Curcumin monomer regulates ferroptosis via the melatonin receptor 2/cyclic adenosine monophosphate/protein kinase A/inositol-requiring enzyme 1 pathway to treat ischemic stroke.

Neurological dysfunction during ischemic stroke can lead to severe neural damage. Curcumin, a natural polyphenolic compound, has shown significant neuroprotective effects in the context of cerebral ischemia, though the detailed mechanisms remain insufficiently understood. This study aims to determine whether curcumin pre-treatment provides neuroprotection against ischemic stroke (IS) and to elucidate the underlying molecular pathways. A middle cerebral artery occlusion (MCAO) model was induced and pre-treated with 50, 100, or 200 mg/kg of curcumin. The impact of curcumin on ischemic injury was evaluated by assessing neurological deficits, cerebral edema, and blood-brain barrier (BBB) permeability using neurological scoring, brain water content analysis, and Evans blue staining. Neuronal morphology and apoptosis were assessed. An oxygen-glucose deprivation/reperfusion (OGD/R) model was employed using HT-22 cells. Cell viability and apoptosis were measured. Oxidative stress and inflammation were determined, as well as iron levels in brain tissue and cells. Curcumin pre-treatment significantly improved neurological scores, reduced neuronal morphological damage, and ameliorated cerebral edema and BBB disruption in MCAO/R rats. Furthermore, curcumin enhanced cell viability in HT-22 cells following OGD/R, reduced apoptosis, and alleviated ferroptosis, oxidative stress, and inflammation through activation of the melatonin receptor 2 (MT2)/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/inositol-requiring enzyme 1 (IRE1) signaling pathway. We conclude that curcumin enhances neuron survival and provides neuroprotection against IS by activating the MT2/cAMP/PKA/IRE1 pathway.