Melatonin protects primary cultures of rat cortical neurones from NMDA excitotoxicity and hypoxia/reoxygenation.
Studies on rat cortical cultures show that glutamate (10 microM) or hypoxia followed by reoxygenation causes damage to the cells as indexed by a release of lactate dehydrogenase (LDH). These effects could be counteracted by the N-methyl-D-aspartate (NMDA) antagonist MK-801 (2 microM) but not by the kainate/AMPA antagonist CNQX (100 microM). These data favour the view that the damage caused to the cells by glutamate and hypoxia/reperfusion is mediated via NMDA receptors. The damage to the cells could also be prevented by melatonin (100 microM). The melatonin effect is not mediated by specific receptors because it was not blunted by the melatonin antagonist, luzindole. Moreover, NMDA stimulated an accumulation of 45Ca2+ by cortical neurones, but although this effect was counteracted by MK-801, melatonin was ineffective, which showed that the neuroprotective effect of melatonin is not elicited by direct action with NMDA receptors. Ascorbate and iron stimulated the production of free radicals in a retinal cell preparation. Chelation of the iron with deferoxamine prevented this process as did melatonin while MK-801 had no effect. The combined findings suggest that melatonin counteracts the in vitro destructive effects of NMDA or hypoxia/reperfusion by preventing accumulation of excessive free radicals.
Cazevieille
C
C
Nuffield Laboratory of Ophthalmology, Oxford University, UK.
Safa
R
R
Osborne
N N
NN
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D002534:Hypoxia, Brain / Q000378:metabolism / Q000517:prevention & control*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008550:Melatonin / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D016202:N-Methylaspartate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D007770:L-Lactate Dehydrogenase; D008550:Melatonin; D010100:Oxygen