Manganese (Mn) and iron (Fe) serve as essential cofactors for numerous enzymes and play critical roles in neural functions within the central nervous system. However, chronic overexposure to these metals can disrupt neurophysiological homeostasis. The mechanisms underlying combined Mn-Fe exposure induced neurotoxicity remain unclear. Sodium para-aminosalicylate (PAS-Na), a non-steroidal anti-inflammatory drug capable of crossing the blood-brain barrier, has demonstrated efficacy in treating Mn poisoning. This study investigated the neurotoxic effects of Mn-Fe co-exposure in rats and evaluated the protective role of PAS-Na. Our findings reveal that Mn-Fe co-exposure induced significant weight gain suppression, increased liver coefficient, and extensive motor dysfunction manifested as coordination deficits, balance disturbance, and reduced muscle endurance. Histopathological analysis demonstrated severe neurodegeneration in the substantia nigra, characterized by neuronal atrophy, Nissl body depletion, and dopaminergic neuron loss (evidenced by reduced TH⁺ cells and TH protein expression). Furthermore, co-exposure disrupted metal homeostasis, elevating nigral Fe and Ca levels, and activating the NF-κB pathway, upregulating pro-inflammatory cytokines (IL-1β, TNF-α, IL-6). Notably, PAS-Na treatment (160-240 mg/kg) dose-dependently attenuated these effects through two mechanisms: (1) modulating metal accumulation (particularly Fe) and (2) suppressing NF-κB-mediated neuroinflammation, with preferential inhibition of TNF-α. These findings highlight PAS-Na's potential as a preventive therapy for metal-induced neurodegeneration, particularly in occupational co-exposure scenarios. The study provides novel insights into synergistic Mn-Fe neurotoxicity and identifies NF-κB inhibition as a promising therapeutic target.
