Role of manganese in brain health and disease: Focus on oxidative stress

Manganese (Mn) is an essential trace element crucial for various physiological processes, but excessive exposure can lead to significant health concerns, particularly neurotoxicity. This review synthesizes current knowledge on Mn-induced oxidative stress and its role in cellular dysfunction and disease. We discuss how Mn promotes toxicity through multiple mechanisms, primarily through reactive oxygen species (ROS) generation, which leads to oxidative stress and disruption of cellular processes. The review examines key pathways affected by Mn toxicity, including mitochondrial dysfunction, endoplasmic reticulum stress, inflammasome activation, and epigenetic modifications. Recent studies have identified promising therapeutic compounds, including both synthetic and natural substances such as probucol, metformin, curcumin, resveratrol, and daidzein, which demonstrate protective effects through various mechanisms, including antioxidant enhancement, mitochondrial function preservation, and epigenetic pathway modulation. Understanding these mechanisms provides new insights into potential therapeutic strategies for Mn-induced disorders. This review also highlights future research directions, emphasizing the need for developing targeted therapies and investigating combination approaches to address multiple aspects of Mn toxicity simultaneously.