Department of Biophysics, Panjab University, Chandigarh, India.
Department of Pharmacology, University of Tartu, Tartu, Estonia.
Inflammopharmacology. 2024 Oct;32(5):2801-2820. doi: 10.1007/s10787-024-01549-1. Epub 2024 Aug 13.
Parkinson's disease (PD) is an age-related chronic neurological condition characterized by progressive degeneration of dopaminergic neurons and the presence of Lewy bodies, primarily composed of alpha-synuclein and ubiquitin. The pathophysiology of PD encompasses alpha-synuclein aggregation, oxidative stress, neuroinflammation, mitochondrial dysfunction, and impaired autophagy and ubiquitin-proteasome systems. Among these, the Keap1-Nrf2 pathway is a key regulator of antioxidant defense mechanisms. Nrf2 has emerged as a crucial factor in managing oxidative stress and inflammation, and it also influences ubiquitination through p62 expression. Keap1 negatively regulates Nrf2 by targeting it for degradation via the ubiquitin-proteasome system. Disruption of the Nrf2-Keap1 pathway in PD affects cellular responses to oxidative stress and inflammation, thereby playing a critical role in disease progression. In addition, the role of neuroinflammation in PD has gained significant attention, highlighting the interplay between immune responses and neurodegeneration. This review discusses the various mechanisms responsible for neuronal degeneration in PD, with a special emphasis on the neuroprotective role of the Nrf2-Keap1 pathway. Furthermore, it explores the implications of inflammopharmacology in modulating these pathways to provide therapeutic insights for PD.
帕金森病（PD）是一种与年龄相关的慢性神经疾病，其特征是多巴胺能神经元进行性退化和路易体的存在，路易体主要由α-突触核蛋白和泛素组成。PD 的病理生理学包括α-突触核蛋白聚集、氧化应激、神经炎症、线粒体功能障碍以及自噬和泛素-蛋白酶体系统受损。在这些机制中，Keap1-Nrf2 通路是抗氧化防御机制的关键调节剂。Nrf2 已成为管理氧化应激和炎症的关键因素，它还通过 p62 的表达影响泛素化。Keap1 通过靶向 Nrf2 进行泛素化蛋白酶体降解来负向调节 Nrf2。PD 中 Nrf2-Keap1 通路的破坏会影响细胞对氧化应激和炎症的反应，从而在疾病进展中发挥关键作用。此外，神经炎症在 PD 中的作用引起了广泛关注，强调了免疫反应与神经退行性变之间的相互作用。本综述讨论了导致 PD 中神经元变性的各种机制，特别强调了 Nrf2-Keap1 通路的神经保护作用。此外，还探讨了炎症药理学在调节这些通路方面的意义，为 PD 提供治疗见解。
