Neuroprotective effects of melatonin against anoxia/aglycemia stress, as assessed by synaptic potentials and superoxide production in rat hippocampal slices

Melatonin, which plays an important role in circadian rhythm regulation, is highly potent endogenous free radical scavenger and antioxidant. To clarify the neuroprotective effects of melatonin as a free radical scavenger, we recorded changes in synaptic potentials and monitored the generation of superoxide (O)(2)(-) (using hydroethidine) in the CA1 pyramidal layers of rat hippocampal slices exposed to anoxia/aglycemia ('ischemic') stress. Synaptic responses evoked by stimulation of Schaffer collateral/commissural afferents were suppressed by ischemic stress. When the duration of the stress was 8 min, the suppression was reversible, irrespective of the presence or absence of melatonin treatment, while the amount of O(2)(-) generated was reduced by the presence of melatonin. When stress duration was 12 min, the suppression of synaptic responses lasted more than 90 min, but melatonin significantly improved the recovery. The amount of O(2)(-) generated in the 'recirculation' phase after a 12 min ischemic stress was less in the ischemic alone group than in the melatonin-treated group. This probably reflects that the number of viable cells with the ability to generate O(2)(-) had been reduced by the more severe ischemic stress. Other radical scavengers (ascorbic acid and alpha-tocopherol) had similar effects. These results show that melatonin has the potential to protect the functions of neurons against an ischemic insult by reducing O(2)(-) generation.