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Metabolic Brain Disease

, Volume 32, Issue 4, pp 949–965 | Cite as

The beneficial effects of HMG-CoA reductase inhibitors in the processes of neurodegeneration

  • Seyed Soheil Saeedi Saravi
  • Seyed Sobhan Saeedi Saravi
  • Alireza Arefidoust
  • Ahmad Reza DehpourEmail author
Review Article

Abstract

Statins, cholesterol lowering drugs, have been demonstrated to exert beneficial effects in other conditions such as primary and progressing neurodegenerative diseases beyond their original role. Observation that statins ameliorate the neurodegenerative diseases such as Parkinson’s disease (PD), Alzheimer’s disease (AD), multiple sclerosis (MS) and cerebral ischemic stroke, the neuroprotective effects of these drugs are thought to be linked to their anti-inflammatory, anti-oxidative, and anti-excitotoxic properties. Despite the voluminous literature on the clinical advantages of 3-hydroxy-3-methylglutaryl Co-enzyme A reductase (HMGCR) inhibitors (statins) in cardiovascular system, the neuroprotective effects and the underlying mechanisms are little understood. Hence, the present review tries to provide a critical overview on the statin-induced neuroprotection, which are presumed to be associated with the ability to reduce cholesterol, Amyloid-β and apolipoprotein E (ApoE) levels, decrease reactive oxygen and nitrogen species (ROS and RNS) formation, inhibit excitotoxicity, modulate matrix metalloproteinases (MMPs), stimulate endothelial nitric oxide synthase (eNOS), and increase cerebral blood perfusion. This review is also aimed to illustrate that statins protect neurons against the neuro-inflammatory processes through balancing pro-inflammatory/anti-inflammatory cytokines. Ultimately, the beneficial role of statins in ameliorating the development of PD, AD, MS and cerebral ischemic stroke has been separately reviewed.

Keywords

Statins 3-hydroxy-3-methylglutaryl co-enzyme A reductase Neuroprotection Neurodegenerative diseases 

Abbreviations

HMG-CoA

3-hydroxy-3-methylglutaryl Co-enzyme A

HMGCR

HMG-CoA reductase

PD

Parkinson’s disease

AD

Alzheimer’s disease

MS

Multiple sclerosis

eNOS

Endothelial nitric oxide synthase

ApoE

Apolipoprotein E

LDL

Low-density lipoprotein

IL

Interleukin

TGF-β

Transforming growth factor-beta

TNF-α

Tumor necrosis factor-alpha.

Notes

Compliance with ethical standards

Conflicts of interest

The authors declare that there are no conflicts of interest.

References

  1. Ahn SC (2008) Neuromuscular complications of statins. Phys Med Rehabil Clin N Am 19:47–59PubMedCrossRefGoogle Scholar
  2. Aktas O, Waiczies S, Smorodchenko A, Dorr J, Seeger B, Prozorovski T et al (2003) Treatment of relapsing paralysis in experimental encephalomyelitis by targeting Th1 cells through atorvastatin. J Exp Med 197(6):725–733PubMedPubMedCentralCrossRefGoogle Scholar
  3. Amin KA, Kamel HH, Abd Eltawab MA (2011) The relation of high fat diet, metabolic disturbances and brain oxidative dysfunction: modulation by hydroxy citric acid. Lipids Health Dis 10:74PubMedPubMedCentralCrossRefGoogle Scholar
  4. Archelos JJ, Hartung HP (1997) The role of adhesion molecules in multiple sclerosis: biology, pathogenesis and therapeutic implications. Mol Med Today 3:310–321PubMedCrossRefGoogle Scholar
  5. Arvanitakis Z, Schneider JA, Wilson RS, Bienias JL, Kelly JF, Evans DA et al (2008) Statins, incident Alzheimer disease, change in cognitive function, and neuropathology. Neurology 70(19 Part 2):1795–1802PubMedCrossRefGoogle Scholar
  6. Assini A, Cammarata S, Vitali A, Colucci M, Giliberto L, Borghi R et al (2004) Plasma levels of amyloid beta-protein 42 are increased in women with mild cognitive impairment. Neurology 63(5):828–831PubMedCrossRefGoogle Scholar
  7. Aytan N, Jung T, Tamtürk F, Grune T, Kartal-Ozer N (2008) Oxidative stress related changes in the brain of hypercholesterolemic rabbits. Biofactors 33:225–236PubMedCrossRefGoogle Scholar
  8. Bales KR, Liu F, Wu S, Lin S, Koger D, DeLong C, Hansen JC, Sullivan PM, Paul SM (2009) Human APOE isoform-dependent effects on brain betaamyloid levels in PDAPP transgenic mice. J Neurosci 29:6771–6779PubMedCrossRefGoogle Scholar
  9. Barnham KJ, Masters CL, Bush AI (2004) Neurodegenerative diseases and oxidative stress. Nat Rev Drug Discov 3:205–214PubMedCrossRefGoogle Scholar
  10. Bar-On P, Crews L, Koob AO, Mizuno H, Adame A, Spencer B et al (2008) Statins reduce neuronal alpha-synuclein aggregationin in vitro models of Parkinson’s disease. J Neurochem 105(5):1656–1667PubMedPubMedCentralCrossRefGoogle Scholar
  11. Barone E, Cenini G, Di Domenico F, Martin S, Sultana R, Mancuso C et al (2011) Long term high-dose atorvastatin decreases brain oxidative and nitrosative stress in a preclinical model of alzheimer disease: a novel mechanism of action. Pharmacol Res 63:172–180PubMedCrossRefGoogle Scholar
  12. Barone E, Di Domenico F, Butterfield AD (2014) Statins more than cholesterol lowering agents in Alzheimer disease: their pleiotropic functions as potential therapeutic targets. Biochem Pharmacol 88(4):605–616PubMedCrossRefGoogle Scholar
  13. Baudry M, Bi X, Aguirre C (2013) Progesterone-estrogen interactions in synapticplasticity and neuroprotection. Neuroscience 239:280–294PubMedCrossRefGoogle Scholar
  14. Bedard K, Krause KH (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87:245–313PubMedCrossRefGoogle Scholar
  15. Bellosta S, Via D, Canavesi M, Pfister P, Fumagalli R, Paoletti R et al (1998) HMG-CoA reductase inhibitors reduce MMP-9 secretion by macrophages. Arterioscler Thromb Vasc Biol 18:1671–1678PubMedCrossRefGoogle Scholar
  16. Bellosta S, Ferri N, Bernini F, Paoletti R, Corsini A (2000) Non-lipid-related effects of statins. Ann Med 32:164–176PubMedCrossRefGoogle Scholar
  17. Ben-Ari Y (1985) Limbic seizure and brain damage produced by kainic acid: mechanisms and relevance to human temporal lobe epilepsy. Neuroscience 14:375–403PubMedCrossRefGoogle Scholar
  18. Ben-Ari Y, Cossart R (2000) Kainate, a double agent that generates seizures: two decades of progress. Trends Neurosci 23:580–587PubMedCrossRefGoogle Scholar
  19. Berger C, Xia F, Maurer MH, Schwab S (2008) Neuroprotection by pravastatin in acute ischemic stroke in rats. Brain Res Rev 58:48–56PubMedCrossRefGoogle Scholar
  20. Bersot TP (2011) Drug therapy for hypercholesterolemia and dyslipidemia. In: Laurence LB (ed) Goodman and Gilman’s, the pharmacological basis of therapeutics. McGraw-Hill, New York, pp 877–908Google Scholar
  21. Berthier A, Lemaire-Ewing S, Prunet C, Monier S, Athias A, Bessede G et al (2004) Involvement of a calcium-dependent dephosphorylation of bad associated with the localization of trpc-1 within lipid rafts in 7-ketocholesterol-induced Thp-1 cell apoptosis. Cell Death Differ 11:897–905PubMedCrossRefGoogle Scholar
  22. Bettermann K, Arnold AM, Williamson J, Rapp S, Sink K, Toole JF, Carlson MC, Yasar S, Dekosky S, Burke GL (2012) Statins, risk of dementia, and cognitive function: secondary analysis of the ginkgo evaluation of memory study. J Stroke Cerebrovasc Dis 21(6):436–444PubMedCrossRefGoogle Scholar
  23. Bevilacqua MP, Pober JS, Majeau GR, Cotran RS, Gimbrone MA Jr (1984) Interleukin 1 (IL-1) induces biosynthesis and cell surface expression of procoagulantactivity in human vascular endothelial cells. J Exp Med 160:618–623PubMedCrossRefGoogle Scholar
  24. Bianca M, Abbracchio MP (2005) To be or not to be (inflamed)–is that the question in anti-inflammatory drug therapy of neurodegenerative disorders? Trends Pharmacol Sci 26(10):517–525CrossRefGoogle Scholar
  25. Bien-Ly N, Gillespie AK, Walker D, Yoon SY, Huang Y (2012) Reducing human apolipoprotein E levels attenuates age-dependent Aβ accumulation in mutant human amyloid precursor protein transgenic mice. J Neurosci 32:4803–4811PubMedPubMedCentralCrossRefGoogle Scholar
  26. Bindokas VP, Miller RJ (1995) Excitotoxic degeneration is initiated at non-random sites in cultured rat cerebellar neurons. J Neurosci 15(11):6999–7011PubMedGoogle Scholar
  27. Björnsson OG, Sparks JD, Sparks CE, Gibbons GF (1994) Regulation of VLDL secretion in primary culture of rat hepatocytes: involvement of cAMP and cAMP-dependent protein kinases. Eur J Clin Investig 24:137–148CrossRefGoogle Scholar
  28. Blanco M, Nombela F, Castellanos M, Rodriguez-Yanez M, Garcia-Gil M, Leira R et al (2007) Statin treatmentwithdrawal in ischemic stroke: a controlled randomized study. Neurology 69:904–910PubMedCrossRefGoogle Scholar
  29. Bodovitz S, Klein WL (1996) Cholesterol modulates alpha-secretase cleavage of amyloid precursor protein. J Biol Chem 271:4436–4440PubMedCrossRefGoogle Scholar
  30. Bosco DA, Fowler DM, Zhang Q, Nieva J, Powers ET, Wentworth P Jr, Lerner RA, Kelly JW (2006) Elevated levels of oxidized cholesterol metabolites in Lewy body disease brains accelerate alpha-synuclein fibrilization. Nat Chem Biol 2:249–253PubMedCrossRefGoogle Scholar
  31. Bosel J, Gandor F, Harms C, Synowitz M, Harms U, Djoufack PC et al (2005) Neuroprotective effects of atorvastatin against glutamate-induced excitotoxicity in primary cortical neurones. J Neurochem 92:1386–1398PubMedCrossRefGoogle Scholar
  32. Botti RE, Triscari J, Pan HY, Zayat J (1991) Concentrations of pravastatin and lovastatin in cerebrospinal fluid in healthy subjects. Clin Neuropharmacol 14:256–261PubMedCrossRefGoogle Scholar
  33. Brambilla R, Abbracchio MP (2001) Modulation of cyclooxygenase-2 and brain reactive astrogliosis by purinergic P2 receptors. Ann N Y Acad Sci 939:54–62PubMedCrossRefGoogle Scholar
  34. Brigelius-Flohé R (1999) Tissue-specific functions of individual glutathione peroxidases. Free Radic Biol Med 27:951–965PubMedCrossRefGoogle Scholar
  35. Buhaescu I, Izzedine H (2007) Mevalonate pathway: a review of clinical and therapeutical implications. Clin Biochem 40(9):575–584PubMedCrossRefGoogle Scholar
  36. Buxbaum JD, Cullen EI, Freidhoff LT (2002) Pharmacological concentrations of the HMG-COA reductase inhibitor lovastatin decrease the formation of the Alzheimer B-amyloid peptide in vitro and in patients. Front Biosci 7:50–59Google Scholar
  37. Caccamo D, Campisi A, Curro M, Li Volti G, Vanella A, Ientile R (2004) Excitotoxic and post-ischemic neurodegeneration: involvement of transglutaminases. Amino Acids 27:373–379PubMedCrossRefGoogle Scholar
  38. Castilla GL, Del Carmen Fernandez MM, Lopez Chozas JM, Jimenez H (2008) Statins in stroke prevention: what an internist should know. Eur J Int Med 19(1):8–14CrossRefGoogle Scholar
  39. Cespedes-Rubio A, Jurado FW, Cardona-Gomez GP (2010) P120 catenin/alphaNcateninare molecular targets in the neuroprotection and neuronal plasticity mediated by atorvastatin after focal cerebral ischemia. J Neurosci Res 88:3621–3634PubMedCrossRefGoogle Scholar
  40. Chamniansawat S, Chongthammakun S (2010) A priming role of local estrogen onexogenous estrogen-mediated synaptic plasticity and neuroprotection. Exp Mol Med 44:403–411CrossRefGoogle Scholar
  41. Chan KK, Oza AM, Siu LL (2003) The statins as anticancer agents. Clin Cancer Res 9(1):10–19PubMedGoogle Scholar
  42. Chen J, Zhang C, Jiang H, Li Y, Zhang L, Robin A et al (2005) Atorvastatin induction of VEGF aand BDNF promotes brain plasticity after stroke in mice. J Cereb Blood Flow Metab 25:281–290PubMedPubMedCentralCrossRefGoogle Scholar
  43. Chopp M, Zhang RL, Chen H, Li Y, Jiang N, Rusche JR (1994) Postischemic administration of an anti-Mac-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in rats. Stroke 25:869–876PubMedCrossRefGoogle Scholar
  44. Ciurleo R, Bramanti P, Marino S (2014) Role of statins in the treatment of multiple sclerosis. Pharm Res 87:133–143CrossRefGoogle Scholar
  45. Clark LT (2003) Treating dyslipidemia with statins: the risk-benefit profile. Am Heart J 145(3):387–396PubMedCrossRefGoogle Scholar
  46. Cole SL, Vassar R (2006) Isoprenoids and Alzheimer’s disease: a complex relationship. Neurobiol Dis 22:209–222PubMedCrossRefGoogle Scholar
  47. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ et al (2004) CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative atorvastatin diabetes study (CARDS): multicenter randomized placebo-controlled trial. Lancet 364(9435):685–696PubMedCrossRefGoogle Scholar
  48. Colli S, Eligini S, Lalli M, Camera M, Paoletti R, Tremoli E (1997) Vastatins inhibit tissue factor in cultured human macrophages: a novel mechanism of protectionagainst atherosclerosis. Arterioscler Thromb Vasc Biol 17:265–272PubMedCrossRefGoogle Scholar
  49. Colman E, Szarfman A, Wyeth J, Mosholder A, Jillapalli D, Levine J et al (2008) An evaluation of a datamining signal for amyotrophic lateral sclerosis and statins detected in FDA's spontaneous adverse event reporting system. Pharmacoepidemiol Drug Saf 17:1068–1076PubMedCrossRefGoogle Scholar
  50. Cordle A, Koenigsknecht-Talboo J, Wilkinson B, Limpert A, Landreth G (2005) Mechanisms of statin-mediated inhibition of small G-protein function. J Biol Chem 280:34202–34209PubMedCrossRefGoogle Scholar
  51. Corsini A, Bellosta S, Baetta R, Fumagalli R, Paoletti R, Bernini F (1999) New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacol Ther 84:413–428PubMedCrossRefGoogle Scholar
  52. Crews L, Mizuno H, Desplats P, Rockenstein E, Adame A, Patrick C, Winner B, Winkler J, Masliah E (2008) Alpha-synuclein alters notch-1 expression and neurogenesis in mouse embryonic stem cells and in the hippocampus of transgenic mice. J Neurosci 28:4250–4260PubMedPubMedCentralCrossRefGoogle Scholar
  53. Cunningham C, Wilcockson DC, Campion S, Lunnon K, Perry VH (2005) Central and systemic endotoxin challenges exacerbate the local infl ammatory response and increase neuronal death during chronic neurodegeneration. J Neurosci 25(40):9275–9284PubMedCrossRefGoogle Scholar
  54. Daneschvar DL, Aronson MD, Smetana GW (2015) Do statins prevent Alzheimer's disease? A narrative review. Eur J Int Med 26:666–669CrossRefGoogle Scholar
  55. de Lau LM, Koudstaal PJ, Hofman A, Breteler MM (2006) Serum cholesterol levels and the risk of Parkinson’s disease. Am J Epidemiol 164:998–1002PubMedCrossRefGoogle Scholar
  56. de Oliveir J, Moreira EL, Mancini G, Hort MA, Latini A, Ribeiro-do-Valle RM et al (2013) Diphenyl Diselenide prevents Corticocerebral mitochondrial dysfunction and oxidative stress induced by hypercholesterolemia in LDL receptor knockout mice. Neurochem Res 38:2028–2036CrossRefGoogle Scholar
  57. de Oliveira J, Hort MA, Moreira EL, Glaser V, Ribeiro-do-Valle RM, Prediger RD et al (2011) Positive correlation between elevated plasma cholesterol levels and cognitive impairments in LDL receptor knockout mice: relevance of cortico-cerebral mitochondrial dysfunction and oxidative stress. Neuroscience 197(16):99–106PubMedCrossRefGoogle Scholar
  58. Del Zoppo GJ (1998) The role of platelets in ischemic stroke. Neurology 51(suppl 3):S9–S14PubMedCrossRefGoogle Scholar
  59. Dobolyi A, Vincze C, Pál G, Lovas G (2012) The neuroprotective functions of transforming growth factor beta proteins. Int J Mol Sci 13:8219–8258PubMedPubMedCentralCrossRefGoogle Scholar
  60. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA et al (1998) Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air force/Texas coronary atherosclerosis prevention study. JAMA 279(20):1615–1622PubMedCrossRefGoogle Scholar
  61. Drory VE, Bronipolsky T, Artamonov I, Nefussy B (2008) Influence of statins treatment on survival in patients with amyotrophic lateral sclerosis. J Neurol Sci 273:81–83PubMedCrossRefGoogle Scholar
  62. Dupuis L, Corcia P, Fergani A et al (2008) Dyslipidemia is a protective factor in amyotrophic lateral sclerosis. Neurology 70:1004–1009PubMedCrossRefGoogle Scholar
  63. Ehrenstein MR, Jury EC, Mauri C (2005) Statins for atherosclerosis—as good as it gets? N Engl J Med 252:73–75CrossRefGoogle Scholar
  64. Erdös B, Snipes JA, Tulbert CD, Katakam P, Miller AW, Busija DW (2006) Rosuvastatin improves cerebrovascular function in Zucker obese rats by inhibiting NAD(P)H oxidase-dependent superoxide production. Am J Physiol Heart Circ Physiol 290(3):H1264–H1270PubMedCrossRefGoogle Scholar
  65. Etminan M, Samii A, Brophy JM (2010) Statin use and risk of epilepsy: a nested case–control study. Neurology 75:1496–1500PubMedCrossRefGoogle Scholar
  66. Farmer JA, Torre-Amione G (2000) Comparative tolerability of the HMG-CoA reductase inhibitors. Drug Saf 23(3):197–213PubMedCrossRefGoogle Scholar
  67. Farooqui AA, Ong W-Y, Horrocks LA, Chen P, Farooqui T (2007) Comparison of biochemical effects of statins and fish oil in brain: the battle of the titans. Brain Res Rev 56:443–471PubMedCrossRefGoogle Scholar
  68. Faulkner JR, Herrmann JE, Woo MJ, Tansey KE, Doan NB, Sofroniew MV (2004) Reactive astrocytes protect tissue and preserve function after spinal cord injury. J Neurosci 24:2143–2155PubMedCrossRefGoogle Scholar
  69. Floris S, Blezer EL, Schreibelt G, Dopp E, van der Pol SM, Schadee-Eestermans IL et al (2004) Blood-brain barrier permeability and monocyte infiltration in experimental allergic encephalomyelitis: a quantitative MRI study. Brain 127:616–627PubMedCrossRefGoogle Scholar
  70. Fonseca ACRG, Resende R, Oliveira CR, Pereira CMF (2010) Cholesterol and statins in Alzheimer's disease: current controversies. Exp Neurol 223:282–293PubMedCrossRefGoogle Scholar
  71. Fontaine V, Mohand-Said S, Hanoteau N, Fuchs C, Pfizenmaier K, Eisel U (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:RC216PubMedGoogle Scholar
  72. Frantseva MV, Perez Velazquez JL, Tsoraklidis G, Mendonca AJ, Adamchik Y, Mills LR et al (2000) Oxidative stress is involved in seizure induced neurodegeneration in the kindling model of epilepsy. Neuroscience 97:431–435PubMedCrossRefGoogle Scholar
  73. Fryer HJ, Wolf DH, Knox RJ, Strittmatter SM, Pennica D, O’Leary RM et al (2000) Brain-derived neurotrophic factor induces excitotoxic sensitivity in cultured embryonic rat spinal motor neurons through activation of the phosphatidylinositol 3-kinase pathway. J Neurochem 74:582–595PubMedCrossRefGoogle Scholar
  74. Fukumoto Y, Libby P, Rabkin E, Hill CC, Enomoto M, Hirouchi Y et al (2001) Statins alter smooth muscle cell accumulation and collagen content in established atheroma of Watanabe heritable hyperlipidemic rabbits. Circulation 103:993–999PubMedCrossRefGoogle Scholar
  75. Ganne F, Vasse M, Beaudeux JL, Peynet J, Francois A, Mishal Z et al (2000) Cerivastatin, an inhibitor of HMG-CoA reductase, inhibits urokinase/urokinase-receptor expression and MMP-9 secretion by peripheral blood monocytes – apossible protective mechanism against atherothrombosis. Thromb Haemost 84(4):680–688PubMedGoogle Scholar
  76. Ghosh A, Roy A, Matras J, Brahmachari S, Gendelman HE, Pahan K (2009) Simvastatin inhibits the activation of p21ras and prevents the loss of dopaminergic neurons in a mouse model of Parkinson's disease. J Neurosci 29:13543–13556PubMedPubMedCentralCrossRefGoogle Scholar
  77. Ginsberg HN, Goldberg I (1998) Disorders of lipoprotein metabolism. In: Fauci AS, Braunwald E, Isselbacher KJ, Wilson JD, Martin JB, Kasper DL, Hauser SL, Longo DL (eds) Harrison’s Principles of Internal Medicine. McGraw-Hill, New York, pp 2138–2149Google Scholar
  78. Greenwood J, Walters CE, Pryce G, Kanuga N, Beraud E, Baker D et al (2003) Lovastatin inhibits brain endothelial cell rho-mediated lymphocyte migration and attenuates experimental autoimmune encephalomyelitis. FASEB J 17:905–907PubMedGoogle Scholar
  79. Greenwood J, Steinman L, Zamvil SS (2006) Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat Rev Immunol 6(5):358–370PubMedCrossRefGoogle Scholar
  80. Groemping Y, Rittinger K (2005) Activation and assembly of the NADPH oxidase: a structural perspective. Biochem J 386:401–416PubMedPubMedCentralCrossRefGoogle Scholar
  81. Guasti L, Marino F, Cosentino M, Maio RC, Rasini E, Ferrari M et al (2008) Prolonged statin-associated reduction in neutrophil reactive oxygen species and angiotensin II type 1 receptor expression: 1-year follow-up. Eur Heart J 29:1118–1126PubMedCrossRefGoogle Scholar
  82. Guillaume D, Bertrand P, Dea D, Davignon J, Poirier J (1996) Apolipoprotein E and low-density lipoprotein binding and internalization in primary cultures of rat astrocytes: isoform- specific alterations. J Neurochem 66:2410–2418PubMedCrossRefGoogle Scholar
  83. Gunstad J, Spitznagel MB, Glickman E, Alexander T, Juvancic-Heltzel J, Walter K et al (2008) Beta-amyloid is associated with reduced cognitive function in healthy older adults. J Neuropsychiatr Clin Neurosci 20(3):327–330CrossRefGoogle Scholar
  84. Hamelin BA, Turgeon J (1998) Hydrophilicity/lipophilicity: relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors. Trends Pharmacol Sci 19(1):26–37PubMedCrossRefGoogle Scholar
  85. Han JH, Kim YJ, Han ES, Lee CS (2007) Prevention of 7-ketocholesterol-induced mitochondrial damage and cell death by calmodulin inhibition. Brain Res 1137:11–19PubMedCrossRefGoogle Scholar
  86. Hauwel M, Furon E, Canova C, Griffiths M, Neal J, Gasque P (2005) Innate (inherent) control of brain infection, brain inflammation and brain repair: the role of microglia, astrocytes, protective glial stem cells and stromal ependymal cells. Brain Res Brain Res Rev 48:220–233PubMedCrossRefGoogle Scholar
  87. Heart Protection Study Collaborative Group (2002) MRC/BHF heart protection study of cholesterol lowering with simvastatin in high-risk individuals: a randomised placebo-controlled trial. Lancet 360(9326):7–22CrossRefGoogle Scholar
  88. Heppner FL, Greter M, Marino D, Falsig J, Raivich G, Hövelmeyer N et al (2005) Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nat Med 11:146–152PubMedCrossRefGoogle Scholar
  89. Hering H, Lin CC, Sheng M (2003) Lipid rafts in the maintenance of synapses, dendritic spines, and surface AMPA receptor stability. J Neurosci 23:3262–3271PubMedGoogle Scholar
  90. Hernandez-Romero MC, Arguelles S, Villaran RF, de Pablos RM, Delgado-Cortes MJ (2008) Simvastatin prevents the inflammatory process and the dopaminergic degeneration induced by the intranigral injection of lipopolysaccharide. J Neurochem 105:445–459PubMedCrossRefGoogle Scholar
  91. Hildebrandt H, Haldenwanger A, Eling P (2009) False recognition correlates with amyloid-beta (1–42) but not with total tau in cerebrospinal fluid of patients with dementia and mild cognitive impairment. J Alzheimers Dis 16(1):157–165PubMedCrossRefGoogle Scholar
  92. Hoglund K, Blennow K (2007) Effect of HMG-CoA reductase inhibitors on betaamyloid peptide levels: implications for Alzheimer’s disease. CNS Drug 21:449–462CrossRefGoogle Scholar
  93. Hong H, Zeng JS, Kreulen DL, Kaufman DI, Chen AF (2006) Atorvastatin protects against cerebral infarction via inhibition of NADPH oxidase-derived superoxide in ischemic stroke. Am J Physiol Heart Circ Physiol 291(5):H2210–H2215PubMedCrossRefGoogle Scholar
  94. Hooff GP, Wood WG, Muller WE, Eckert GP (2010) Isoprenoids, small GTPasesand Alzheimer’s disease. Biochim Biophys Acta 1801:896–905PubMedPubMedCentralCrossRefGoogle Scholar
  95. Hu P, Kalb RG (2003) BDNF heightens the sensitivity of motor neurons to excitotoxic insults through activation of TrkB. J Neurochem 84:1421–1430PubMedCrossRefGoogle Scholar
  96. Hu G, Antikainen R, Jousilahti P, Kivipelto M, Tuomilehto J (2008) Total cholesterol and the risk of Parkinson disease. Neurology 70:1972–1979PubMedCrossRefGoogle Scholar
  97. Huang X, Chen H, Miller WC, Mailman RB, Woodard JL, Chen PC et al (2007) Lower low-density lipoprotein cholesterol levels are associated with Parkinson’s disease. Mov Disord 22:377–381PubMedPubMedCentralCrossRefGoogle Scholar
  98. Huang X, Alonso A, Guo X, Umbach DM, Lichtenstein ML, Ballantyne CM, Mailman RB, Mosley TH, Chen H (2015) Statins, plasma cholesterol, and risk of Parkinson's disease: a prospective study. Mov Disord 30(4):552–559PubMedPubMedCentralCrossRefGoogle Scholar
  99. Infanger DW, Sharma RV, Davisson RL (2006) NADPH oxidases of the brain: distribution, regulation, and function. Antioxid Redox Signal 8:1583–1596PubMedCrossRefGoogle Scholar
  100. Ischiropoulos H, Beckman JS (2003) Oxidative stress and nitration in neurodegeneration: cause, effect, or association? J Clin Invest 111:163–169PubMedPubMedCentralCrossRefGoogle Scholar
  101. Jiang JL, Wang S, Li NS, Zhang XH, Deng HW, Li YJ (2007) The inhibitory effect of simvastatin on the ADMA-induced inflammatory reaction is mediated by MAPK pathways in endothelial cells. Biochem Cell Biol 85:66–77PubMedCrossRefGoogle Scholar
  102. Jones P, Kafonek S, Laurora I, Hunninghake D (1998) Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). Am J Cardiol 81(5):582–587PubMedCrossRefGoogle Scholar
  103. Jones PH, Davidson MH, Stein EA, Bays HE, McKenney JM, Miller E et al (2003) Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). Am J Cardiol 92(2):152–160PubMedCrossRefGoogle Scholar
  104. Jope RS, Yuskaitis CJ, Beurel E (2007) Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics. Neurochem Res 32(4–5):577–595PubMedCrossRefGoogle Scholar
  105. Joy TR, Hegele RA (2009) Narrative review: statin-related myopathy. Ann Intern Med 150:858–868PubMedCrossRefGoogle Scholar
  106. Kojro E, Gimpl G, Lammich S, Marz W, Fahrenholz F (2001) Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the alpha–secretase ADAM 10. Proc Natl Acad Sci U S A 98:5815–5820PubMedPubMedCentralCrossRefGoogle Scholar
  107. Koob AO, Ubhi K, Paulsson JF, Kelly J, Rockenstein E, Mante M et al (2010) Lovastatin ameliorates alpha-synuclein accumulation and oxidation in transgenic mouse models of alpha-synucleinopathies. Exp Neurol 221:267–274PubMedCrossRefGoogle Scholar
  108. Kurata T, Miyazaki K, Kozuki M, Morimoto N, Ohta Y, Ikeda Y et al (2011) Progressive neurovascular disturbances in the cerebral cortex of alzheimer’s disease-model mice: protection by atorvastatin and pitavastatin. Neuroscience 197:358–368PubMedCrossRefGoogle Scholar
  109. Kureishi Y, Luo Z, Shiojima I, Bialik A, Fulton D, Lefer DJ et al (2000) The hmgcoa reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med 6:1004–1010PubMedPubMedCentralCrossRefGoogle Scholar
  110. Kust BM, Copray JC, Brouwer N, Troost D, Boddeke HW (2002) Elevated levels of neurotrophins inhumanbiceps brachii tissue of amyotrophic lateral sclerosis. Exp Neurol 177:419–427PubMedCrossRefGoogle Scholar
  111. Kwak B, Mulhaupt F, Myit S, Mach F (2000) Statins as a newly recognized type of immunomodulator. Nat Med 6:1399–1402PubMedCrossRefGoogle Scholar
  112. Landmesser U, Bahlmann F, Mueller M, Spiekermann S, Kirchhoff N, Schulz S et al (2005) Simvastatin versus ezetimibe: pleiotropic and lipid-lowering effects on endothelial function in humans. Circulation 111:2356–2363PubMedCrossRefGoogle Scholar
  113. Laufs U, La Fata V, Plutzky J, Liao JK (1998) Upregulation of endothelial nitric oxide synthase by hmg coa reductase inhibitors. Circulation 97:1129–1135PubMedCrossRefGoogle Scholar
  114. Lee JK, Won J-S, Singh AK, Singh I (2008) Statin inhibits kainic acid-induced seizure and associated inflammation and hippocampal cell death. Neurosci Lett 440:260–264PubMedPubMedCentralCrossRefGoogle Scholar
  115. Lehr HA, Seemuller J, Hubner C, Menger MD, Messmer K (1993) Oxidized LDL-induced leukocyte/endothelium interaction in vivo involves the receptor for platelet activating factor. Arterioscler Thromb 13:1013–1018PubMedCrossRefGoogle Scholar
  116. Li Z, Aizenman CD, Cline HT (2002) Regulation of rho GTPases by crosstalk and neuronal activity in vivo. Neuron 33:741–750PubMedCrossRefGoogle Scholar
  117. Li L, Cao D, Kim H, Lester R, Fukuchi K (2006) Simvastatin enhances learning and memory independent of amyloid load in mice. Ann Neurol 60:729–739PubMedCrossRefGoogle Scholar
  118. Li G, Larson EB, Sonnen JA, Shofer JB, Petrie EC, Schantz A et al (2007) Statin therapy is associated with reduced neuropathologic changes of Alzheimer disease. Neurology 69:878–885PubMedCrossRefGoogle Scholar
  119. Liao JK (2002) Isoprenoids as mediators of the biological effects of statins. J Clin Invest 110:285–288PubMedPubMedCentralCrossRefGoogle Scholar
  120. Liberto CM, Albrecht PJ, Herx LM, Yong VW, Levison SW (2004) Pro-regenerative properties of cytokineactivated astrocytes. J Neurochem 89:1092–1100PubMedCrossRefGoogle Scholar
  121. Lim JH, Lee JC, Lee YH, Choi IY, Oh YK, Kim HS et al (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 97:140–150PubMedCrossRefGoogle Scholar
  122. Ling Q, Tejada-Simon MV (2016) Statins and the brain: new perspective for old drugs. Prog Neuro-Psychopharmacol Biol Psychiatry 66:80–86CrossRefGoogle Scholar
  123. Littarru GP, Langsjoen P (2007) Coenzyme Q10 and statins: biochemical and clinical implications. Mitochondrion 7(Suppl):S168–S174PubMedCrossRefGoogle Scholar
  124. Liu T, McDonnell PC, Young PR, White RF, Siren AL, Hallenbeck JM, Barone FC, Feurestein GZ (1993) Interleukin-1 beta mRNA expression in ischemic rat cortex. Stroke 24:1746–1751PubMedCrossRefGoogle Scholar
  125. Lordan S, Mackrill JJ, O'Brien NM (2009) Oxysterols and mechanisms of apoptotic signaling: implications in the pathology of degenerative diseases. J Nutr Biochem 20:321–336PubMedCrossRefGoogle Scholar
  126. Ma T, Zhao Y, Kwak Y-D, Yang Z, Thompson R, Luo Z et al (2009) Statin’s excitoprotection is mediated by sAPP and the subsequent attenuation ofcalpain-induced truncation events, likely via Rho-ROCK signaling. J Neurosci 29:11226–11236PubMedPubMedCentralCrossRefGoogle Scholar
  127. Mackay DJG, Hall A (1998) Rho GTPases. J Biol Chem 273:20685–20688PubMedCrossRefGoogle Scholar
  128. Mailman T, Hariharan M, Karten B (2011) Inhibition of neuronal cholesterol biosynthesis with lovastatin leads to impaired synaptic vesicle release even in the presence of lipoproteins or geranylgeraniol. J Neurochem 119:1002–1015PubMedCrossRefGoogle Scholar
  129. Marchetti L, Klein M, Schlett K, Pfizenmaier K, Eisel UL (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 279:32869–32881PubMedCrossRefGoogle Scholar
  130. Marwarha G, Rhen T, Schommer T, Ghribi O (2011) The oxysterol 27-hydroxycholesterol regulates α-synuclein and tyrosine hydroxylase expression levels in human neuroblastoma cells through modulation of liver X receptors and estrogen receptors – relevance to Parkinson’s disease. J Neurochem 119:1119–1136PubMedPubMedCentralCrossRefGoogle Scholar
  131. Meda L, Cassatella MA, Szendrei GI, Otvos L Jr, Baron P, Villalba M et al (1995) Activation of microglial cells by β-amyloid protein and interferon. Nature 374:647–650PubMedCrossRefGoogle Scholar
  132. Molinuevo JL, Llado A, Rami L (2005) Memantine: targeting glutamate excitotoxicity in Alzheimer’s disease and other dementias. Am J Alzheimers Dis Other Demen 20:77–85PubMedCrossRefGoogle Scholar
  133. Monje ML, Toda H, Palmer TD (2003) Inflammatory blockade restores adult hippocampal neurogenesis. Science 302:1760–1765PubMedCrossRefGoogle Scholar
  134. Montaner S, Perona R, Saniger L, Lacal JC (1998) Multiple signalling pathways lead to the activation of the nuclear factor kappaB by the rho family of GTPases. J Biol Chem 273:12779–12785PubMedCrossRefGoogle Scholar
  135. Montaner J, Chacón P, Krupinski J, Rubio F, Millán M, Molina CA, Hereu P, Quintana M, Alvarez-Sabín J (2008) Simvastatin in the acute phase of ischemic stroke: a safety and efficacy pilot trial. Eur J Neurol 15(1):82–90Google Scholar
  136. Nassief A, Marsh JD (2008) Statin therapy for stroke prevention. Stroke 39(3):1042–1048PubMedCrossRefGoogle Scholar
  137. Nefussy B, Hirsch J, Cudkowicz ME, Drory VE (2011) Gender-based effect of statins on functional decline in amyotrophic lateral sclerosis. J Neurol Sci 300:23–27PubMedCrossRefGoogle Scholar
  138. Neuhaus O, Strasser-Fuchs S, Fazekas F, Kieseier BC, Nieder-wieser G, Hartung HP (2002) Statins as immunomodulators. Comparison with interferon-b1b in MS. Neurology 59:990–997PubMedCrossRefGoogle Scholar
  139. Neuhaus O, Stüve O, Zamvil SS, Hartung H-P (2004) Are statins a treatment option for multiple sclerosis? Lancet Neurol 3:369–371PubMedCrossRefGoogle Scholar
  140. Ostrowski SM, Wilkinson BL, Golde TE, Landreth G (2007) Statins reduce amyloid-beta production through inhibition of protein isoprenylation. J Biol Chem 282:26832–26844PubMedCrossRefGoogle Scholar
  141. Otunola GA, Oloyede OB, Oladiji AT, Afolayan AJ (2014) Selected 1 spices an their combination modulate hypercholesterolemia-induced oxidative stress in experimental rats. Biol Res 47:5PubMedPubMedCentralGoogle Scholar
  142. Pahan K, Sheikh FG, Namboodiri AM, Singh I (1997) Lovas- tatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat primary astrocytes, microglia, and macrophages. J Clin Invest 100:2671–2679PubMedPubMedCentralCrossRefGoogle Scholar
  143. Paintlia AS, Paintlia MK, Singh AK, Stanislaus R, Gilg AG, Barbosa E et al (2004) Regulation of gene expression associated with acute experimental autoimmune encephalomyelitis by lovastatin. J Neurosci Res 77:63–81PubMedCrossRefGoogle Scholar
  144. Paintlia AS, Paintlia MK, Khan M, Vollmer T, Singh AK, Singh I (2005) HMGCoA reductase inhibitor augments survival and differentiation of oligodendrocyte progenitors in animal model of multiple sclerosis. FASEB J 19:1407–1421PubMedCrossRefGoogle Scholar
  145. Paintlia AS, Paintlia MK, Singh I, Singh AK (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 169:1012–1025PubMedPubMedCentralCrossRefGoogle Scholar
  146. Paintlia AS, Paintlia MK, Singh I, Skoff RB, Singh AK (2009) Combination therapy of lovastatin and rolipram provides neuroprotection and promotes neurorepair in inflammatory demyelination model of multiple sclerosis. Glia 57:182–193PubMedPubMedCentralCrossRefGoogle Scholar
  147. Panini SR, Yang L, Rusinol AE, Sinensky MS, Bonventre JV, Leslie CC (2001) Arachidonate metabolism and the signaling pathway of induction of apoptosis by oxidized ldl/oxysterol. J Lipid Res 42:1678–1686PubMedGoogle Scholar
  148. Papassotiropoulos A, Streffer JR, Tsolaki M, Schmid S, Thal D, Nicosia F et al (2003) Increased brain beta-amyloid load, phosphorylated tau, and risk of Alzheimer disease associated with an intronic CYP46 polymorphism. Arch Neurol 60:29–35PubMedCrossRefGoogle Scholar
  149. Pappolla MA, Smith MA, Bryant-Thomas T, Bazan N, Petanceska S, Perry G et al (2002) Cholesterol, oxidative stress, and Alzheimer’s disease: expanding the horizons of pathogenesis. Free Radic Biol Med 33(2):173–181PubMedCrossRefGoogle Scholar
  150. Park E, Velumian AA, Fehlings MG (2004) The role of excitotoxicity in secondary mechanisms of spinal cord injury: a review with an emphasis on the implications for white matter degeneration. J Neurotrauma 21:754–774PubMedCrossRefGoogle Scholar
  151. Paul R, Choudhury A, Borah A (2015) Cholesterol - a putative endogenous contributor towards Parkinson’s disease. Neurochem Int 90:125–133PubMedCrossRefGoogle Scholar
  152. Pestana RRF, Kinjo ER, Hernandes MS, Britto LRG (2010) Reactive oxygen species generated by NADPH oxidase are involved in neurodegeneration in the pilocarpine model of temporal lobe epilepsy. Neurosci Lett 484:187–191PubMedCrossRefGoogle Scholar
  153. Piermartiri TC, Vandresen-Filho S, de Araujo HB, Martins WC, Dal’agnolo D, Stroeh E et al (2009) Atorvastatin prevents hippocampal cell death due to quinolinic acid-induced seizures in mice by increasing Akt phosphorylation and glutamate uptake. Neurotox Res 16:106–115PubMedCrossRefGoogle Scholar
  154. Ponce J, de la Ossa NP, Hurtado O, Millan M, Arenillas JF, Davalos A et al (2008) Simvastatin reduces the association of NMDA receptors to lipid rafts: a cholesterol-mediated effect in neuroprotection. Stroke 39:1269–1275PubMedCrossRefGoogle Scholar
  155. Posada-Duque RA, Velasquez-Carvajal D, Eckert GP, Cardona-Gomez GP (2013) Atorvastatin requires geranylgeranyl transferase-I and Rac1 activation to exert neuronal protection and induce plasticity. Neurochem Int 62:433–445PubMedCrossRefGoogle Scholar
  156. Postiglione A, Avvedimento EV, Paterno R (2007) Farnesyl transferase inhibitors induce neuroprotection by inhibiting Ha-Ras signalling pathway. Eur J Neurosci 26:3261–3266PubMedCrossRefGoogle Scholar
  157. Pott Godoy MC, Tarelli R, Ferrari CC, Sarchi MI, Pitossi FJ (2008) Central and systemic IL-1 exacerbates neurodegeneration and motor symptoms in a model of Parkinson’s disease. Brain 131(7):1880–1894PubMedCrossRefGoogle Scholar
  158. Prasanthi JR, Dasari B, Marwarha G, Larson T, Chen X, Geiger JD et al (2010) Caffeine protects against oxidative stress and Alzheimer's disease-like pathology in rabbit hippocampus induced by cholesterol-enriched diet. Free Radic Biol Med 49:1212–1220PubMedPubMedCentralCrossRefGoogle Scholar
  159. Prosser LA, Stinnett AA, Goldman PA, Williams LW, Hunink M, Goldman L et al (2000) Cost-effectiveness of cholesterol-lowering therapies according to selected patient characteristics. Ann Intern Med 132(10):769–779PubMedCrossRefGoogle Scholar
  160. Ramirez C, Tercero I, Pineda A, Burgos JS (2011) Simvastatin is the statin that most efficiently protects against kainate-induced excitotoxicity and memory impairment. J Alzheimers Dis 24:161–174PubMedGoogle Scholar
  161. Rantham Prabhakara JP, Feist G, Thomasson S, Thompson A, Schommer E, Ghribi O (2008) Differential effects of 24-hydroxycholesterol and 27-hydroxycholesterol on tyrosine hydroxylase and alpha-synuclein in human neuroblastoma SH-SY5Y cells. J Neurochem 107:1722–1729PubMedCrossRefGoogle Scholar
  162. Reiner A, Albin RL, Anderson KD, D’Amato CJ, Penney JB, Young AB (1988) Differential loss of striatal projection neurons in Huntington disease. Proc Natl Acad Sci U S A 85:5733–5737PubMedPubMedCentralCrossRefGoogle Scholar
  163. Roy A, Pahan K (2011) Prospects of statins in Parkinson disease. Neuroscience 17:244–255CrossRefGoogle Scholar
  164. Russo E, di Paola ED, Gareri P, Siniscalchi A, Labate A, Gallelli L et al (2013) Pharmacodynamic potentiation of antiepileptic drugs’ effects by some HMG-CoA reductase inhibitors against audiogenic seizures in DBA/2 mice. Pharmacol Res 70:1–12PubMedCrossRefGoogle Scholar
  165. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG et al (1996) The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and recurrent events trial investigators. N Engl J Med 335(14):1001–1009PubMedCrossRefGoogle Scholar
  166. Saeedi Saravi SS, Dehpour AR (2016) Potential role of organochlorine pesticides in th pathogenesis o neurodevelopmental, neurodegenerative, and neurobehavioral disorders: a review. Life Sci 145:255–264PubMedCrossRefGoogle Scholar
  167. Saeedi Saravi SS, Saeedi Saravi SS, Arefidoust A, Dehpour AR (2017) Current insights into pathogenesis of Parkinson’s disease: approach to mevalonate pathway and protective role of statins. Biomed Pharmacother 90:724–730PubMedCrossRefGoogle Scholar
  168. Saheki A, Terasaki T, Tamai I, Tsuji A (1994) In vivo and in vitro blood-brain barrier transport of 3-hydroxy-3-methylglutaryl coenzyme a (HMG-CoA) reductase inhibitors. Pharm Res 11:305–311PubMedCrossRefGoogle Scholar
  169. Sanan DA, Weisgraber KH, Russell SJ, Mahley RW, Huang D, Saunders A, Schmechel D, Wisniewski T, Frangione B, Roses AD et al (1994) Apolipoprotein E associates with beta amyloid peptide of Alzheimer’s disease to form novel monofibrils. Isoform apoE4 associates more efficiently than apoE3. J Clin Invest 94:860–869PubMedPubMedCentralCrossRefGoogle Scholar
  170. Sano M, Bell KL, Galasko D, Galvin JE, Thomas RG, van Dyck CH, Aisen PS (2011) A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease. Neurology 77:556–563PubMedPubMedCentralCrossRefGoogle Scholar
  171. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D et al (2001) Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 285:1711–1718PubMedCrossRefGoogle Scholar
  172. SEARCH Collaborative Group, Link E, Parish S, Armitage J, Bowman L, Heath S, Matsuda F et al (2008) SLCO1B1 variants and statin-induced myopathy — a genome wide study. N Engl J Med 359:789–799CrossRefGoogle Scholar
  173. Selley ML (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):1–6PubMedCrossRefGoogle Scholar
  174. Semenova MM, Maki-Hokkonen AM, Cao J, Komarovski V, Forsberg KM, Koistinaho M et al (2007) Rho mediates calciumdependent activation of p38alpha and subsequent excitotoxic cell death. Nat Neurosci 10:436–443PubMedGoogle Scholar
  175. Sena A, Pedrosa R, Graca MM (2003) Therapeutic potential of lovastatin in multiple sclerosis. J Neurol 250:754–755PubMedCrossRefGoogle Scholar
  176. Sena A, Pedrosa R, Morais MG (2007) Beneficial effect of statins in multiple sclerosis: is it dose-dependent? Atherosclerosis 191:462PubMedCrossRefGoogle Scholar
  177. Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G, Caulfield M et al (2003) Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian cardiac outcomes trial–lipid lowering arm (ASCOTLLA): a multicentre randomised controlled trial. Lancet 361(9364):1149–1158PubMedCrossRefGoogle Scholar
  178. Sheng Z, Jia X, Kang M (2016) Statin use and risk of Parkinson’s disease: a meta-analysis. Behav Brain Res 309:29–34PubMedCrossRefGoogle Scholar
  179. Shepardson NE, Shankar GM, Selkoe DJ (2011) Cholesterol level and statin use in Alzheimer disease: II. Review of human trials and recommendations. Arch Neurol 68:1385–1392PubMedPubMedCentralCrossRefGoogle Scholar
  180. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, Macfarlane PW et al (1995) Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 333(20):1301–1307PubMedCrossRefGoogle Scholar
  181. Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM et al (2002) Prospective study of pravastatin in the elderly at risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 360(9346):1623–1630PubMedCrossRefGoogle Scholar
  182. Shitara Y, Sugiyama Y (2006) Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme a (HMG-CoA) reductase inhibitors: drug-drug interactions and interindividual differences in transporter and metabolic enzyme functions. Pharmacol Ther 112:71–105PubMedCrossRefGoogle Scholar
  183. Simons M, Keller P, De Strooper B, Beyreuther K, Dotti CG, Simons K (1998) Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. Proc Natl Acad Sci U S A 95:6460–6464PubMedPubMedCentralCrossRefGoogle Scholar
  184. Sironi L, Cimino M, Guerrini U, Calvio AM, Lodetti B, Asdente M et al (2003) Treatment with statins after induction of focal ischemia in rats reduces the extent of brain damage. Arterioscler Thromb Vasc Biol 23:322–327PubMedCrossRefGoogle Scholar
  185. Skaletz-Rorowski A, Lutchman M, Kureishi Y, Lefer DJ, Faust JR, Walsh K (2003) HMG-CoA reductase inhibitors promote cholesterol-dependent Akt/PKB translocation to membrane domains in endothelial cells. Cardiovasc Res 57(1):253–264PubMedCrossRefGoogle Scholar
  186. Smith KB, Kang P, Sabbagh MN (2017) The effect of statins on rate of cognitive decline in mild cognitive impairment. Alzheimer Dementia Trans Res Clin Intervent 3:149–156. doi: 10.1016/j.trci.2017.01.001 CrossRefGoogle Scholar
  187. Song G, Ouyang G, Bao S (2005) The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med 9(1):59–71PubMedCrossRefGoogle Scholar
  188. Stanislaus R, Singh AK, Singh I (2001) Lovastatin treatment decreases mononuclear cell infiltration into the CNS of Lewis rats with experimental allergic encephalomyelitis. J Neurosci Res 66(2):155–162PubMedCrossRefGoogle Scholar
  189. Streit WJS (2005) Microglia and neuroprotection: implication for Alzheimer’s disease. Brain Res Rev 48:234–239PubMedCrossRefGoogle Scholar
  190. Strle K, Zhou JH, Shen WH, Broussard SR, Johnson RW, Freund GG et al (2001) Interleukin-10 in the brain. Crit Rev Immunol 21:427–449PubMedCrossRefGoogle Scholar
  191. Stüve O, Youssef S, Weber MS, Nessler S, von Budingen HC, Hemmer B et al (2006) Immunomodulatory synergy by combination of atorvastatin and glatiramer acetate in treatment of CNS autoimmunity. J Clin Invest 116:1037–1044PubMedPubMedCentralCrossRefGoogle Scholar
  192. Switzer JA, Hess DC (2006) Statins in stroke: prevention, protection and recovery. Expert Rev Neurother 6:195–202PubMedCrossRefGoogle Scholar
  193. Tejada-Simon MV (2015) Modulation of actin dynamics by Rac 1 to target cognitive function. J Neurochem 133(6):767–779PubMedCrossRefGoogle Scholar
  194. Thirumangalakudi L, Prakasam A, Zhang R, Bimonte-Nelson H, Sambamurti K, Kindy MS et al (2008) High cholesterol-induced neuroinflammation and amyloid precursor protein processing correlate with loss of working 1 memory in mice. J Neurochem 106:475–485PubMedPubMedCentralCrossRefGoogle Scholar
  195. Tong XK, Lecrux C, Rosa-Neto P, Hamel E (2012) Age-dependent rescue by simvastatin of Alzheimer's disease cerebrovascular and memory deficits. J Neurosci 32(14):4705–4715PubMedCrossRefGoogle Scholar
  196. Tonkin AM, Colquhoun D, Emberson J, Hague W, Keech A, Lane G et al (2000) Effects of pravastatin in 3260 patients with unstable angina: results from the LIPID study. Lancet 356(9245):1871–1875PubMedCrossRefGoogle Scholar
  197. Townsend KP, Shytle DR, Bai Y, San N, Zeng J, Freeman M et al (2004) Lovastatin modulation of microglial activation via suppression of functional CD40 expression. J Neurosci Res 78:167–176PubMedCrossRefGoogle Scholar
  198. Tramontina AC, Wartchow KM, Rodrigues L, Biasibetti R, Quincozes-Santos A, Bobermin L, Tramontin F, Gonçalves CA (2011) The neuroprotective effect of two statins: simvastatin and pravastatin on a streptozotocin-induced model o Alzheimer's disease in rats. J Neural Transm 118(11):1641–1649PubMedCrossRefGoogle Scholar
  199. Trapp T, Olah L, Holker I, Besselmann M, Tiesler C, Maeda K et al (2001) GTPase RhoB: an early predictor of neuronal death after transient focal ischemia in mice. Mol Cell Neurosci 17:883–894PubMedCrossRefGoogle Scholar
  200. Tricarico PM, Marcuzzi A, Piscianz E, Monasta L, Crovella S, Kleiner G (2013) Mevalonate kinase deficiency and Neuroinflammation: balance between apoptosis and Pyroptosis. Int J Mol Sci 14:23274–23288PubMedPubMedCentralCrossRefGoogle Scholar
  201. Trousson A, Bernard S, Petit PX, Liere P, Pianos A, El Hadri K et al (2009) 25-hydroxycholesterol provokes oligodendrocyte cell line apoptosis and stimulates the secreted phospholipase a2 type iia via lxr beta and pxr. J Neurochem 109:945–958PubMedCrossRefGoogle Scholar
  202. Tsuji A, Saheki A, Tamai I, Terasaki T (1993) Transport mechanism of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors at the blood-brain barrier. J Pharmacol Exp Ther 267:1085–1090PubMedGoogle Scholar
  203. Tziomalos K, Giampatzis V, Bouziana SD, Spanou M, Papadopoulou SKM, Angelopoulou SM, Konstantara F, Savopoulos C, Hatzitolios AI (2015) Comparative effects of more versus less aggressive treatment with statins on the long-term outcome of patients with acute ischemic stroke. Atherosclerosis 243:65–70PubMedCrossRefGoogle Scholar
  204. Uzum G, Akgun-Dar K, Aksu U (2010) The effects of atorvastatin on memory deficit and seizure susceptibility in pentylentetrazole-kindled rats. Epilepsy Behav 19:284–289PubMedCrossRefGoogle Scholar
  205. Valenza M, Rigamonti D, Goffredo D, Zuccato C, Fenu S, Jamot L, Strand A, Tarditi A, Woodman B, Racchi M et al (2005) Dysfunction of the cholesterol biosynthetic pathway in Huntington’s disease. J Neurosci 25:9932–9939PubMedCrossRefGoogle Scholar
  206. van der Most PJ, Dolga AM, Nijholt IM, Luiten PGM, Eisel ULM (2009) Statins: mechanisms of neuroprotection. Prog Neurobiol 88:64–75PubMedCrossRefGoogle Scholar
  207. van Gool WA, van de Beek D, Eikelenboom P (2010) Systemic infection and delirium: when cytokines and acetylcholine collide. Lancet 375(9716):773–775PubMedCrossRefGoogle Scholar
  208. Vance JE (2012) Dysregulation of cholesterol balance in the brain: contribution to neurodegenerative diseases. Dis Model Mech 5:746–755PubMedPubMedCentralCrossRefGoogle Scholar
  209. Vance JE (2014) MAM (mitochondria-associated membranes) in mammalian cells: lipids and beyond. Biochim Biophys Acta 1841(4):595–609Google Scholar
  210. Vaughan CJ, Delanty N (1999) Neuroprotective properties of statins in cerebral ischemia and stroke. Stroke 30:1969–1973PubMedCrossRefGoogle Scholar
  211. Vaya J, Schipper HM (2007) Oxysterols, cholesterol homeostasis, and alzheimer disease. J Neurochem 102:1727–1737PubMedCrossRefGoogle Scholar
  212. Veillard NR, Mach F (2002) Statins: the new aspirin? Cell Mol Life Sci 59:1771–1786PubMedCrossRefGoogle Scholar
  213. Vollmer T, Key L, Durkalski V, Tyor W, Corboy J, Markovic-Plese S et al (2004) Oral simvastatin treatment in relapsingremitting multiple sclerosis. Lancet 363:1607–1608PubMedCrossRefGoogle Scholar
  214. Voora D, Shah SH, Spasojevic I, Ali S, Reed CR, Salisbury BA et al (2009) The SLCO1B1*5 genetic variant is associated with statin-induced side effects. J Am Coll Cardiol 54:1609–1619PubMedPubMedCentralCrossRefGoogle Scholar
  215. Wahner AD, Bronstein JM, Bordelon YM, Ritz B (2008) Statin use and the risk of Parkinson disease. Neurology 70:1418–1422PubMedPubMedCentralCrossRefGoogle Scholar
  216. Walder CE, Green SP, Darbonne WC, Mathias J, Rae J, Dinauer MC et al (1997) Ischemic stroke injury is reduced in mice lacking a functional NADPH oxidase. Stroke 28:2252–2258PubMedCrossRefGoogle Scholar
  217. Wallerath T, Poleo D, Li H, Forstermann U (2003) Red wine increases the expression of human endothelial nitric oxide synthase: a mechanism that may contribute to its beneficial cardiovascular effects. J Am Coll Cardiol 41:471–478PubMedCrossRefGoogle Scholar
  218. Wang Q, Wang PH, McLachlan C, Wong PT (2005a) Simvastatin reverses the downregulation of dopamine D1 and D2 receptor expression in the prefrontal cortex of 6-hydroxydopamine-induced parkinsonian rats. Brain Res 1045(1–2):229–233PubMedCrossRefGoogle Scholar
  219. Wang Q, Ting WL, Yang H, Wong PT (2005b) High doses of simvastatin upregulate dopamine D1 and D2 receptor expression in the rat prefrontal cortex: possible involvement of endothelial nitric oxide synthase. Br J Pharmacol 144(7):933–939PubMedPubMedCentralCrossRefGoogle Scholar
  220. Wang Q, Tang XN, Yenari MA (2007) The inflammatory response in stroke. J Neuroimmunol 184(1–2):53–68PubMedCrossRefGoogle Scholar
  221. Wang Q, Zengin A, Deng C, Li Y, Newell KA, Yang GY et al (2009) High dose of simvastatin induces hyperlocomotive and anxiolytic-like activities: the association with the up-regulation of NMDA receptor binding in the rat brain. Exp Neurol 216:132–138PubMedCrossRefGoogle Scholar
  222. Wang Q, Yan J, Chen X, Li J, Yang Y, Weng JP (2011) Statins: multiple neuroprotective mechanisms in neurodegenerative diseases. Exp Neurol 230:27–34PubMedCrossRefGoogle Scholar
  223. Wassmann S, Laufs U, Baumer AT, Muller K, Konkol C, Sauer H et al (2001) Inhibition of geranylgeranylation reduces angiotensin IImediated free radical production in vascular smooth muscle cells: involvement of angiotensin AT1 receptor expression and Rac1 GTPase. Mol Pharmacol 59:646–654PubMedGoogle Scholar
  224. Waters D, Schwart GG, Olsson AG, Zeiher A, Oliver MF, Ganz P et al (2002) Effects of atorvastatin on stroke in patients with unstable angina on non-Q-wave myocardial infarction: a myocardial ischemia reduction with aggressive cholesterol lowering (MIRACL) substudy. Circulation 106:1690–1695PubMedCrossRefGoogle Scholar
  225. Weber C, Erl W, Weber KSC, Weber PC (1997) HMG-CoA reductase inhibitors decrease CD11b expression and CD11b-dependent adhesion of monocytes to endothelium and reduce increased adhesiveness of monocytes isolated from patients with hypercholesterolemia. J Am Coll Cardiol 30:1212–1217PubMedCrossRefGoogle Scholar
  226. Weitz-Schmidt G, Welzenbach K, Brinkmann V, Kamata T, Kallen J, Bruns C et al (2001) Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat Med 7:687–692PubMedCrossRefGoogle Scholar
  227. Wolfrum S, Dendorfer A, Rikitake Y, Stalker TJ, Gong Y, Scalia R et al (2004) Inhibition of rho-kinase leads to rapid activation of phosphatidylinositol 3-kinase/protein kinase Akt and cardiovascular protection. Arterioscler Thromb Vasc Biol 24:1842–1847PubMedPubMedCentralCrossRefGoogle Scholar
  228. Wolozin B, Manger J, Bryant R, Cordy J, Green RC, McKee A (2006) Reassessing the relationship between cholesterol, statins and Alzheimer’s disease. Acta Neurol Scand Suppl 18:63–70CrossRefGoogle Scholar
  229. Wolozin B, Wang SW, Li NC, Lee A, Lee TA, Kazis LE (2007) Simvastatin is associated with a reduced incidence of dementia and Parkinson’s disease. BMC Med 5:20–30PubMedPubMedCentralCrossRefGoogle Scholar
  230. Won JS, Im YB, Key L, Singh I, Singh AK (2003) The involvement of glucose metabolism in the regulation of inducible nitric oxide synthase gene expression in glial cells: possible role of glucose-6-phosphate dehydrogenase and CCAAT/enhancing binding protein. J Neurosci 23:7470–7478PubMedGoogle Scholar
  231. Won JS, Im YB, Khan M, Contreras M, Singh AK, Singh I (2008) Lovastatin inhibits amyloid precursor protein (APP) beta-cleavage through reduction of APP distribution in Lubrol WX extractable low density lipid rafts. J Neurochem 105:1536–1549PubMedPubMedCentralCrossRefGoogle Scholar
  232. Wong B, Lumma WC, Smith AM, Sisko JT, Wright SD, Cai TQ (2001) Statins suppressTHP-1 cell migration and secretion of matrix metalloproteinase 9 by inhibitinggeranylgeranylation. J Leukoc Biol 69(6):959–962PubMedGoogle Scholar
  233. Wood WG, Eckert GP, Igbavboa U, Muller WE (2003) Amyloid beta-protein interactions with membranes and cholesterol: causes or casualties of Alzheimer’s disease. Biochim Biophys Acta 1610:281–290CrossRefGoogle Scholar
  234. Wood WG, Eckert GP, Igbavboa U, Muller WE (2010) Statins and neuroprotection: a prescription to move the field forward. Ann N Y Acad Sci 1199:69–76PubMedPubMedCentralCrossRefGoogle Scholar
  235. Yi JH, Hazell AS (2006) Excitotoxic mechanisms and the role of astrocytic glutamate transporters in traumatic brain injury. Neurochem Int 48:394–403PubMedCrossRefGoogle Scholar
  236. Youssef S, Stuve O, Patarroyo JC, Ruiz PJ, Radosevich JL, Hur EM (2002) The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 420:78–84PubMedCrossRefGoogle Scholar
  237. Zacco A, Togo J, Spence K, Ellis A, Lloyd D, Furlong S et al (2003) 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors protect cortical neurons from excitotoxicity. J Neurosci 23:11104–11111PubMedGoogle Scholar
  238. Zhang W, Wang T, Qin L, Gao HM, Wilson B, Ali SF (2004) Neuroprotective effect of dextromethorphan in the MPTP Parkinson’s disease model: role of NADPH oxidase. FASEB J 18:589–591PubMedGoogle Scholar
  239. Zipp F, Waiczies S, Aktas O, Neuhaus O, Hemmer B, Schraven B et al (2007) Nitsch. Impact of HMG-CoA reductase inhibition on brain pathology. Trends Pharmacol Sci 28:342–349PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Seyed Soheil Saeedi Saravi
    • 1
    • 2
    • 3
  • Seyed Sobhan Saeedi Saravi
    • 4
  • Alireza Arefidoust
    • 2
    • 3
  • Ahmad Reza Dehpour
    • 2
    • 3
    Email author
  1. 1.Department of Toxicology-Pharmacology, Faculty of PharmacyGuilan University of Medical SciencesRashtIran
  2. 2.Department of Pharmacology, School of MedicineTehran University of Medical SciencesTehranIran
  3. 3.Experimental Medicine Research Center, School of MedicineTehran University of Medical SciencesTehranIran
  4. 4.Department of Toxicology-Pharmacology, Faculty of PharmacyMazandaran University of Medical SciencesSariIran

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