title: Simvastatin attenuates axonal injury after experimental traumatic brain injury and promotes neurite outgrowth of primary cortical neurons.
abstract: The beneficial effects of simvastatin on experimental traumatic brain injury (TBI) have been demonstrated in previous studies. In this study, we investigated the effects of simvastatin on axonal injury and neurite outgrowth after experimental TBI and explored the underlying mechanisms. Wistar rats were subjected to controlled cortical impact or sham surgery. Saline or simvastatin was administered for 14 days. A modified neurological severity score (mNSS) test was performed to evaluate functional recovery. Immunohistochemistry studies using synaptophysin, neurofilament H (NF-H) and amyloid-β precursor protein (APP) were performed to examine synaptogenesis and axonal injury. Primary cortical neurons (PCNs) were subjected to oxygen glucose deprivation (OGD) followed by various treatments. Western blot analysis was utilized to assess the activation of phosphatidylinositol-3 kinase (PI-3K)/Akt/mammalian target of rapamycin (mTOR) and glycogen synthase kinase 3β (GSK-3β)/adenomatous polyposis coli (APC) pathways. Simvastatin decreased the density of APP-positive profiles and increased the density of NF-H -positive profiles. Simvastatin reduced mNSS, which was correlated with the increase of axonal density. Simvastatin treatment stimulated the neurite outgrowth of PCNs after OGD, which was attenuated by LY294002 and enhanced by lithium chloride (LiCl). Simvastatin activated Akt and mTOR, inactivated GSK-3β and dephosphorylated APC in the injured PCNs. Our data suggest that simvastatin reduces axonal injury, enhances neurite outgrowth and promotes neurological functional recovery after experimental TBI. The beneficial effects of simvastatin on neurite outgrowth may be mediated through manipulation of the PI-3K/Akt/mTOR and PI-3K/GSK-3β/APC pathways.
authors.affiliation: Department of Neurosurgery, Henry Ford Hospital, Detroit, MI 48202, USA.
authors.forename: Hongtao
authors.initials: H
authors.lastname: Wu
authors.forename: Asim
authors.initials: A
authors.lastname: Mahmood
authors.forename: Changsheng
authors.initials: C
authors.lastname: Qu
authors.forename: Ye
authors.initials: Y
authors.lastname: Xiong
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000473:pathology; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000473:pathology; D008297:Male; D016501:Neurites / Q000187:drug effects* / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D019821:Simvastatin