Melatonin-induced neuroprotection after closed head injury is associated with increased brain antioxidants and attenuated late-phase activation of NF-kappaB and AP-1.
Traumatic brain injury (TBI) is followed by massive production of reactive oxygen species (ROS), which mediate secondary cellular damage. Low molecular weight antioxidants (LMWA) constitute one of the defense mechanisms of the brain, and their levels correlate with post-TBI outcome. Melatonin, the main pineal hormone, possesses antioxidant properties. We investigated the effects of melatonin on neurobehavioral recovery, brain LMWA, and activation of the redox-sensitive transcription factors nuclear factor-kappaB (NF-kappaB) and AP-1 in mice subjected to closed head injury (CHI). Given 1 h after CHI, melatonin facilitated recovery during at least 1 wk (P<0.05) and decreased lesion size by approximately twofold (P<0.01). The dose response displayed a bell-shape, i.e., neuroprotection was achieved with 5 but not 1 or 10 mg/kg. At the neuroprotective dose, melatonin treatment was associated with sustained (4 days) elevation of brain LMWA, including ascorbic acid (P<0.05). In contrast, LMWA were unaffected by the administration of the neuroprotective endocannabinoid 2-arachidonoyl glycerol. Furthermore, melatonin did not alter early phase (24 h) CHI-induced activation of NF-kappaB and AP-1; however, it blocked the robust late-phase (8 days) activation of NF-kappaB and decreased that of AP-1 to below basal levels. Our results demonstrate that melatonin induces neuroprotection, presumably via potentiation of brain antioxidants and attenuation of NF-kappaB and AP-1 activation.
Department of Pharmacology, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
Sara M
SM
Beni
Ron
R
Kohen
Russel J
RJ
Reiter
Dun-Xian
DX
Tan
Esther
E
Shohami
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D016489:Head Injuries, Closed / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D007700:Kinetics; D008550:Melatonin / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010084:Oxidation-Reduction; D018808:Transcription Factor AP-1 / Q000378:metabolism
D000975:Antioxidants; D016328:NF-kappa B; D018696:Neuroprotective Agents; D018808:Transcription Factor AP-1; D008550:Melatonin