N-Acetyl Serotonin Protects Neural Progenitor Cells Against Oxidative Stress-Induced Apoptosis and Improves Neurogenesis in Adult Mouse Hippocampus Following Traumatic Brain Injury
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In this study, with primary mouse neural progenitor cells (NPCs), we investigated the neuroprotective effect of a tropomyosin-related kinase receptor B (TrkB) agonist, N-acetyl serotonin (NAS), against hydrogen peroxide (H2O2)-induced toxicity. We found that pre-incubation with NAS not only ameliorates H2O2-induced cell viability loss, lactate dehydrogenase (LDH) release, and proliferative and migratory capacity impairments, but counteracts H2O2-triggered production of nitric oxide (NO), reactive oxygen species (ROS), malondialdehyde (MDA), and 8-hydroxy-deoxyguanosine (8-OHdG) in a dose-dependent manner. Additionally, pre-treatment with NAS was able to attenuate H2O2-induced apoptosis in NPCs, evidenced by the decreased percentage of apoptotic cells and altered expression of apoptosis-related factors. Furthermore, in differentiated NPCs, NAS improves H2O2-induced reduction in neurite growth. Mechanistic studies revealed that the protective effects of NAS in NPCs may be mediated by the TrkB/PI3K/Akt/ cAMP response element binding protein (CREB) signaling cascades. In a mouse traumatic brain injury (TBI) model, we found that systemic administration of 30 mg/kg NAS could improve hippocampal neurogenesis, manifested by the increased number of SOX-2-positive cells and increased expression of phosphorylated CREB in the dentate gyrus (DG) area. Treatment with NAS also ameliorates cognitive impairments caused by TBI, as assessed by Y-maze and contextual and cued fear conditioning tests. Taken together, these results provide valuable insights into the neuroprotective and neuroregenerative effects of NAS, suggesting it may have therapeutic potential for the treatment of TBI.
KeywordsN-acetyl serotonin Neural progenitor cell Apoptosis Oxidative stress Hippocampal neurogenesis Traumatic brain injury
All authors thank Dr. Jin Li for his kind assistance in data collection and analysis.
Compliance with Ethical Standards
Conflict of Interest
All authors declare that they have no conflict of interest related to this study.
- Blaya MO, Tsoulfas P, Bramlett HM, Dietrich WD (2015) Neural progenitor cell transplantation promotes neuroprotection, enhances hippocampal neurogenesis, and improves cognitive outcomes after traumatic brain injury. Exp Neurol 264:67–81. https://doi.org/10.1016/j.expneurol.2014.11.014 CrossRefGoogle Scholar
- Huang EJ, Reichardt LF (2003) Trk receptors: roles in neuronal signal transduction. Annu Rev Biochem 72:609–642. https://doi.org/10.1146/annurev.biochem.72.121801.161629 CrossRefGoogle Scholar
- Hyder AA, Wunderlich CA, Puvanachandra P, Gururaj G, Kobusingye OC (2007) The impact of traumatic brain injuries: a global perspective. NeuroRehabilitation 22(5):341–353Google Scholar
- Shoji H, Takao K, Hattori S, Miyakawa T (2014) Contextual and cued fear conditioning test using a video analyzing system in mice. J Vis Exp 85. https://doi.org/10.3791/50871
- Stoleru B, Popescu AM, Tache DE, Neamtu OM, Emami G, Tataranu LG, Buteica AS, Dricu A, Purcaru SO (2013) Tropomyosin-receptor-kinases signaling in the nervous system. Maedica (Buchar) 8(1):43–48Google Scholar
- Tullai JW, Chen J, Schaffer ME, Kamenetsky E, Kasif S, Cooper GM (2007) Glycogen synthase kinase-3 represses cyclic AMP response element-binding protein (CREB)-targeted immediate early genes in quiescent cells. J Biol Chem 282(13):9482–9491. https://doi.org/10.1074/jbc.M700067200 CrossRefGoogle Scholar
- Yoo JM, Lee BD, Sok DE, Ma JY, Kim MR (2017) Neuroprotective action of N-acetyl serotonin in oxidative stress-induced apoptosis through the activation of both TrkB/CREB/BDNF pathway and Akt/Nrf2/antioxidant enzyme in neuronal cells. Redox Biol 11:592–599. https://doi.org/10.1016/j.redox.2016.12.034 CrossRefGoogle Scholar