PMID- 18260796 OWN - NLM STAT- MEDLINE DCOM- 20080415 LR - 20220330 IS - 0897-7151 (Print) IS - 0897-7151 (Linking) VI - 25 IP - 2 DP - 2008 Feb TI - Simvastatin-mediated upregulation of VEGF and BDNF, activation of the PI3K/Akt pathway, and increase of neurogenesis are associated with therapeutic improvement after traumatic brain injury. PG - 130-9 LID - 10.1089/neu.2007.0369 [doi] AB - This study was undertaken to evaluate the effect of simvastatin, a cholesterol-lowering agent, on the Akt-mediated signaling pathway and neurogenesis in the dentate gyrus (DG) of the hippocampus in rats after traumatic brain injury (TBI). Adult male Wistar rats were divided into three groups: (1) sham group (n = 8); (2) saline control group (n = 40); and (3) simvastatin-treated group (n = 40). Controlled cortical impact (CCI) injury was performed over the left parietal lobe. Simvastatin was administered orally at a dose of 1 mg/kg starting at day 1 after TBI and then daily for 14 days. Bromodeoxyuridine (BrdU) was injected intraperitoneally into rats. A modified Morris Water Maze (WM) task was performed between 31 and 35 days after treatment to test spatial memory (n = 8/group). Animals were sacrificed at 1, 3, 7, 14, and 35 days after treatment (n = 8/group/time point). Western blot was utilized to investigate the changes in the Akt-mediated signaling pathway. Enzyme-linked immunosorbent assay (ELISA) analyses were employed to measure vascular endothelial growth factor (VEGF) and brain-derived neurotrophin factor (BDNF) expression. Immunohistochemical and fluorescent staining were performed to detect the BrdU- and neuronal nuclei (NeuN)/BrdU-positive cells. Our data show that simvastatin treatment increases phosphorylation of v-akt murine thymoma viral oncogene homolog (Akt), glycogen synthase kinase-3beta (GSK-3beta), and cAMP response element-binding proteins (CREB); elevates the expression of BDNF and VEGF in the DG; increases cell proliferation and differentiation in the DG; and enhances the recovery of spatial learning. These data suggest that the neurorestorative effect of simvastatin may be mediated through activation of the Akt-mediated signaling pathway, subsequently upregulating expression of growth factors and inducing neurogenesis in the DG of the hippocampus, thereby leading to restoration of cognitive function after TBI in rats. FAU - Wu, Hongtao AU - Wu H AD - Department of Neurosurgery, Henry Ford Health System, Detroit, Michigan, USA. FAU - Lu, Dunyue AU - Lu D FAU - Jiang, Hao AU - Jiang H FAU - Xiong, Ye AU - Xiong Y FAU - Qu, Changsheng AU - Qu C FAU - Li, Bo AU - Li B FAU - Mahmood, Asim AU - Mahmood A FAU - Zhou, Dong AU - Zhou D FAU - Chopp, Michael AU - Chopp M LA - eng GR - R01 NS052280-01A1/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PL - United States TA - J Neurotrauma JT - Journal of neurotrauma JID - 8811626 RN - 0 (Antimetabolites) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors) RN - 0 (Vascular Endothelial Growth Factor A) RN - AGG2FN16EV (Simvastatin) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.11.1 (Oncogene Protein v-akt) RN - EC 2.7.11.26 (Glycogen Synthase Kinase 3) RN - G34N38R2N1 (Bromodeoxyuridine) SB - IM MH - Animals MH - Antimetabolites MH - Blotting, Western MH - Brain Hemorrhage, Traumatic/*drug therapy/pathology/physiopathology MH - Brain-Derived Neurotrophic Factor/*biosynthesis MH - Bromodeoxyuridine MH - Cell Proliferation/drug effects MH - Cyclic AMP Response Element-Binding Protein/biosynthesis MH - Glycogen Synthase Kinase 3/biosynthesis MH - Hydroxymethylglutaryl-CoA Reductase Inhibitors/*pharmacology MH - Immunohistochemistry MH - Male MH - Maze Learning/drug effects/physiology MH - Memory/drug effects/physiology MH - Neurons/drug effects/physiology MH - Oncogene Protein v-akt/*physiology MH - Phosphatidylinositol 3-Kinases/*physiology MH - Rats MH - Rats, Wistar MH - Signal Transduction/*physiology MH - Simvastatin/*pharmacology MH - Up-Regulation/drug effects MH - Vascular Endothelial Growth Factor A/*biosynthesis EDAT- 2008/02/12 09:00 MHDA- 2008/04/16 09:00 CRDT- 2008/02/12 09:00 PHST- 2008/02/12 09:00 [pubmed] PHST- 2008/04/16 09:00 [medline] PHST- 2008/02/12 09:00 [entrez] AID - 10.1089/neu.2007.0369 [doi] PST - ppublish SO - J Neurotrauma. 2008 Feb;25(2):130-9. doi: 10.1089/neu.2007.0369.