Manganese and related neurotoxic pathways: A potential therapeutic target in neurodegenerative diseases

Neurodegenerative diseases comprise a group of disorders characterized by progressive loss of neurons over a period of time due to various factors such as oxidative stress, inflammation, accumulation of toxic proteins, excitotoxicity, and metal overexposure. Among those, chronic exposure to manganese (Mn) is known to initiate neurodegeneration resembling extrapyramidal effects like Parkinson's disease (PD). Mn overexposure leads to mitochondrial dysfunction by inhibiting the complexes of electron transport chains (ETC), thus generating oxidative stress (OS). It also alter calcium homeostasis, dysregulate enzyme activity, and an imbalance in neurotransmitters level like dopamine, serotonin etc. Mn in excess convert the monomer form of α-synuclein into oligomers that are toxic to neurons. Furthermore, it increases the exocytosis of misfolded α-synuclein, which activates microglia, chemokines, and proinflammatory cytokines. Despite the critical research and investment, no preventive or disease-modifying treatment has been found because of diverse pathological factors. This review focuses on the pathological involvement of Mn and its mechanistic similarities with various neurodegenerative diseases. Further, the source of Mn exposure, various transporters, and its kinetics inside the human body is compiled. The relationship between Mn overexposure and pathogenesis of PD, Huntington's disease (HD), and Alzheimer's disease (AD) has been discussed. Over and above that, the emerging treatment approaches for Mn toxicity utilizing bioinformatics tools, chelation therapy with calcium ethylenediamine tetra-acetic acid (Ca²⁺EDTA), para-aminosalicylic acid (PAS), and phytochemicals like flavonoids that are known to rescue neurons from oxidative stress and inflammation are enveloped in the compilation.