来 当TrkB阻断时，黑质致密部(SNPC)神经元中的信号可阻止这种神经保护。在……里面 与神经毒性模型的结果相比，STN DBS应用于α-突触核蛋白(α-SYN)的过表达 模型产生了好坏参半的神经保护结果。STN DBS对黑质纹状体系统的保护作用 因此，联核症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 交替性突触核病模型：α-SYN预形成纤维(Pff)模型。α-SYN pff模型共享密钥 特发性帕金森病的特征及其与特发性帕金森病的相关性可能比α-SYN的过度表达更具相关性 模型，潜在地提供更大的预测有效性。使用α-SYN PFF模型，我们将确定 STN DBS对SNPC胞体、SNPC黑质纹状体终末和M1皮质纹状体具有神经保护作用 神经元。我们将进一步调查长期STN DBS对神经保护潜在仲裁者的影响 疾病修饰：神经炎症和脑源性神经营养因子。

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.