School of Medicine, University of Nottingham, Royal Derby Hospital Centre, Derby DE22 3DT, UK.
Department of Biological Sciences, College of Science, King Faisal University, P.O. Box 400, Al-Ahsa 31982, Saudi Arabia.
Int J Mol Sci. 2023 Jul 3;24(13):11022. doi: 10.3390/ijms241311022.
There are currently no pharmacological treatments available that completely halt or reverse the progression of Parkinson's Disease (PD). Hence, there is an unmet need for neuroprotective therapies. Lewy bodies are a neuropathological hallmark of PD and contain aggregated α-synuclein (α-syn) which is thought to be neurotoxic and therefore a suitable target for therapeutic interventions. To investigate this further, a systematic review was undertaken to evaluate whether anti-α-syn therapies are effective at preventing PD progression in preclinical in vivo models of PD and via current human clinical trials. An electronic literature search was performed using MEDLINE and EMBASE (Ovid), PubMed, the Web of Science Core Collection, and Cochrane databases to collate clinical evidence that investigated the targeting of α-syn. Novel preclinical anti-α-syn therapeutics provided a significant reduction of α-syn aggregations. Biochemical and immunohistochemical analysis of rodent brain tissue demonstrated that treatments reduced α-syn-associated pathology and rescued dopaminergic neuronal loss. Some of the clinical studies did not provide endpoints since they had not yet been completed or were terminated before completion. Completed clinical trials displayed significant tolerability and efficacy at reducing α-syn in patients with PD with minimal adverse effects. Collectively, this review highlights the capacity of anti-α-syn therapies to reduce the accumulation of α-syn in both preclinical and clinical trials. Hence, there is potential and optimism to target α-syn with further clinical trials to restrict dopaminergic neuronal loss and PD progression and/or provide prophylactic protection to avoid the onset of α-syn-induced PD.
目前尚无能够完全阻止或逆转帕金森病（PD）进展的药物治疗方法。因此，需要神经保护疗法。路易体是 PD 的神经病理学标志，包含聚集的α-突触核蛋白（α-syn），被认为具有神经毒性，因此是治疗干预的合适靶点。为了进一步研究这一点，进行了系统评价，以评估抗α-syn 疗法是否能有效预防 PD 临床前体内模型和当前人类临床试验中的 PD 进展。使用 MEDLINE 和 EMBASE（Ovid）、PubMed、Web of Science Core Collection 和 Cochrane 数据库进行了电子文献检索，以收集调查靶向α-syn 的临床证据。新型临床前抗α-syn 疗法可显著减少α-syn 聚集。对啮齿动物脑组织的生化和免疫组织化学分析表明，这些治疗方法减少了α-syn 相关的病理学并挽救了多巴胺能神经元的丢失。一些临床研究没有提供终点，因为它们尚未完成或在完成之前就已终止。已完成的临床试验显示出在降低 PD 患者的α-syn 方面具有良好的耐受性和疗效，且副作用最小。总的来说，这篇综述强调了抗α-syn 疗法在临床前和临床试验中减少α-syn 积累的能力。因此，有潜力和乐观的前景可以通过进一步的临床试验来靶向α-syn，以限制多巴胺能神经元的丢失和 PD 的进展，或提供预防性保护以避免由α-syn 引起的 PD 的发生。
