The protective effect of melatonin on brain ischemia and reperfusion in rats and humans: In vivo assessment and a randomized controlled trial

Abstract Carotid endarterectomy ( CEA ) is the treatment of choice for carotid stenosis. Some patients develop ischemia and reperfusion (I/R) injury after CEA . This study was designed to investigate the neuroprotective effects of melatonin on I/R injury in both rats and humans. To this end, 36 male rats were evaluated, and a double‐blind randomized controlled trial ( RCT ) including 60 patients was performed. A rat model of middle cerebral artery occlusion was used to mimic cerebral I/R. After 2 hour of occlusion and 24 hour of reperfusion, blood samples and brain tissues were harvested for further assessments. Compared with the vehicle treatment, melatonin decreased the expression of nuclear factor κ light‐chain‐enhancer of activated B cells ( NF ‐κB) and S100 calcium‐binding protein β (S100β) ( P < 0.05) and markedly increased the expression of nuclear erythroid 2‐related factor 2 (Nrf2), superoxide dismutase ( SOD ), catalase ( CAT ), and glutathione peroxidase ( GP x) ( P < 0.05). The participants in the RCT took 6 mg/d melatonin orally from 3 days before surgery to 3 days after surgery. Blood samples were drawn at the following times: baseline; pre‐anesthesia; carotid reconstruction completion; and 6, 24, and 72 hour after CEA . Compared with the oral placebo treatment, melatonin decreased the expression of NF ‐κB, tumor necrosis factor‐α, interleukin‐6 ( IL ‐6), and S100β ( P < 0.05) and increased the expression of Nrf2, SOD , CAT , and GP x ( P < 0.05) in patients after CEA . Our findings suggested that melatonin could ameliorate brain I/R injury after CEA and that this outcome was essentially due to the antioxidant and anti‐inflammatory effects of melatonin.