Delayed melatonin administration promotes neuronal survival, neurogenesis and motor recovery, and attenuates hyperactivity and anxiety after mild focal cerebral ischemia in mice

Melatonin is a potent antioxidant with neuroprotective activity in animal models of ischemic stroke, which based on its lack of serious toxicity has raised hopes that it might be used for human stroke treatment in the future. This study investigated how subacute delivery of melatonin, starting at 24 hr after stroke onset, and continuing for 29 days (4 mg/kg/day; via drinking water), influences neuronal survival, endogenous neurogenesis, motor recovery and locomotor activity in C57Bl6/j mice submitted to 30-min middle cerebral artery occlusion. Histologic studies showed that melatonin improved neuronal survival and enhanced neurogenesis, even when applied 1 day after stroke. Cell survival was associated with a long-lasting improvement of motor and coordination deficits, evaluated by the grip strength and RotaRod tests, as well as with attenuation of hyperactivity and anxiety of the animals as revealed in open field tests. The robust functional neurologic improvements encourage proof-of-concept studies with melatonin in human stroke patients.