Repeated doses of melatonin protects against focal cerebral ischemia in the rat

Abstract

We studied the time window of neuroprotection against focal ischemia by a single dose or repeated doses of melatonin (MT) at 5 mg/kg. Adult male Sprague-Dawley rats (280 to 360 g) were anesthetized with sodium pentobarbital (60 mg/kg, I.P.) to undergo reversible right-sided endovascular middle cerebral artery occlusion (MCAO) for 3 hours. Arterial blood pressure, heart rate and cerebral blood flow were monitored, and rectal temperature was kept between 36.5 and 37.5 ºC throughout anesthesia. The control rats received 1 I.P. dose of the vehicle at the onset of ischemia, whereas experimental groups of rats received either 1 I.P. dose of MT at 0 or 60 minutes after onset of ischemia or 3 doses of MT at 1, 24, and 48 hours after onset of ischemia. The rats were decapitated on day 3 of MCAO, and their brains were stained with 2% triphenyltetrazolium chloride for determination of infarction. Results were compared using 2-tailed student’s t test. When compared to the relative infarct volume of 27.0±4.6% (mean±SEM; 7 rats) in the control group, a single (5 mg/kg) I.P. dose of MT did not significantly reduce the relative infarct volume (20.1±4.1% in the 0-minute group [8 rats]; 19.8±3.2% in the 60-minute group [9 rats]). Nevertheless, the relative infarct volume was significantly reduced to 13.9±3.4% (8 rats, P < 0.05) in the group which received 3 doses of MT. There was no significant difference in hemodynamic parameters among the groups. Thus, repeated doses rather than a single dose of exogenous MT protects against focal cerebral ischemia, when given 60 minutes after onset of ischemia. Supported by the CRCG Research Grant 10202138 of the University of Hong Kong