Melatonin at repeated doses alleviates hyperglycemia-exacerbated cerebral ischemia-reperfusion injury at 72 h via anti-inflammation and anti-apoptosis

Objective We aimed to investigate how hyperglycemia would exacerbate cerebral ischemia-reperfusion injury (CIRI) in a rat model of type 1 diabetes mellitus (T1DM) and explore the beneficial effects of multiple doses of melatonin in T1DM induced CIRI. Method The T1DM rat model was induced with streptozocin, and melatonin (10mg/kg) was injected at 0.5h before ischemia as well as at 24 and 48h after reperfusion. Results When compared to normoglycemic (NG) rats, T1DM rats had hyperglycemia with weight loss before CIRI. Despite comparable degrees of ischemia and initial reperfusion, T1DM rats tended to have greater weight loss and had worse neurological deficits and larger infarct volume than NG rats up to 72h after CIRI. Persistent activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway but not of apoptosis or calpains was a crucial factor in T1DM-mediated exacerbation of CIRI at 72h. Despite lacking effects on baseline hyperglycemia, ischemia and initial reperfusion, melatonin at multiple doses lessened post-CIRI weight loss, neurological deficits and infarct volume in T1DM rats at 72h. when compared to vehicle-treated T1DM rats with CIRI. Beneficial effects of melatonin treatment included decreased activation of NF-κB pathway, apoptosis and calpains, leading to reduced expression of inducible nitric oxide synthase and enhanced neuronal density. Conclusion Melatonin at multiple doses can alleviate T1DM-mediated exacerbation of CIRI at 72h through anti-inflammation and anti-apoptosis.