The neuroplasticity potential of melatonin following transient focal cerebral ischemia in rats

Introduction: Melatonin (N-aceyl-5-methoxytryptamine) is a well-known, potent free radical scavenger and an antioxidant (1-2). It is known that melatonin reduces infarct volumes and enhances neurobehavioral and electrophysiological recoveries following transient middle cerebral artery (MCA) occlusion and reperfusion in rats (3). In this study, we examined the melatonin's potential for neuroplasticity at 1, 7 and 28 days after reperfusion in rats subjected to MCA occlusion for 1 hour. Methods: Adult male Sprague-Dawley rats, weighing 200-260 gm, were subjected to intraluminal MCA occlusion for 60 minutes. Local cerebral blood perfusion and physiological parameters were measured. Melatonin (5 mg/kg) or vehicle was given intraperitoneally at the commencement of reperfusion. Brain was sectioned and stained using the Golgi-Cox procedure (4), and spines density was quantified in the second-, third-order basilar dendrites of the pyramidal neurons in the ischemic core (layer II-III), penumbra (layer III-IV), and layer V-VI of forepaw and hindpaw areas in the ischemic hemisphere, as well as in the layer V-VI of the contralateral intact brain. Results: At 7 days of reperfusion, our data indicate that melatonin did not affect core temperature, local cerebral blood flow or other physiological parameters. Melatonin treatment, however, significantly enhanced dendritic spines density in the second-, third-order basilar dendrites of the pyramidal cells. As compared to the vehicle-treated controls, in the ischemic core of the ispilateral (25±20% vs. 2±0% and 32±23% vs. 2±0%, P<0.05, respectively); in the penumbra of the ispilateral (41±6% vs. 21±5% and 44±8% vs. 25±10%, P<0.001, respectively ); in the layer V-VI of the ispilateral (59±5% vs. 28±8% and 74±14% vs. 37±11%, P<0.001, respectively); in the layer V-VI of the contalateral (50±6% vs. 43±6% and 91±3% vs. 84±4%, P<0.05, respectively). In addition, melatonin improves neurobehavioral outcome at various time points measured following transient focal cerebral ischemia. Conclusion: Melatonin has the potential to improve neurobehavioral outcome after stroke via upregulating the dendritic spine density in the residual cortical neurons in the ischemic hemisphere as well as in the non-injured, intact brain. The findings support melatonin's potential for decreasing ischemic brain injury in the territory at risk of ischemia and also suggest that it may have a beneficial role of neuroplasticity for the contralateral, intact brain in the filed of ischemic stroke.