The role of PI-3 kinases/AKT pathway on the neuroprotective effect of melatonin after cerebral ischemia

Apart from its metabolic functions, melatonin is a potent neuroprotective molecule owing to its antioxidative actions. However, the roles of melatonin receptors and signalling in the neuroprotective effects of melatonin after cerebral ischemia remain unknown. With the use of mice model of cerebral ischemia and PI-3Kinase/AKT pathway inhibitor wortmannin, I evaluated the effects of melatonin on functional recovery, brain injury, edema formation, signaling pathways resulting from ischemic brain injury. In this study, It is shown that melatonin treatment significantly decreases the infarct volume and brain edema after middle cerebral artery occlusion and this decrease is reversed by i.c.v injection of wortmannin. It is also demonstrated that melatonin treatment increases AKT phosphorylation after cerebral ischemia and the inhibition of AKT with Wortmannin reverses neuroprotective action of melatonin after 30 and 90 min of focal cerebral ischemia. Furthermore, melatonin treatment increases the number of surviving neurons, and decreases the number of TUNEL positive cells, which is a indicator of apoptosis. These results provide evidence that the neuroprotective effects of melatonin appear to be mediated through PI-3Kinase/Akt pathway. Furthermore, the robust functional improvement encourages proof-of-concept studies with melatonin in stroke patients.