Melatonin Attenuates Cerebral Ischemia/Reperfusion Injury through Inducing Autophagy. Neuroendocrinology INTRODUCTION:The aim of this study was to investigate how melatonin administration for 3 days or 7 days following cerebral ischemia (CI) injury would affect autophagy and, therefore, survival in neurons of the penumbra region. Moreover, it was also aimed at determining how this melatonin treatment would affect the neurological deficit score and rotarod and adhesive removal test durations. METHODS:Focal CI (90 min) was achieved in a total of 105 rats utilizing a middle cerebral artery occlusion model. After the start of reperfusion, the groups were treated with melatonin (10 mg/kg/day) for 3 days or 7 days. In all groups, neurological deficit scoring, rotarod, and adhesive removal tests were executed during reperfusion. Infarct areas were determined by TTC (2,3,5-triphenyltetrazolium chloride) staining at the end of the 3rd and 7th days of reperfusion. Beclin-1, LC3, p62, and caspase-3 protein levels were assessed using Western blot and immunofluorescence methods in the brain tissues. Moreover, penumbra areas were evaluated by transmission electron microscopy (TEM). RESULTS:Following CI, it was observed that melatonin treatment improved the rotarod and adhesive removal test durations from day 5 and reduced the infarct area after CI. It also induced autophagic proteins Beclin-1, LC3, and p62 and suppressed the apoptotic protein cleaved caspase-3. According to TEM findings, melatonin treatment partially reduced the damage in neurons after CI. CONCLUSION:Melatonin treatment following CI reduced the infarct area and induced the autophagic proteins Beclin-1, LC3, and p62 by inhibiting the apoptotic caspase-3 protein. The functional reflection of melatonin treatment on neurological test scores was became significant from the 5th day onward. 10.1159/000531567

Melatonin and ischemia-reperfusion injury of the brain. Cervantes Miguel,Moralí Gabriela,Letechipía-Vallejo Graciela Journal of pineal research This review summarizes the reports that have documented the neuroprotective effects of melatonin against ischemia/reperfusion brain injury. The studies were carried out on several species, using models of acute focal or global cerebral ischemia under different treatment schedules. The neuroprotective actions of melatonin were observed during critical evolving periods for cell processes of immediate or delayed neuronal death and brain injury, early after the ischemia/reperfusion episode. Late neural phenomena accounting either for brain damage or neuronal repair, plasticity and functional recovery taking place after ischemia/reperfusion have been rarely examined for the protective actions of melatonin. Special attention has been paid to the advantageous characteristics of melatonin as a neuroprotective drug: bioavailability into brain cells and cellular organelles targeted by morpho-functional derangement; effectiveness in exerting several neuroprotective actions, which can be amplified and prolonged by its metabolites, through direct and indirect antioxidant activity; prevention and reversal of mitochondrial malfunction, reducing inflammation, derangement of cytoskeleton organization, and pro-apoptotic cell signaling; lack of interference with thrombolytic and neuroprotective actions of other drugs; and an adequate safety profile. Thus, the immediate results of melatonin actions in reducing infarct volume, necrotic and apoptotic neuronal death, neurologic deficits, and in increasing the number of surviving neurons, may improve brain tissue preservation. The potential use of melatonin as a neuroprotective drug in clinical trials aimed to improve the outcome of patients suffering acute focal or global cerebral ischemia should be seriously considered. 10.1111/j.1600-079X.2007.00551.x