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 (GPx) (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 GPx (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.

Disruption of endothelial cell function is a principle event in cardiovascular disease. Accordingly, therapies have mostly focused on repairing the endothelium, but little attention has been paid to the reconstruction of glycocalyx, which covers the endothelium and protects the function of endothelial cells. Sulodexide has a similar glycosaminoglycan structure to glycocalyx, so it is assumed to be effective in remodeling the glycocalyx following damage. We assessed the effect of sulodexide on glycocalyx remodeling and endothelial function in the balloon-injury rat carotid artery model. Electron micrographs showed that sulodexide (2mg/kg, administered by intraperitoneal injection for seven days after injury) could reconstruct the endothelial glycocalyx and recover the clear cytoarchitecture. With regard to endothelial function, sulodexide increased endothelial nitric oxide synthase level, attenuated endothelial hyperplasia, and inhibited platelet aggregation that benefitted from glycocalyx reforming. Sulodexide decreased the glycocalyx damage related expression of CD31 and intercellular cell adhesion molecule-1 in endothelium, accompanying by the downregulation of leukocyte counts and C-reactive protein levels. The levels of the atherosclerosis-related factors, osteopontin and vascular cell adhesion molecule-1, which increased in activated endothelial cells lacking glycocalyx, were normalized by sulodexide. Along with the benefit of glycocalyx reconstruction, sulodexide reversed the dyslipidemia. Moreover, sulodexide prevented CD68-positive inflammatory cells infiltration into the vascular wall, presumably as a result of glycocalyx reconstruction. In summary, sulodexide treatment reconstructed glycocalyx which therefore preserved endothelial function and attenuated the expression of inflammatory factors, and decreased the blood coagulation and lipid metabolism, all of which are important for vascular healing.

No abstract