title: Neuroprotective effect of N-acyl 5-hydroxytryptamines on glutamate-induced cytotoxicity in HT-22 cells.
abstract: Some endocannabinoids have been known to express anti-inflammatory and antioxidant actions independent of cannabinoid receptors. In this respect, we investigated whether N-acyl 5-hydroxytryptamines (5-HTs) might prevent against glutamate-induced oxidative cytotoxicity in HT-22 cells, and attempted to elucidate the mechanism for their cytoprotective action. N-acyl 5-HTs with palmitoyl, stearoyl, arachidonoyl or docosahexaenoyl chain expressed a remarkable protective effect on glutamate-induced cytotoxicity. Additionally, glutamate-induced oxidative stress, represented by the increase of reactive oxygen species level and the reduction of glutathione level, was prevented markedly by N-acyl 5-HTs at submicromolar levels. Further, N-palmitoyl 5-HT, the most cytoprotective, enhanced antioxidant defense by up-regulating the expression of antioxidant enzymes such as heme oxygenase-1, glutamate-cysteine ligase catalytic subunit or NAD(P)H quinine oxidoreductase-1 in the presence or absence of glutamate. Consistent with this, N-palmitoyl 5-HT stimulated nuclear translocation of Nrf2 in early phase (2 h), and this effect was remarkably suppressed by inhibitors of PI3K, PDK-1, Akt or p38 MAPK. Additionally, N-palmitoyl 5-HT suppressed glutamate-induced activation of ERK in late phase (12 h), but not in early phase (2 h), presumably supporting the implication of MEK/ERK pathway in glutamate-induced cytotoxicity. Collectively, it is suggested that N-acyl 5-HTs may attenuate glutamate-induced cytotoxicity via the activation of PI3K/PDK-1/Akt- and p38 MAPK-dependent Nrf2 signaling in early phase as well as the suppression of MEK/ERK pathway in late phase.
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon, 305-764, Republic of Korea.
authors.forename: Mei Chen
authors.initials: MC
authors.lastname: Jin
authors.forename: Jae-Myung
authors.initials: JM
authors.lastname: Yoo
authors.forename: Dai-Eun
authors.initials: DE
authors.lastname: Sok
authors.forename: Mee Ree
authors.initials: MR
authors.lastname: Kim
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D005973:Glutamine / Q000633:toxicity*; D006801:Humans; D020935:MAP Kinase Signaling System; D018696:Neuroprotective Agents / Q000494:pharmacology*; D012701:Serotonin / Q000494:pharmacology*
chemical_list: D018696:Neuroprotective Agents; D005973:Glutamine; D012701:Serotonin