Manganese Induces Dopaminergic Neurodegeneration via Microglial Activation in a Rat Model of Manganism

Manganese is an essential trace element required for normaldevelopment and bodily functions. However, exposure of the brainto excessive amounts of manganese results in neurotoxicity.Although previous studies examining manganese neurotoxicityhave focused on neuronal injury, especially direct injury todopaminergic neurons, the effects of manganese-induced neurotoxicityon glial cells have not been reported. The current study wasdesigned to examine the effect of manganese on microglial activation,and the underlying mechanism of manganese-induced dopaminergicneuronal injury in vivo. We established an animal model of manganismby intrastriatal injection of MnCl₂·4H₂O into male Sprague-Dawleyrats. One day after administration of manganese, a few microglialcells in the substantia nigra (SN) were activated, althoughthe number of tyrosine hydroxylase (TH)–immunoreactiveneurons in the SN was unaffected. Seven days after administrationof manganese, a marked reduction in the number of TH-immunoreactiveneurons was observed in the SN, and the majority of microglialcells were activated. We found that manganese upregulated induciblenitric oxide synthase (iNOS) and tumor necrosis factor (TNF-)gene expression, as well as iNOS, TNF-, and interleukin-1β(IL-1β) protein levels in the SN. Furthermore, treatmentwith minocycline, an inhibitor of microglial activation, attenuatedmicroglial activation and mitigated IL-1β, TNF-, and iNOSproduction as well as dopaminergic neurotoxicity induced bymanganese. These results suggested that dopaminergic neuronscould be damaged by manganese neurotoxicity, and that the activatedmicroglial cells and their associated activation products playedan important role in this neurodegenerative process.