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.

项目摘要 丘脑下核深脑刺激（STN DBS）治疗帕金森氏症的基本运动症状 自1994年报道以来，疾病（PD）已有急剧增加。DBS是经过审查，安全且 有效的PD神经外科治疗。曾经考虑过与患者接受的最后路由的治疗 诊断后大约10 - 16年的神经外科手术，STN DBS现在已获得FDA批准，以便早在 诊断后四年和症状效率可能优于当时的医疗疗法。问题 保持谁将最能通过额外和早期的刺激治疗受益。具体来说， 早期STN DB是否可以修改PD的进展的问题尚未在 适当设计的临床试验。勒壳的多巴胺能神经蛋白酶几乎在四个之内完成 多年的PD诊断和先于ni骨神经元的丧失。那就是试图的神经保护疗法 在疾病持续时间的受试者中，无法对骨纹状体系统进行保护比 这个四年的时间表。几项临床研究已经调查了STN DBS是否具有减速或 停止PD的进展。但是，所有这些研究中的共同线程是受试者招收 启动STN DBS时是中晚期PD。最近，试点试验表明STN DBS 在PD诊断的2年内应用于接收STN DB的受试者，可安全有效 担心休息震颤的速度较慢。这表明早期DB可能会减慢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 在大鼠和 非人类隐私。在我们的实验室中，我们以前已经表明，STN DBS显着增加了大脑 骨纹状体系统和原发性运动皮层（M1）中的衍生神经营养因子（BDNF）。此外，我们 已直接将STN DBS的神经保护作用与BDNF-胶质素受体激酶B（TRKB）联系起来 trkB阻断时，黑质Nigra Pars Commanta（SNPC）神经元的信号传导可防止这种神经保护作用。在 与神经毒性模型的结果形成鲜明对比，STN DBS应用于α-突触核蛋白（α-Syn）过表达 模型产生了混合的神经保护结果。 STN DBS是否可以保护底层纹状体系统 因此，突触核苷的背景仍然是一个悬而未决的问题。在本提案中，我们雇用 替代突触核酸模型：α-Syn预形的原纤维（PFF）模型。 α-Syn PFF模型共享密钥 特发性PD的特征，可能与特发性PD相比，可能与α-Syn的过表达更为疾病 模型，有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 STN DBS可以提供​​SNPC细胞体，SNPC黑质纹状体末端和M1皮质纹状体的神经保护作用 神经元。我们将进一步调查长期STN DB对神经保护的潜在仲裁者的影响 和疾病调整：神经炎症和BDNF。