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.
Some N-acyl dopamines have been reported to show anti-inflammatory and immunomodulatory activities. In this respect, we examined the immunosuppressive effect of N-acyl dopamines on splenocytes of BALB/c mice. First, when the effect of each endocannabinoid or its derivative on Con A-induced proliferation of splenocytes, N-arachidonoyl dopamine (NADA), N-oleoyl dopamine (OLDA) and N-palmitoyl dopamine (PALDA) potently suppressed Con A-mediated splenocyte proliferation with IC 50 value of 1.84, 2.45, and 8.54 mM, respectively, indicating that NADA and OLDA were more immunosuppressive than PALDA. In related study, the immunosuppressive effect of NADA or PALDA was antagonized partially by CB1 antagonist, SR141716, and TRPV1 antagonist, 5 0 -iodoresiniferatoxin (5 0 -IRTX), but not CB2 antagonist, AM630. Meanwhile, the effect of OLDA was suppressed partially by 5 0 -IRTX, but not other antagonists. In further study to support the immunosuppressive activity of N-acyl dopamines, the effect of N-acyl dopamaines on the release of cytokines was investigated. Noteworthy, NADA (IC 50 , 0.53 mM), OLDA (IC 50 , 0.78 mM) and PALDA (IC 50 , 2.45 mM) inhibited the secretion of interferon-g from Con A-stimulated splenocytes concentrationdependently. A similar suppression of the release of tumor necrosis factor alpha-a and interleukin-2 was also expressed by N-acyl dopamines. Additionally, the suppressive effect of NADA or PALDA on cytokine release was antagonized partly by SR141716 or 5 0 -IRTX, and that of OLDA was antagonized partly by 5 0 -IRTX. Separately, NADA and OLDA enhanced the level of 12(S)-hydroxyeicosatetraenoic acid an endogenous TRPV1 agonist. These findings suggest that N-acyl dopamines may express immunomodulatory action through pathways involving CB1 and TRPV1 receptors in splenocytes.
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