Statins: Mechanisms of neuroprotection

Akiyama, 2000, Inflammation and Alzheimer's disease, Neurobiol. Aging, 21, 383, 10.1016/S0197-4580(00)00124-X Aktas, 2003, Treatment of relapsing paralysis in experimental encephalomyelitis by targeting Th1 cells through atorvastatin, J. Exp. Med., 197, 725, 10.1084/jem.20021425 Allen, 2007, Lipid raft microdomains and neurotransmitter signalling, Nat. Rev. Neurosci., 8, 128, 10.1038/nrn2059 Arvanitakis, 2008, Statins, incident Alzheimer disease, change in cognitive function, and neuropathology, Neurology, 70, 1795, 10.1212/01.wnl.0000288181.00826.63 Asahi, 2005, Protective effects of statins involving both eNOS and tPA in focal cerebral ischemia, J. Cereb. Blood Flow Metab., 25, 722, 10.1038/sj.jcbfm.9600070 Balduini, W., De, A., V, Mazzoni, E., Cimino, M., 2001. Simvastatin protects against long-lasting behavioral and morphological consequences of neonatal hypoxic/ischemic brain injury. Stroke 32, pp. 2185–2191. Balduini, 2003, Prophylactic but not delayed administration of simvastatin protects against long-lasting cognitive and morphological consequences of neonatal hypoxic-ischemic brain injury, reduces interleukin-1beta and tumor necrosis factor-alpha mRNA induction, and does not affect endothelial nitric oxide synthase expression, Stroke, 34, 2007, 10.1161/01.STR.0000080677.24419.88 Bar-On, 2008, Statins reduce neuronal alpha-synuclein aggregation in in vitro models of Parkinson's disease, J. Neurochem., 105, 1656, 10.1111/j.1471-4159.2008.05254.x Bate, 2007, Squalestatin protects neurons and reduces the activation of cytoplasmic phospholipase A2 by Abeta(1-42), Neuropharmacology, 53, 222, 10.1016/j.neuropharm.2007.05.003 Baytan, 2006, Fluvastatin alters psychomotor performance and daily activity but not the spatial memory in rats, Tohoku J. Exp. Med., 209, 311, 10.1620/tjem.209.311 Becker, 2008, Use of statins and the risk of Parkinson's disease: a retrospective case-control study in the UK, Drug Safety, 31, 399, 10.2165/00002018-200831050-00004 Benarroch, 2007, Lipid rafts, protein scaffolds, and neurologic disease, Neurology, 69, 1635, 10.1212/01.wnl.0000279590.22544.c3 Berger, 2008, Neuroprotection by pravastatin in acute ischemic stroke in rats, Brain Res. Rev., 58, 48, 10.1016/j.brainresrev.2007.10.010 Bi, 2004, Inhibition of geranylgeranylation mediates the effects of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors on microglia, J. Biol. Chem., 279, 48238, 10.1074/jbc.M405442200 Birnbaum, 2008, Combining beta interferon and atorvastatin may increase disease activity in multiple sclerosis, Neurology, 71, 1390, 10.1212/01.wnl.0000319698.40024.1c Blanco, 2007, Statin treatment withdrawal in ischemic stroke: a controlled randomized study, Neurology, 69, 904, 10.1212/01.wnl.0000269789.09277.47 Blank, 2007, Atorvastatin inhibits T cell activation through 3-hydroxy-3-methylglutaryl coenzyme A reductase without decreasing cholesterol synthesis, J. Immunol., 179, 3613, 10.4049/jimmunol.179.6.3613 Botti, 1991, Concentrations of pravastatin and lovastatin in cerebrospinal fluid in healthy subjects, Clin. Neuropharmacol., 14, 256, 10.1097/00002826-199106000-00010 Casani, 2005, Pravastatin reduces thrombogenicity by mechanisms beyond plasma cholesterol lowering, Thromb. Haemost., 94, 1035, 10.1160/TH05-04-0245 Castilla, 2008, Statins in stroke prevention: what an internist should know, Eur. J. Intern. Med., 19, 8, 10.1016/j.ejim.2007.05.010 Chen, 2008, Atorvastatin promotes presenilin-1 expression and Notch1 activity and increases neural progenitor cell proliferation after stroke, Stroke, 39, 220, 10.1161/STROKEAHA.107.490946 Chen, 2005, Atorvastatin induction of VEGF and BDNF promotes brain plasticity after stroke in mice, J. Cereb. Blood Flow Metab., 25, 281, 10.1038/sj.jcbfm.9600034 Chen, 2003, Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke, Ann. Neurol., 53, 743, 10.1002/ana.10555 Chen, 1997, Preservation of endogenous antioxidant activity and inhibition of lipid peroxidation as common mechanisms of antiatherosclerotic effects of vitamin E, lovastatin and amlodipine, J. Am. Coll. Cardiol., 30, 569, 10.1016/S0735-1097(97)00158-7 Cicha, 2004, Monitoring the cellular effects of HMG-CoA reductase inhibitors in vitro and ex vivo, Arterioscler. Thromb. Vasc. Biol., 24, 2046, 10.1161/01.ATV.0000145943.19099.a3 Clark, 2003, Treating dyslipidemia with statins: the risk-benefit profile, Am. Heart J., 145, 387, 10.1067/mhj.2003.70 Cole, 2006, Isoprenoids and Alzheimer's disease: a complex relationship, Neurobiol. Dis., 22, 209, 10.1016/j.nbd.2005.11.007 Collins, 2004, Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions, Lancet, 363, 757, 10.1016/S0140-6736(04)15690-0 Cordle, 2005, Mechanisms of statin-mediated inhibition of small G-protein function, J. Biol. Chem., 280, 34202, 10.1074/jbc.M505268200 Corsini, 1999, New insights into the pharmacodynamic and pharmacokinetic properties of statins, Pharmacol. Ther., 84, 413, 10.1016/S0163-7258(99)00045-5 Cramer, 2008, Use of statins and incidence of dementia and cognitive impairment without dementia in a cohort study, Neurology, 71, 344, 10.1212/01.wnl.0000319647.15752.7b de Lau, 2006, Serum cholesterol levels and the risk of Parkinson's disease, Am. J. Epidemiol., 164, 998, 10.1093/aje/kwj283 Dimmeler, 2001, HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway, J. Clin. Invest., 108, 391, 10.1172/JCI200113152 Dolga, 2008, TNF-alpha-mediates neuroprotection against glutamate-induced excitotoxicity via NF-kappaB-dependent up-regulation of K2.2 channels, J. Neurochem., 107, 1158, 10.1111/j.1471-4159.2008.05701.x Dolga, A.M., Granic, I., Nijholt, I.M., Nyakas, C., van der Zee, E.A., Luiten, P.G., Eisel, U.L., 2009. Pretreatment with Lovastatin prevents N-methyl-d-aspartate-induced neurodegeneration in the magnocellular nucleus basalis and behavioral dysfunction. J. Alzheimer's Dis. 17 (2). Dolga, 2008, Lovastatin induces neuroprotection through tumor necrosis factor receptor 2 signaling pathways, J. Alzheimer's. Dis., 13, 111, 10.3233/JAD-2008-13201 Douglass, 2005, Single-molecule microscopy reveals plasma membrane microdomains created by protein–protein networks that exclude or trap signaling molecules in T cells, Cell, 121, 937, 10.1016/j.cell.2005.04.009 Dunn, 2006, Isoprenoids determine Th1/Th2 fate in pathogenic T cells, providing a mechanism of modulation of autoimmunity by atorvastatin, J. Exp. Med., 203, 401, 10.1084/jem.20051129 Eggermont, 2006, Exercise, cognition and Alzheimer's disease: more is not necessarily better, Neurosci. Biobehav. Rev., 30, 562, 10.1016/j.neubiorev.2005.10.004 Ehehalt, 2003, Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts, J. Cell Biol., 160, 113, 10.1083/jcb.200207113 Endres, 2004, Targeting eNOS for stroke protection, Trends Neurosci., 27, 283, 10.1016/j.tins.2004.03.009 Ericsson, 1993, Distribution of prenyltransferases in rat tissues. Evidence for a cytosolic all-trans-geranylgeranyl diphosphate synthase, J. Biol. Chem., 268, 832, 10.1016/S0021-9258(18)54009-6 Essig, 1998, 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors increase fibrinolytic activity in rat aortic endothelial cells. Role of geranylgeranylation and Rho proteins, Circ. Res., 83, 683, 10.1161/01.RES.83.7.683 Etienne-Manneville, 2002, Rho GTPases in cell biology, Nature, 420, 629, 10.1038/nature01148 Fassbender, 2002, Effects of statins on human cerebral cholesterol metabolism and secretion of Alzheimer amyloid peptide, Neurology, 59, 1257, 10.1212/WNL.59.8.1257 Fenton, 2005, Statins and thrombin, Curr. Drug Targets. Cardiovasc. Haematol. Disord., 5, 115, 10.2174/1568006043586189 Ferro, 2000, Inhibition of tissue-factor-mediated thrombin generation by simvastatin, Atherosclerosis, 149, 111, 10.1016/S0021-9150(99)00291-9 Floris, 2004, Blood-brain barrier permeability and monocyte infiltration in experimental allergic encephalomyelitis: a quantitative MRI study, Brain, 127, 616, 10.1093/brain/awh068 Fontaine, 2002, Neurodegenerative and neuroprotective effects of tumor necrosis factor (TNF) in retinal ischemia: opposite roles of TNF receptor 1 and TNF receptor 2, J. Neurosci., 22, RC216, 10.1523/JNEUROSCI.22-07-j0001.2002 Franke, 2007, Bcl-2 upregulation and neuroprotection in guinea pig brain following chronic simvastatin treatment, Neurobiol. Dis., 25, 438, 10.1016/j.nbd.2006.10.004 Garcia-Roman, 2001, Lovastatin induces apoptosis of spontaneously immortalized rat brain neuroblasts: involvement of nonsterol isoprenoid biosynthesis inhibition, Mol. Cell Neurosci., 17, 329, 10.1006/mcne.2000.0904 Ghittoni, 2005, Simvastatin inhibits T-cell activation by selectively impairing the function of Ras superfamily GTPases, FASEB J., 19, 605, 10.1096/fj.04-2702fje Gibbs, 1997, The potential of farnesyltransferase inhibitors as cancer chemotherapeutics, Annu. Rev. Pharmacol. Toxicol., 37, 143, 10.1146/annurev.pharmtox.37.1.143 Goldstein, 1990, Regulation of the mevalonate pathway, Nature, 343, 425, 10.1038/343425a0 Gouni-Berthold, 2008, Effects of ezetimibe and/or simvastatin on LDL receptor protein expression and on LDL receptor and HMG-CoA reductase gene expression: a randomized trial in healthy men, Atherosclerosis, 198, 198, 10.1016/j.atherosclerosis.2007.09.034 Greenwood, 2006, Statin therapy and autoimmune disease: from protein prenylation to immunomodulation, Nat. Rev. Immunol., 6, 358, 10.1038/nri1839 Greenwood, 2003, Lovastatin inhibits brain endothelial cell Rho-mediated lymphocyte migration and attenuates experimental autoimmune encephalomyelitis, FASEB J., 17, 905, 10.1096/fj.02-1014fje Guasti, 2008, Prolonged statin-associated reduction in neutrophil reactive oxygen species and angiotensin II type 1 receptor expression: 1-year follow-up, Eur. Heart J., 29, 1118, 10.1093/eurheartj/ehn138 Hajjar, 2002, The impact of the use of statins on the prevalence of dementia and the progression of cognitive impairment, J. Gerontol. A Biol. Sci. Med. Sci., 57, M414, 10.1093/gerona/57.7.M414 Hamelin, 1998, Hydrophilicity/lipophilicity: relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors, Trends Pharmacol. Sci., 19, 26, 10.1016/S0165-6147(97)01147-4 Hernandez-Perera, 1998, Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells, J. Clin. Invest., 101, 2711, 10.1172/JCI1500 Hernandez-Romero, 2008, Simvastatin prevents the inflammatory process and the dopaminergic degeneration induced by the intranigral injection of lipopolysaccharide, J. Neurochem., 105, 445, 10.1111/j.1471-4159.2007.05148.x Heumann, 2000, Transgenic activation of Ras in neurons promotes hypertrophy and protects from lesion-induced degeneration, J. Cell Biol., 151, 1537, 10.1083/jcb.151.7.1537 Hillyard, 2004, Simvastatin inhibits lymphocyte function in normal subjects and patients with cardiovascular disease, Atherosclerosis, 175, 305, 10.1016/j.atherosclerosis.2004.03.018 Hoglund, 2007, Effect of HMG-CoA reductase inhibitors on beta-amyloid peptide levels: implications for Alzheimer's disease, CNS Drugs, 21, 449, 10.2165/00023210-200721060-00002 Huang, 2007, Lower low-density lipoprotein cholesterol levels are associated with Parkinson's disease, Mov. Disord., 22, 377, 10.1002/mds.21290 Hussein, 1997, Reduced susceptibility of low density lipoprotein (LDL) to lipid peroxidation after fluvastatin therapy is associated with the hypocholesterolemic effect of the drug and its binding to the LDL, Atherosclerosis, 128, 11, 10.1016/S0021-9150(96)05972-2 Ischiropoulos, 2003, Oxidative stress and nitration in neurodegeneration: cause, effect, or association?, J. Clin. Invest., 111, 163, 10.1172/JCI200317638 Jacobson, 2004, Cytoskeletal activation and altered gene expression in endothelial barrier regulation by simvastatin, Am. J. Respir. Cell Mol. Biol., 30, 662, 10.1165/rcmb.2003-0267OC Johnson-Anuna, 2005, Chronic administration of statins alters multiple gene expression patterns in mouse cerebral cortex, J. Pharmacol. Exp. Ther., 312, 786, 10.1124/jpet.104.075028 Jope, 2007, Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics, Neurochem. Res., 32, 577, 10.1007/s11064-006-9128-5 Kirsch, 2003, Statin effects on cholesterol micro-domains in brain plasma membranes, Biochem. Pharmacol., 65, 843, 10.1016/S0006-2952(02)01654-4 Kretz, 2006, Simvastatin promotes heat shock protein 27 expression and Akt activation in the rat retina and protects axotomized retinal ganglion cells in vivo, Neurobiol. Dis., 21, 421, 10.1016/j.nbd.2005.08.003 Kuipers, 2005, Statins affect cell-surface expression of major histocompatibility complex class II molecules by disrupting cholesterol-containing microdomains., Hum. Immunol., 66, 653, 10.1016/j.humimm.2005.04.004 Kuipers, 2007, Immunomodulation by statins: inhibition of cholesterol vs. isoprenoid biosynthesis, Biomed. Pharmacother., 61, 400, 10.1016/j.biopha.2007.06.005 Kureishi, 2000, The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals, Nat. Med., 6, 1004, 10.1038/79510 Lee, 2008, Atorvastatin attenuates mitochondrial toxin-induced striatal degeneration, with decreasing iNOS/c-Jun levels and activating ERK/Akt pathways, J. Neurochem., 104, 1190, 10.1111/j.1471-4159.2007.05044.x Lewis, 2005, Lovastatin alters the isoprenoid biosynthetic pathway in acute myelogenous leukemia cells in vivo, Leuk. Res., 29, 527, 10.1016/j.leukres.2004.10.007 Li, 2007, Statin therapy is associated with reduced neuropathologic changes of Alzheimer disease, Neurology, 69, 878, 10.1212/01.wnl.0000277657.95487.1c Li, 2006, Simvastatin enhances learning and memory independent of amyloid load in mice, Ann. Neurol., 60, 729, 10.1002/ana.21053 Li, 2005, The HMG-CoA reductase inhibitor lovastatin reverses the learning and attention deficits in a mouse model of neurofibromatosis type 1, Curr. Biol., 15, 1961, 10.1016/j.cub.2005.09.043 Li, 2005, Regulation of PTEN by Rho small GTPases, Nat. Cell Biol., 7, 399, 10.1038/ncb1236 Liao, 2005, Pleiotropic effects of statins, Annu. Rev. Pharmacol. Toxicol., 45, 89, 10.1146/annurev.pharmtox.45.120403.095748 Lieberman, 2005, Statins, cholesterol, Co-enzyme Q10, and Parkinson's disease, Parkinsonism Relat. Disord., 11, 81, 10.1016/j.parkreldis.2004.07.012 Lim, 2006, Simvastatin prevents oxygen and glucose deprivation/reoxygenation-induced death of cortical neurons by reducing the production and toxicity of 4-hydroxy-2E-nonenal, J. Neurochem., 97, 140, 10.1111/j.1471-4159.2006.03715.x Lindberg, 2005, Effects of statins on microglia, J. Neurosci. Res., 82, 10, 10.1002/jnr.20615 Littarru, 2007, Coenzyme Q10 and statins: biochemical and clinical implications, Mitochondrion, 7, S168, 10.1016/j.mito.2007.03.002 Liu, 2009, Evidence for statin pleiotropy in humans: differential effects of statins and ezetimibe on rho-associated coiled-coil containing protein kinase activity, endothelial function, and inflammation, Circulation, 119, 131, 10.1161/CIRCULATIONAHA.108.813311 Llevadot, 2001, HMG-CoA reductase inhibitor mobilizes bone marrow – derived endothelial progenitor cells, J. Clin. Invest., 108, 399, 10.1172/JCI200113131 Lu, 2004, Atorvastatin reduces neurological deficit and increases synaptogenesis, angiogenesis, and neuronal survival in rats subjected to traumatic brain injury, J. Neurotrauma, 21, 21, 10.1089/089771504772695913 Lu, 2004, Atorvastatin reduction of intravascular thrombosis, increase in cerebral microvascular patency and integrity, and enhancement of spatial learning in rats subjected to traumatic brain injury, J. Neurosurg., 101, 813, 10.3171/jns.2004.101.5.0813 Lu, 2007, Statins increase neurogenesis in the dentate gyrus, reduce delayed neuronal death in the hippocampal CA3 region, and improve spatial learning in rat after traumatic brain injury, J. Neurotrauma, 24, 1132, 10.1089/neu.2007.0288 Luccarini, 2008, Combined treatment with atorvastatin and minocycline suppresses severity of EAE, Exp. Neurol., 211, 214, 10.1016/j.expneurol.2008.01.022 Lutjohann, 2004, High doses of simvastatin, pravastatin, and cholesterol reduce brain cholesterol synthesis in guinea pigs, Steroids, 69, 431, 10.1016/j.steroids.2004.03.012 Mahmood, 2007, Treatment of traumatic brain injury with a combination therapy of marrow stromal cells and atorvastatin in rats, Neurosurgery, 60, 546, 10.1227/01.NEU.0000255346.25959.99 Marchetti, 2004, Tumor necrosis factor (TNF)-mediated neuroprotection against glutamate-induced excitotoxicity is enhanced by N-methyl-d-aspartate receptor activation. Essential role of a TNF receptor 2-mediated phosphatidylinositol 3-kinase-dependent NF-kappa B pathway, J. Biol. Chem., 279, 32869, 10.1074/jbc.M311766200 Marcoff, 2007, The role of coenzyme Q10 in statin-associated myopathy: a systematic review, J. Am. Coll. Cardiol., 49, 2231, 10.1016/j.jacc.2007.02.049 Marz, 2007, Statins induce differentiation and cell death in neurons and astroglia, Glia, 55, 1, 10.1002/glia.20422 Masamura, 2003, Pitavastatin-induced thrombomodulin expression by endothelial cells acts via inhibition of small G proteins of the Rho family, Arterioscler. Thromb. Vasc. Biol., 23, 512, 10.1161/01.ATV.0000060461.64771.F0 Mattson, 2005, NF-kappaB in the survival and plasticity of neurons, Neurochem. Res., 30, 883, 10.1007/s11064-005-6961-x Mauch, 2001, CNS synaptogenesis promoted by glia-derived cholesterol, Science, 294, 1354, 10.1126/science.294.5545.1354 McTaggart, 2001, Preclinical and clinical pharmacology of Rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, Am. J. Cardiol., 87, 28B, 10.1016/S0002-9149(01)01454-0 Meske, 2003, Blockade of HMG-CoA reductase activity causes changes in microtubule-stabilizing protein tau via suppression of geranylgeranylpyrophosphate formation: implications for Alzheimer's disease, Eur. J. Neurosci., 17, 93, 10.1046/j.1460-9568.2003.02433.x Michikawa, 1999, Inhibition of cholesterol production but not of nonsterol isoprenoid products induces neuronal cell death, J. Neurochem., 72, 2278, 10.1046/j.1471-4159.1999.0722278.x Molyneux, 2008, Coenzyme q10: is there a clinical role and a case for measurement?, Clin. Biochem. Rev., 29, 71 Montaner, 2008, Simvastatin in the acute phase of ischemic stroke: a safety and efficacy pilot trial, Eur. J. Neurol., 15, 82, 10.1111/j.1468-1331.2007.02015.x Morikawa, 2002, The effect of statins on mRNA levels of genes related to inflammation, coagulation, and vascular constriction in HUVEC. Human umbilical vein endothelial cells, J. Atheroscler. Thromb., 9, 178, 10.5551/jat.9.178 Moro, 2004, Role of nitric oxide after brain ischaemia, Cell Calcium, 36, 265, 10.1016/j.ceca.2004.02.011 Munro, 2003, Lipid rafts: elusive or illusive?, Cell, 115, 377, 10.1016/S0092-8674(03)00882-1 Nassief, 2008, Statin therapy for stroke prevention, Stroke, 39, 1042, 10.1161/STROKEAHA.107.501361 Ness, 1996, Inhibitors of cholesterol biosynthesis increase hepatic low-density lipoprotein receptor protein degradation, Arch. Biochem. Biophys., 325, 242, 10.1006/abbi.1996.0030 Nusse, 1996, Localization of G alpha 0 to growth cones in PC12 cells: role of G alpha 0 association with receptors and G beta gamma, J. Cell Sci., 109, 221, 10.1242/jcs.109.1.221 Ostrowski, 2007, Statins reduce amyloid-beta production through inhibition of protein isoprenylation, J. Biol. Chem., 282, 26832, 10.1074/jbc.M702640200 Paintlia, 2005, HMG-CoA reductase inhibitor augments survival and differentiation of oligodendrocyte progenitors in animal model of multiple sclerosis, FASEB J., 19, 1407, 10.1096/fj.05-3861com Paintlia, 2008, Inhibition of rho family functions by lovastatin promotes myelin repair in ameliorating experimental autoimmune encephalomyelitis, Mol. Pharmacol., 73, 1381, 10.1124/mol.107.044230 Paintlia, 2004, Regulation of gene expression associated with acute experimental autoimmune encephalomyelitis by Lovastatin, J. Neurosci. Res., 77, 63, 10.1002/jnr.20130 Paintlia, 2006, Immunomodulatory effect of combination therapy with lovastatin and 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside alleviates neurodegeneration in experimental autoimmune encephalomyelitis, Am. J. Pathol., 169, 1012, 10.2353/ajpath.2006.051309 Paintlia, 2009, Combination therapy of lovastatin and rolipram provides neuroprotection and promotes neurorepair in inflammatory demyelination model of multiple sclerosis, Glia, 57, 182, 10.1002/glia.20745 Pan, 1993, Pharmacokinetics of pravastatin in elderly versus young men and women, Ann. Pharmacother., 27, 1029, 10.1177/106002809302700902 Parle, 2007, Reversal of memory deficits by Atorvastatin and Simvastatin in rats, Yakugaku Zasshi, 127, 1125, 10.1248/yakushi.127.1125 Paul, 2008, Oral high-dose atorvastatin treatment in relapsing-remitting multiple sclerosis, PLoS ONE, 3, e1928, 10.1371/journal.pone.0001928 Pavlov, 1995, An in vitro study of the effects of lovastatin on human fetal brain cells, Neurotoxicol. Teratol., 17, 31, 10.1016/0892-0362(95)91641-W Ponce, 2008, Simvastatin reduces the association of NMDA receptors to lipid rafts: a cholesterol-mediated effect in neuroprotection, Stroke, 39, 1269, 10.1161/STROKEAHA.107.498923 Pooler, 2006, The 3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibitor pravastatin enhances neurite outgrowth in hippocampal neurons, J. Neurochem., 97, 716, 10.1111/j.1471-4159.2006.03763.x Puccetti, 2005, Mechanisms for antiplatelet action of statins, Curr. Drug Targets Cardiovasc. Haematol. Disord., 5, 121, 10.2174/1568006043586161 Qiu, 1991, Ras isoprenylation is required for ras-induced but not for NGF-induced neuronal differentiation of PC12 cells, J. Cell Biol., 115, 795, 10.1083/jcb.115.3.795 Qu, 2005, Effect of atorvastatin on spatial memory, neuronal survival, and vascular density in female rats after traumatic brain injury, J. Neurosurg., 103, 695, 10.3171/jns.2005.103.4.0695 Rikitake, 2005, Rho GTPases, statins, and nitric oxide, Circ. Res., 97, 1232, 10.1161/01.RES.0000196564.18314.23 Rodriguez, 2002, Use of lipid-lowering drugs in older adults with and without dementia: a community-based epidemiological study, J. Am. Geriatr. Soc., 50, 1852, 10.1046/j.1532-5415.2002.50515.x Saheki, 1994, In vivo and in vitro blood-brain barrier transport of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, Pharm. Res., 11, 305, 10.1023/A:1018975928974 Salins, 2007, Lovastatin protects human neurons against Abeta-induced toxicity and causes activation of beta-catenin-TCF/LEF signaling, Neurosci. Lett., 412, 211, 10.1016/j.neulet.2006.07.045 Samii, 2008, Statin use and the risk of Parkinson disease: a nested case control study, J. Clin. Neurosci., 15, 1272, 10.1016/j.jocn.2008.01.016 Santanello, 1997, Effect of pharmacologic lipid lowering on health-related quality of life in older persons: results from the Cholesterol Reduction in Seniors Program (CRISP) Pilot Study, J. Am. Geriatr. Soc., 45, 8, 10.1111/j.1532-5415.1997.tb00971.x Schulz, 2004, HMG-CoA reductase inhibition causes neurite loss by interfering with geranylgeranylpyrophosphate synthesis, J. Neurochem., 89, 24, 10.1046/j.1471-4159.2003.02305.x Selley, 2005, Simvastatin prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced striatal dopamine depletion and protein tyrosine nitration in mice, Brain Res., 1037, 1, 10.1016/j.brainres.2004.02.083 Sena, 2003, Therapeutic potential of lovastatin in multiple sclerosis, J. Neurol., 250, 754, 10.1007/s00415-003-1070-8 Sena, 2007, Beneficial effect of statins in multiple sclerosis: is it dose-dependent?, Atherosclerosis, 191, 462, 10.1016/j.atherosclerosis.2006.08.010 Shepherd, 2002, Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial, Lancet, 360, 1623, 10.1016/S0140-6736(02)11600-X Shimamura, 2007, Delayed postischemic treatment with fluvastatin improved cognitive impairment after stroke in rats, Stroke, 38, 3251, 10.1161/STROKEAHA.107.485045 Simons, 2002, Cholesterol, lipid rafts, and disease, J. Clin. Invest., 110, 597, 10.1172/JCI0216390 Simons, 2002, Treatment with simvastatin in normocholesterolemic patients with Alzheimer's disease: A 26-week randomized, placebo-controlled, double-blind trial, Ann. Neurol., 52, 346, 10.1002/ana.10292 Sinensky, 1990, Differential inhibitory effects of lovastatin on protein isoprenylation and sterol synthesis, J. Biol. Chem., 265, 19937, 10.1016/S0021-9258(17)45464-0 Sironi, 2003, Treatment with statins after induction of focal ischemia in rats reduces the extent of brain damage, Arterioscler. Thromb. Vasc. Biol., 23, 322, 10.1161/01.ATV.0000044458.23905.3B Skaletz-Rorowski, 2003, Statin therapy and angiogenesis, Curr. Opin. Lipidol., 14, 599, 10.1097/00041433-200312000-00008 Song, 2005, The activation of Akt/PKB signaling pathway and cell survival, J. Cell Mol. Med., 9, 59, 10.1111/j.1582-4934.2005.tb00337.x Stuve, 2006, Immunomodulatory synergy by combination of atorvastatin and glatiramer acetate in treatment of CNS autoimmunity, J. Clin. Invest., 116, 1037, 10.1172/JCI25805 Takai, 2001, Small GTP-binding proteins, Physiol. Rev., 81, 153, 10.1152/physrev.2001.81.1.153 Tanaka, 2000, Geranylgeranyl-pyrophosphate, an isoprenoid of mevalonate cascade, is a critical compound for rat primary cultured cortical neurons to protect the cell death induced by 3-hydroxy-3-methylglutaryl-CoA reductase inhibition, J. Neurosci., 20, 2852, 10.1523/JNEUROSCI.20-08-02852.2000 Thelen, 2006, Brain cholesterol synthesis in mice is affected by high dose of simvastatin but not of pravastatin, J. Pharmacol. Exp. Ther., 316, 1146, 10.1124/jpet.105.094136 Tsuji, 1993, Transport mechanism of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors at the blood-brain barrier, J. Pharmacol. Exp. Ther., 267, 1085 Turner, 2008, Effects of lovastatin on Rho isoform expression, activity, and association with guanine nucleotide dissociation inhibitors, Biochem. Pharmacol., 75, 405, 10.1016/j.bcp.2007.08.031 Undas, 2001, Simvastatin depresses blood clotting by inhibiting activation of prothrombin, factor V, and factor XIII and by enhancing factor Va inactivation, Circulation, 103, 2248, 10.1161/01.CIR.103.18.2248 Urbich, 2002, Double-edged role of statins in angiogenesis signaling, Circ. Res., 90, 737, 10.1161/01.RES.0000014081.30867.F8 Vollmer, 2004, Oral simvastatin treatment in relapsing-remitting multiple sclerosis, Lancet, 363, 1607, 10.1016/S0140-6736(04)16205-3 Wagner, 2000, Improvement of nitric oxide-dependent vasodilatation by HMG-CoA reductase inhibitors through attenuation of endothelial superoxide anion formation, Arterioscler. Thromb. Vasc. Biol., 20, 61, 10.1161/01.ATV.20.1.61 Wahner, 2008, Statin use and the risk of Parkinson disease, Neurology, 70, 1418, 10.1212/01.wnl.0000286942.14552.51 Waiczies, 2005, Atorvastatin induces T cell anergy via phosphorylation of ERK1, J. Immunol., 174, 5630, 10.4049/jimmunol.174.9.5630 Wang, 2007, Simvastatin and atorvastatin improve behavioral outcome, reduce hippocampal degeneration, and improve cerebral blood flow after experimental traumatic brain injury, Exp. Neurol., 206, 59, 10.1016/j.expneurol.2007.03.031 Wassmann, 2001, Inhibition of geranylgeranylation reduces angiotensin II-mediated free radical production in vascular smooth muscle cells: involvement of angiotensin AT1 receptor expression and Rac1 GTPase, Mol. Pharmacol., 59, 646, 10.1124/mol.59.3.646 Weis, 2002, Statins have biphasic effects on angiogenesis, Circulation, 105, 739, 10.1161/hc0602.103393 Weitz-Schmidt, 2001, Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site, Nat. Med., 7, 687, 10.1038/89058 Wierzbicki, 2003, The lipid and non-lipid effects of statins, Pharmacol. Ther., 99, 95, 10.1016/S0163-7258(03)00055-X Wolfrum, 2004, Inhibition of Rho-kinase leads to rapid activation of phosphatidylinositol 3-kinase/protein kinase Akt and cardiovascular protection, Arterioscler. Thromb. Vasc. Biol., 24, 1842, 10.1161/01.ATV.0000142813.33538.82 Wolozin, 2006, Re-assessing the relationship between cholesterol, statins and Alzheimer's disease, Acta Neurol. Scand. Suppl., 185, 63, 10.1111/j.1600-0404.2006.00687.x Wolozin, 2007, Simvastatin is associated with a reduced incidence of dementia and Parkinson's disease, BMC Med., 5, 20, 10.1186/1741-7015-5-20 Won, 2008, Lovastatin inhibits amyloid precursor protein (APP) beta-cleavage through reduction of APP distribution in Lubrol WX extractable low density lipid rafts, J. Neurochem., 105, 1536, 10.1111/j.1471-4159.2008.05283.x Wu, 2008, 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, J. Neurotrauma, 25, 130, 10.1089/neu.2007.0369 Xiang, 2008, Simvastatin induces cell death in a mouse cerebellar slice culture (CSC) model of developmental myelination, Exp. Neurol. Yaffe, 2002, Serum lipoprotein levels, statin use, and cognitive function in older women, Arch. Neurol., 59, 378, 10.1001/archneur.59.3.378 Youssef, 2002, The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease, Nature, 420, 78, 10.1038/nature01158 Zacco, 2003, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors protect cortical neurons from excitotoxicity, J. Neurosci., 23, 11104, 10.1523/JNEUROSCI.23-35-11104.2003 Zhang, 1996, Protein prenylation: molecular mechanisms and functional consequences, Annu. Rev. Biochem., 65, 241, 10.1146/annurev.bi.65.070196.001325 Zhang, 2005, Multitargeted effects of statin-enhanced thrombolytic therapy for stroke with recombinant human tissue-type plasminogen activator in the rat, Circulation, 112, 3486, 10.1161/CIRCULATIONAHA.104.516757 Zhang, 2007, The PI3K/Akt pathway mediates the neuroprotective effect of atorvastatin in extending thrombolytic therapy after embolic stroke in the rat, Arterioscler. Thromb. Vasc. Biol., 27, 2470, 10.1161/ATVBAHA.107.150748 Zipp, 2007, Impact of HMG-CoA reductase inhibition on brain pathology, Trends Pharmacol. Sci., 28, 342, 10.1016/j.tips.2007.05.001