Melatonin mitigates type 1 diabetes‐aggravated cerebral ischemia‐reperfusion injury through anti‐inflammatory and anti‐apoptotic effects

INTRODUCTION: Cerebral ischemia and diabetes mellitus (DM) are common diseases that often coexist and interact with each other. DM doubles the risk of ischemic stroke, and cerebral ischemia causes stress‐induced hyperglycemia. Most experimental stroke studies used healthy animals. Melatonin is neuroprotective against cerebral ischemia–reperfusion injury (CIRI) in non‐DM, normoglycemic animals through anti‐oxidant effect, anti‐inflammation, and anti‐apoptosis. Previous studies have also reported a negative correlation between hyperglycemia and urinary melatonin metabolite. OBJECTIVES: The present study investigated the effects of type 1 DM (T1DM) on CIRI in rats and the role of melatonin against CIRI in T1DM animals. RESULTS: Our results revealed that T1DM aggravated CIRI, leading to greater weight loss, increased infarct volume, and worse neurological deficit. T1DM aggravated the post‐CIRI activation of nuclear factor kappa B (NF‐κB) pathway and increase in pro‐apoptotic markers. A single intraperitoneal injection of melatonin at 10 mg/kg given 30 min before ischemia onset attenuated CIRI in T1DM rats, resulting in less weight loss, decreased infarct volume, and milder neurological deficit when compared with the vehicle group. Melatonin treatment achieved anti‐inflammatory and anti‐apoptotic effects with reduced NF‐κB pathway activation, reduced mitochondrial cytochrome C release, decreased calpain‐mediated spectrin breakdown product (SBDP), and decreased caspase‐3‐mediated SBDP. The treatment also led to fewer iNOS+ cells, milder CD‐68+ macrophage/microglia infiltration, decreased TUNEL+ apoptotic cells, and better neuronal survival. CONCLUSIONS: T1DM aggravates CIRI. Melatonin treatment is neuroprotective against CIRI in T1DM rats via anti‐inflammatory and anti‐apoptotic effects.