Manganese modifies Neurotrophin-3 (NT3) and its tropomyosin receptor kinase C (TrkC) in the cortex: Implications for manganese-induced neurotoxicity

Manganese (Mn), an essential micronutrient, has the potential to induce apoptosis. The NT3/TrkC ligand/receptor pair known as part of the classic neurotrophic theory plays a critical role in neuronal survival. However, whether the NT3/TrkC-mediated signaling pathways are involved in Mn-induced apoptosis of cortical neurons remains unknown. The present study was designed to investigate the interactions between NT3/TrkC-mediated signaling pathways and Mn-induced apoptosis in cortical neurons. This study showed that subacute Mn exposure significantly increased the levels of pro-apoptotic Bax while decreasing the levels of anti-apoptotic Bcl 2 in the cortex compared with the corresponding control. Markedly reduced NT3 and TrkC levels along with decreased Ras/MAPK and PI3/Akt signaling in the cortex were observed following subacute Mn exposure. We further found increased levels of Bax, cleaved caspase-3, and the total apoptosis rate, and decreased levels of Bcl 2, NT3, TrkC, and Ras/MAPK and PI3/Akt signaling in Mn-treated primary cortical neurons. Pretreatment with hNT3 or Z-VAD-FAM ameliorated Mn-induced apoptosis by increasing the levels of NT3 and TrkC and its Ras/MAPK and PI3/Akt signaling pathways. Taken together, our findings clearly indicate that NT3/TrkC and mediated Ras/MAPK and PI3/Akt signaling pathways play a crucial role in Mn-induced neurotoxicity.