Manganese modifies Neurotrophin-3 (NT3) and its tropomyosin receptor kinase C (TrkC) in the cortex: Implications for manganese-induced neurotoxicity
- Food Chem Toxicol. 2020 Jan:135:110925. doi: 10.1016/j.fct.2019.110925.
- 1. Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning, 530021, China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, 530021, China.
- 2. Center for Reproductive Medicine and Genetics, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, China.
- 3. Department of Occupational Health and Environmental Health, School of Public Health, Guangxi Medical University, Nanning, 530021, China.
- 4. Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, China.
- 5. Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning, 530021, China.
- 6. Department of Occupational Health and Environmental Health, School of Public Health, Guangxi Medical University, Nanning, 530021, China. Electronic address: [email protected].
- 7. Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning, 530021, China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, 530021, China. Electronic address: [email protected].
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.