Melatonin improves presynaptic protein, SNAP-25, expression and dendritic spine density and enhances functional and electrophysiological recovery following transient focal cerebral ischemia in rats.

Synapto-dendritic dysfunction and rearrangement takes place over time at the peri-infarct brain after stroke, and the event plays an important role in post-stroke functional recovery. Here, we evaluated whether melatonin would modulate the synapto-dendritic plasticity after stroke. Adult male Sprague-Dawley rats were treated with melatonin (5 mg/kg) or vehicle at reperfusion onset after transient occlusion of the right middle cerebral artery (tMCAO) for 90 min. Local cerebral blood perfusion, somatosensory electrophysiological recordings and neurobehavioral tests were serially measured. Animals were sacrificed at 7 days after tMCAO. The brain was processed for Nissl-stained histology, Golgi-Cox-impregnated sections, or Western blotting for presynaptic proteins, synaptosomal-associated protein of 25 kDa (SNAP-25) and synaptophysin (a calcium-binding protein found on presynaptic vesicle membranes). Relative to controls, melatonin-treated animals had significantly reduced infarction volumes (P < 0.05) and improved neurobehavioral outcomes, as accessed by sensorimotor and rota-rod motor performance tests (P < 0.05, respectively). Melatonin also significantly improved the SNAP-25, but not synaptophysin, protein expression in the ischemic brain (P < 0.05). Moreover, melatonin significantly improved the dendritic spine density and the somatosensory electrophysiological field potentials both in the ischemic brain and the contralateral homotopic intact brain (P < 0.05, respectively). Together, melatonin not only effectively attenuated the loss of presynaptic protein, SANP-25, and dendritic spine density in the ischemic territory, but also improved the reductions in the dendritic spine density in the contralateral intact brain. This synapto-dendritic plasticity may partly account for the melatonin-mediated improvements in functional and electrophysiological circuitry after stroke.