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

<jats:title>Abstract</jats:title><jats:p>Carotid endarterectomy (<jats:styled-content style="fixed-case">CEA</jats:styled-content>) is the treatment of choice for carotid stenosis. Some patients develop ischemia and reperfusion (I/R) injury after <jats:styled-content style="fixed-case">CEA</jats:styled-content>. 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 (<jats:styled-content style="fixed-case">RCT</jats:styled-content>) 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 (<jats:styled-content style="fixed-case">NF</jats:styled-content>‐κB) and S100 calcium‐binding protein β (S100β) (<jats:italic>P</jats:italic> < 0.05) and markedly increased the expression of nuclear erythroid 2‐related factor 2 (Nrf2), superoxide dismutase (<jats:styled-content style="fixed-case">SOD</jats:styled-content>), catalase (<jats:styled-content style="fixed-case">CAT</jats:styled-content>), and glutathione peroxidase (<jats:styled-content style="fixed-case">GP</jats:styled-content>x) (<jats:italic>P</jats:italic> < 0.05). The participants in the <jats:styled-content style="fixed-case">RCT</jats:styled-content> 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 <jats:styled-content style="fixed-case">CEA</jats:styled-content>. Compared with the oral placebo treatment, melatonin decreased the expression of <jats:styled-content style="fixed-case">NF</jats:styled-content>‐κB, tumor necrosis factor‐α, interleukin‐6 (<jats:styled-content style="fixed-case">IL</jats:styled-content>‐6), and S100β (<jats:italic>P</jats:italic> < 0.05) and increased the expression of Nrf2, <jats:styled-content style="fixed-case">SOD</jats:styled-content>,<jats:styled-content style="fixed-case"> CAT</jats:styled-content>, and <jats:styled-content style="fixed-case">GP</jats:styled-content>x (<jats:italic>P</jats:italic> < 0.05) in patients after <jats:styled-content style="fixed-case">CEA</jats:styled-content>. Our findings suggested that melatonin could ameliorate brain I/R injury after <jats:styled-content style="fixed-case">CEA</jats:styled-content> and that this outcome was essentially due to the antioxidant and anti‐inflammatory effects of melatonin.</jats:p>