Effect of memantine on the survival of an ischemic random skin flap and the underlying mechanism

Background: Skin flap transplantation is a common wound repair method in orthopedic surgery, but skin flap necrosis remains problematic. Memantine, an excitatory amino acid receptor antagonist, is currently used in the treatment of moderate to severe Alzheimer's disease, due to its ability to promote angiogenesis and reduce oxidative stress. This study investigated the effect of memantine on the survival of random skin flaps in SpragueDawley (SD) rats. Materials and methods: Thirty six male SD rats were divided into control, high-dose (20 mg/kg per day), and lowdose (10 mg/kg per day) groups and underwent a McFarland flap procedure. Seven days later, the survival of the flap was evaluated, The microvascular density and neutrophil density were measured by hematoxylin and eosin staining. Lead angiography was used to detect angiogenesis, and laser Doppler was used to detect blood perfusion. Expression levels of vascular endothelial growth factor (VEGF), interleukin (IL)-1 beta, IL-6, tumor necrosis factor (TNF)-alpha, Toll-like receptor (TLR) 4, nuclear factor kappa B(NF-Kappa B) and Mitogen-activated protein kinase(MAPK)were detected by immunohistochemistry. Oxidative stress was evaluated by measuring the levels of malondialdehyde (MDA) and superoxide dismutase (SOD). Results: Compared with the control group, the flap survival area of memantine group, especially the high-dose group, was larger, VEGF expression, microvascular density, angiogenesis, blood perfusion, and superoxide dismutase in the flap were higher in the Memantine-H group than in the Memantine-L and control groups (P < 0.01). In addition, levels of neutrophil density, IL-1 beta, IL-6, TNF-alpha, TLR4, NF-Kappa B, MAPK and malondialdehyde decreased significantly in the Memantine-H group (P < 0.01). Conclusions: Memantine can promote the survival of skin flap in rats by improving the blood supply, promoting angiogenesis, inhibiting the inflammatory response, and reducing ischemia-reperfusion injury.