Simvastatin Treatment Induces Angiogenesis and Improves Functional Outcome After Traumatic Brain Injury in RatsAsim Mahmood, MD1, Hongtao Wu1, Michael Chopp, MD11Detroit, MI United States Keywords: outcome, angiogenesis, traumatic brain injury, medication, animal model
Angiogenesis may promote recovery after injury.
The present study was designed to investigate the effects of simvastatin on angiogenesis and proangiogenic VEGFR-2/AKT/eNOS signal transduction pathway after TBI in rats.
Adult male Wistar rats (n=16) were used.
Adult male Wistar rats (n=16) were injured with controlled cortical impact and treated either with simvastatin 1 mg/kg (n=8) or saline (n=8) administered orally, for 14 days starting 1 day after TBI. A sham group (n=8) was neither injured nor treated. Neurological function was assessed using footfault test. Rats were sacrificed 14 days after treatment and brain samples were processed for immunohistochemical staining. Enzyme-linked immunosorbent Assays (ELISA) were also performed to measure vascular endothelial growth factor receptor-2 (VEGFR-2). To explore the effects of simvastatin on VEGFR-2/AKT/eNOS signal transduction pathway, phosphorylation of eNOS (endothelial nitric oxide synthase) and AKT (v-akt murine thymoma viral oncogene homolog) was measured with Western blot analysis.
Our results showed that functional outcome was significantly improved in simvastatin-treated animals (p, less than 0.05). Immunohistochemical studies showed that simvastatin treatment induced angiogenesis in the lesion boundary zone and hippocampus. ELISA studies showed that simvastatin treatment significantly increased the expression of VEGFR-2 (p, less than 0.05). Western blot analysis demonstrated that phosphorylation of AKT and eNOS was also significantly enhanced by simvastatin treatment (p, less than 0.05).
This is a rat study.
Simvastatin induces activation of proangiogenic VEGFR-2/AKT/eNOS pathway and enhances angiogenesis after TBI.
Simvastatin-induced angiogenesis may be partly responsible for functional benefits seen with simvastatin treatment of TBI. Project Roles:
A. Mahmood (), H. Wu (), M. Chopp ()