Combined effects of melatonin and valproic acid in cerebral ischemia via modulation of oxidative stress and melatonin receptors

BACKGROUND: Ischemic stroke is a major cause of mortality and disability worldwide, with limited effective neuroprotective treatments. Epigenetic modulation and oxidative stress regulation have emerged as promising therapeutic targets. This study aimed to evaluate the neuroprotective effects of melatonin and valproic acid, alone and in combination, in a rat model of cerebral ischemia. METHODS: Male Wistar rats were randomly divided into nine groups including sham, MCAO, vehicle, melatonin, valproic acid, and different combination treatment groups. Cerebral ischemia was induced using the middle cerebral artery occlusion (MCAO) method. Neurological deficits, infarct volume, brain edema, antioxidant activity, and gene expression of HDAC1, HDAC3, MT1, and MT2 were evaluated. RESULTS: Both melatonin and valproic acid significantly improved neurological outcomes, reduced infarct volume, and decreased brain edema compared to the MCAO group. Combination therapy, particularly at high doses, showed significantly greater neuroprotective effects than monotherapy. These effects were associated with downregulation of HDAC1 and HDAC3 expression, upregulation of MT1 and MT2 receptors, and increased antioxidant enzyme activity including catalase and superoxide dismutase levels. CONCLUSION: Combined administration of melatonin and valproic acid exerts synergistic neuroprotective effects in cerebral ischemia through modulation of oxidative stress, epigenetic regulation, and melatonin receptor signaling. This combination may represent a promising therapeutic strategy for ischemic stroke.