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

项目摘要 丘脑底核脑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，PD的发病率急剧增加。DBS是一个经过审查，安全， 有效的神经外科治疗PD。曾经被认为是最后的治疗手段， 神经外科大约诊断后10-16年，FDDBS现在被FDA批准使用， 四年后确诊和对症治疗的疗效可能上级当时的药物治疗。问题 仍然是谁将最好地受益于额外的和更早的刺激治疗。具体而言是 早期DBS是否可以改变PD的进展，这一问题还有待于在一个研究中进行研究。 适当设计的临床试验。壳核的多巴胺能去神经支配在四年内几乎完成 多年的PD诊断和黑质神经元的损失之前。因此，寻求神经保护疗法， 保护黑质纹状体系统不能在疾病持续时间超过 这四年的时间。几项临床研究已经调查了DBS是否有能力减缓或 阻止PD的发展。然而，所有这些研究的共同点是， 当开始DBS时，患者处于中晚期PD。最近，一项试点试验表明， 在PD诊断后2年内应用安全有效，接受DBS治疗的受试者表现出 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。 我们小组和其他人的临床前研究表明，DBS可以防止 神经毒素损伤引起的大鼠黑质纹状体多巴胺（DA）神经元变性， 非人类灵长类动物在我们的实验室中，我们以前已经表明，脑深部电刺激显著增加脑- 黑质纹状体系统和初级运动皮质（M1）中的衍生神经营养因子（BDNF）。我们还 已经将脑源性DBS的神经保护作用与BDNF-原肌球蛋白受体激酶B型（trk B）直接联系起来 在黑质丘脑部（SNpc）神经元中的信号传导作为trkB阻断阻止了这种神经保护。在 与神经毒性模型的结果相反，在α-突触核蛋白（α-syn）过表达中应用了DBS 模型产生了混合的神经保护结果。脑深部电刺激是否能保护黑质纹状体系统， 因此，突触核蛋白病的背景仍然是一个悬而未决的问题。在本建议中，我们采用了 另一种突触核蛋白病模型：α-syn预成形纤维（PFF）模型。α-syn PFF模型共享密钥 特发性PD的特征，并且可能比α-syn过表达与特发性PD更相关 模型，可能提供更大的预测有效性。使用α-syn PFF模型，我们将确定是否 DBS可对SNpc细胞体、SNpc黑质纹状体终末和M1皮质纹状体神经元提供神经保护作用。 神经元我们将进一步研究长期DBS对神经保护的潜在仲裁者的影响 和疾病修饰：神经炎症和BDNF。

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.