Rotenone-Induced Mitochondrial Dysfunction, Neuroinflammation, Oxidative Stress, and Glial Activation in Parkinson’s and Alzheimer’s Diseases

Rotenone is a lipophilic herbicide extensively utilized in experimental neurodegenerative models because of its capacity to disrupt complex I of the mitochondrial electron transport chain. This inhibition results in reduced ATP synthesis, elevated reactive oxygen species (ROS) formation, and mitochondrial malfunction, which instigates oxidative stress and cellular damage, critical elements in neurodegenerative disorders like Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Alzheimer’s disease (AD). In addition to causing direct neuronal injury, rotenone significantly contributes to the activation of glial cells, specifically microglia and astrocytes. Activated microglia assumes a proinflammatory (M1) phenotype, distinguished by the secretion of inflammatory cytokines including tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1 β), and interleukin 6 (IL-6), with the generation of nitric oxide and ROS, which exacerbate the neuronal injury. Astrocytes can intensify neuroinflammation by secreting proinflammatory molecules and impairing their neuroprotective roles. Our hypothesis is that rotenone is posited to elicit a neuroinflammatory response via mitochondrial malfunction, ROS generation, and the activation of proinflammatory pathways in microglia and astrocytes. This mechanism leads to accelerated neuronal impairment, promoting neurodegeneration. Comprehending the inflammatory pathways activated by rotenone is crucial for pinpointing therapeutic targets to regulate glial responses and mitigate the advancement of neurodegenerative disorders linked to mitochondrial malfunction and chronic inflammation. This review examines the function of glial cells and critical inflammatory pathways, namely Nuclear factor kappa β (NF-κB), Phosphoinositide 3-kinase/Protein kinase B/Mammalian target of rapamycin (PI3K/AKT/mTOR), and Wnt/β-catenin signaling pathway in Parkinson’s disease, Alzheimer’s disease, and ALS, emphasizing illness-specific responses and the translational constraints of rotenone-based models. The objective is to consolidate existing understanding regarding the role of rotenone-induced mitochondrial failure in promoting glial activation and neuroinflammation, highlighting the necessity for additional research into these pathways. Despite the prevalent application of rotenone in experimental models, its specific effects on glial-mediated inflammation are inadequately comprehended, necessitating further investigation to guide the formulation of targeted therapeutic strategies.