Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, 47500 Bandar Sunway, Selangor, Malaysia.
School of Pharmacy, Monash University Malaysia, 47500 Bandar Sunway, Selangor, Malaysia.
Curr Neuropharmacol. 2024;22(1):140-151. doi: 10.2174/1570159X21666230126161524.
Parkinson's disease (PD) is a heterogeneous disease involving a complex interaction between genes and the environment that affects various cellular pathways and neural networks. Several studies have suggested that environmental factors such as exposure to herbicides, pesticides, heavy metals, and other organic pollutants are significant risk factors for the development of PD. Among the herbicides, paraquat has been commonly used, although it has been banned in many countries due to its acute toxicity. Although the direct causational relationship between paraquat exposure and PD has not been established, paraquat has been demonstrated to cause the degeneration of dopaminergic neurons in the substantia nigra . The underlying mechanisms of the dopaminergic lesion are primarily driven by the generation of reactive oxygen species, decrease in antioxidant enzyme levels, neuroinflammation, mitochondrial dysfunction, and ER stress, leading to a cascade of molecular crosstalks that result in the initiation of apoptosis. This review critically analyses the crucial upstream molecular pathways of the apoptotic cascade involved in paraquat neurotoxicity, including mitogenactivated protein kinase (MAPK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT, mammalian target of rapamycin (mTOR), and Wnt/β-catenin signaling pathways.
帕金森病（PD）是一种异质性疾病，涉及基因与环境之间的复杂相互作用，影响多种细胞途径和神经网络。多项研究表明，环境因素如接触除草剂、杀虫剂、重金属和其他有机污染物是 PD 发展的重要危险因素。在除草剂中，百草枯被广泛使用，尽管由于其急性毒性已在许多国家被禁止使用。尽管百草枯暴露与 PD 之间的直接因果关系尚未确立，但百草枯已被证明会导致黑质中多巴胺能神经元的退化。多巴胺能损伤的潜在机制主要由活性氧的产生、抗氧化酶水平的降低、神经炎症、线粒体功能障碍和内质网应激驱动，导致级联分子相互作用，从而引发细胞凋亡。本综述批判性地分析了百草枯神经毒性中涉及细胞凋亡级联的关键上游分子途径，包括丝裂原活化蛋白激酶（MAPK）、磷脂酰肌醇-4,5-二磷酸 3-激酶（PI3K）/AKT、雷帕霉素靶蛋白（mTOR）和 Wnt/β-连环蛋白信号通路。
