Sodium Para‐Aminosalicylate Attenuates Neuroinjury Associated With Combined Manganese–Iron Exposure in Rats and PC12 Cells

ABSTRACT

Combined manganese (Mn) and iron (Fe) exposure is increasingly recognized as a risk factor for neurotoxicity, but the underlying mechanisms and potential interventions remain incompletely understood. Here, PC12 cells and Sprague–Dawley rats were used to investigate neuroinjury induced by combined Mn–Fe exposure and the potential protective effects of sodium para‐aminosalicylate (PAS‐Na). Cognitive performance was evaluated using the Morris water maze and Y‐maze, whereas histopathological changes, regional Mn and Fe accumulation, oxidative‐inflammatory injury, Wnt/β‐catenin/GSK‐3β–related proteins, Tau/Aβ‐related alterations, and apoptosis were assessed in PC12 cells and in the hippocampus and cortex of rats. Combined Mn–Fe exposure induced marked neuroinjury, characterized by impaired spatial learning and memory, neuronal damage in the hippocampus and cortex, increased regional brain Mn and Fe burden, enhanced oxidative stress and neuroinflammation, Tau/Aβ‐related abnormalities, apoptosis, and alterations in Wnt/β‐catenin/GSK‐3β–related protein expression. PAS‐Na attenuated these alterations, with medium and high doses generally showing more consistent effects than the low dose. PAS‐Na treatment was associated with reduced Mn and Fe accumulation in cognition‐related brain regions, partial normalization of Wnt/β‐catenin/GSK‐3β–related protein expression, and attenuation of oxidative‐inflammatory injury and neuropathological changes. These novel findings indicate that PAS‐Na partially alleviates combined Mn–Fe‐induced neuroinjury and is associated with reduced regional metal burden, oxidative‐inflammatory injury, apoptosis, and changes in Wnt/β‐catenin/GSK‐3β–related signaling.