title: 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.
abstract: N-acetyl serotonin (NAS) as a melatonin precursor has neuroprotective actions. Nonetheless, it is not clarified how NAS protects neuronal cells against oxidative stress. Recently, we have reported that N-palmitoyl serotonins possessed properties of antioxidants and neuroprotection. Based on those, we hypothesized that NAS, a N-acyl serotonin, may have similar actions in oxidative stress-induced neuronal cells, and examined the effects of NAS based on in vitro and in vivo tests. NAS dose-dependently inhibited oxidative stress-induced cell death in HT-22 cells. Moreover, NAS suppressed glutamate-induced apoptosis by suppressing expression of AIF, Bax, calpain, cytochrome c and cleaved caspase-3, whereas it enhanced expression of Bcl-2. Additionally, NAS improved phosphorylation of tropomyosin-related kinase receptor B (TrkB) and cAMP response element-binding protein (CREB) as well as expression of brain-derived neurotrophic factor (BDNF), whereas the inclusion of each inhibitor of JNK, p38 or Akt neutralized the neuroprotective effect of NAS, but not that of ERK. Meanwhile, NAS dose-dependently reduced the level of reactive oxygen species, and enhanced the level of glutathione in glutamate-treated HT-22 cells. Moreover, NAS significantly increased expression of heme oxygenase-1, NAD(P)H quinine oxidoreductase-1 and glutamate-cysteine ligase catalytic subunit as well as nuclear translocation of NF-E2-related factor-2. Separately, NAS at 30mg/kg suppressed scopolamine-induced memory impairment and cell death in CA1 and CA3 regions in mice. In conclusion, NAS shows actions of antioxidant and anti-apoptosis by activating TrkB/CREB/BDNF pathway and expression of antioxidant enzymes in oxidative stress-induced neurotoxicity. Therefore, such effects of NAS may provide the information for the application of NAS against neurodegenerative diseases.
authors.affiliation: Korean Medicine-Application Center, Korea Institute of Oriental Medicine, Daegu 41062, Republic of Korea.
authors.forename: Jae-Myung
authors.initials: JM
authors.lastname: Yoo
authors.affiliation: Department of Food and Nutrition, Chungnam National University, Daejeon 34134, Republic of Korea.
authors.forename: Bo Dam
authors.initials: BD
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea.
authors.forename: Dai-Eun
authors.initials: DE
authors.lastname: Sok
authors.affiliation: Korean Medicine-Application Center, Korea Institute of Oriental Medicine, Daegu 41062, Republic of Korea.
authors.forename: Jin Yuel
authors.initials: JY
authors.lastname: Ma
authors.affiliation: Department of Food and Nutrition, Chungnam National University, Daejeon 34134, Republic of Korea. Electronic address: mrkim@cnu.ac.kr.
authors.forename: Mee Ree
authors.initials: MR
authors.lastname: Kim
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000066829:Neuroprotection / Q000187:drug effects; D051058:Oncogene Protein v-akt / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism; D012701:Serotonin / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D000975:Antioxidants; D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D008562:Membrane Glycoproteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D012701:Serotonin; D020813:Receptor, trkB; C000591259:tropomyosin-related kinase-B, human; D051058:Oncogene Protein v-akt; C006389:N-acetylserotonin
keywords: Antioxidant enzymes; Apoptosis; BDNF; Memory impairment; N-acetyl serotonin; Oxidative stress