Endoplasmic reticulum stress signaling involvement in manganese-induced nerve cell damage in organotypic brain slice cultures

Overexposure to manganese (Mn) has been known to induce neuronal damage. However, the mechanisms underlying the neurotoxicity of Mn are still incompletely understood but seem to involve endoplasmic reticulum (ER) stress. The current study investigated whether ER stress signaling was involved in Mn-induced neurotoxicity in organotypic brain slices. After the brain slices were respectively exposed to 400 μM Mn for 0, 6, 12, 18, 24 h, there was a time-dependent increase in apoptotic cell death in slices and levels of lactate dehydrogenase (LDH) in the culture medium. Moreover, Mn was found to upregulate GRP78/94, CHOP and caspase-12 expression. Furthermore, PERK phosphorylation, PERK-mediated phosphorylation of eIF2a and ATF4 mRNA expression increased. IRE1 activation and Xbp1 mRNA splicing also increased. However, ATF6 p90 levels did not change. The findings clearly demonstrated that Mn induced the ER stress via activation of PERK and IRE1 signaling pathway, which contributed to the occurrence of apoptosis in cultured slices.