Effect of melatonin on ischemia reperfusion injury induced by middle cerebral artery occlusion in rats

K Sinha, M N Degaonkar, N R Jagannathan, Y K Gupta
European Journal of Pharmacology 2001 October 5, 428 (2): 185-92
Free radicals have been implicated in neuronal injury during ischemia reperfusion in stroke. Therefore, in the present study, melatonin, a potent antioxidant, was studied in male Wistar rats subjected to 2 h of transient middle cerebral artery occlusion. Melatonin (10, 20 and 40 mg/kg i.p.) was administered four times in an animal at the time of middle cerebral artery occlusion, 1 h after middle cerebral artery occlusion, at the time of reperfusion and 1 h after reperfusion. Two hours after reperfusion, rats were euthanized for estimation of oxidative stress markers (malondialdehyde and reduced glutathione). The doses of 20 and 40 mg/kg of melatonin significantly attenuated the raised level of malondialdehyde (287+/-28, 279+/-52 nmol/g wet tissue, respectively) as compared to the levels (420+/-61 nmol/g wet tissue) in vehicle-treated middle cerebral artery-occluded rats. There was an insignificant change in levels of reduced glutathione at these doses (95+/-42, 88.7+/-36 microg/g wet tissue, respectively) as compared to those in the vehicle-treated middle cerebral artery-occluded rats (108.21+/-21 microg/g wet tissue). However, there was an insignificant difference between 20 and 40 mg/kg treated rats. Therefore, the dose of 20 mg/kg i.p. was used to evaluate the neuroprotective effect by using diffusion-weighted imaging (30 min after reperfusion), assessing the neurological deficit (24 h after middle cerebral artery occlusion) and estimating oxidative stress markers (72 h after middle cerebral artery occlusion). In the 20 mg/kg melatonin-treated group, percent ischemic lesion volume on diffusion-weighted imaging was significantly attenuated (9.8+/-3.9) as compared to that in the vehicle-treated group (21.4+/-4.7). The neurological deficit was significantly improved in the melatonin group (1.8+/-0.06) as compared to that in the vehicle-treated (2.9+/-0.38) group. The level of malondialdehyde (321.4+/-31 nmol/g wet tissue) and reduced glutathione (142.6+/-13 microg/g wet tissue) in the melatonin-treated group was also significantly decreased as compared to the level of malondialdehyde (623+/-22 nmol/g wet tissue) and reduced glutathione (226.6+/-19 microg/wet tissue) in the vehicle-treated group. The present study indicates that melatonin has a neuroprotective action in focal ischemia, which may be attributed to its antioxidant property.

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