Skip to main content
PMC home page
Neurotherapeutics logoLink to Neurotherapeutics
. 2007 Oct;4(4):693–700. doi: 10.1016/j.nurt.2007.08.004

Statins—Treatment option for central nervous system autoimmune disease?

Martin S Weber 1, Lawrence Steinman 2, Scott S Zamvil 1,✉
PMCID: PMC7479672  PMID: 17920550

Summary

Statins, inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, are well-established agents to lower cholesterol levels and prevent cardiovascular morbidity. Independent of their lipid-lowering properties, statins have been shown to exert pleiotropic immunomodulatory effects in various animal models of human autoimmune disease. In experimental autoimmune encephalomyelitis, a murine model for multiple sclerosis, statins prevented disease onset and even reversed paralysis when treatment was initiated after experimental autoimmune encephalomyelitis was fully established. Furthermore, well-tolerated oral statins were recently shown to exert synergistic benefit in experimental autoimmune encephalomyelitis in combination with existing agents for multiple sclerosis therapy. Based primarily on these encouraging results, statins are now being tested in clinical trials as a mono-therapy for multiple sclerosis, as well as in combination with approved disease-modifying therapies.

Key Words: Multiple sclerosis, immunomodulatory agents, statins, experimental autoimmune encephalomyelitis, novel therapy

References

  • 1.Ginsberg HN. Effects of statins on triglyceride metabolism. Am J Cardiol. 1998;81:32B–35B. doi: 10.1016/S0002-9149(98)00035-6. [DOI] [PubMed] [Google Scholar]
  • 2.Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature. 1990;343:425–430. doi: 10.1038/343425a0. [DOI] [PubMed] [Google Scholar]
  • 3.Zhang FL, Casey PJ. Protein prenylation: molecular mechanisms and functional consequences. Annu Rev Biochem. 1996;65:241–269. doi: 10.1146/annurev.bi.65.070196.001325. [DOI] [PubMed] [Google Scholar]
  • 4.Takai Y, Sasaki T, Matozaki T. Small GTP-binding proteins. Physiol Rev. 2001;81:153–208. doi: 10.1152/physrev.2001.81.1.153. [DOI] [PubMed] [Google Scholar]
  • 5.Zamvil SS, Steinman L. The T lymphocyte in experimental allergic encephalomyelitis. Ann. Rev. Immunol. 1990;8:579–621. doi: 10.1146/annurev.iy.08.040190.003051. [DOI] [PubMed] [Google Scholar]
  • 6.Kornek B, Storch MK, Weissert R, et al. Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am J Pathol. 2000;157:267–276. doi: 10.1016/S0002-9440(10)64537-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Youssef S, Stuve O, Patarroyo JC, et al. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature. 2002;420:78–84. doi: 10.1038/nature01158. [DOI] [PubMed] [Google Scholar]
  • 8.Aktas O, Waiczies S, Smorodchenko A, et al. Treatment of relapsing paralysis in experimental encephalomyelitis by targeting Th1 cells through atorvastatin. J Exp Med. 2003;197:725–733. doi: 10.1084/jem.20021425. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Stanislaus R, Gilg AG, Singh AK. Singh I. Immunomodulation of experimental autoimmune encephalomyelitis in the Lewis rats by Lovastatin. Neurosci Lett. 2002;333:167–170. doi: 10.1016/S0304-3940(02)00943-6. [DOI] [PubMed] [Google Scholar]
  • 10.Greenwood J, Walters CE, Pryce G, et al. Lovastatin inhibits brain endothelial cell Rho-mediated lymphocyte migration and attenuates experimental autoimmune encephalomyelitis. Faseb J. 2003;17:905–907. doi: 10.1096/fj.02-1014fje. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med. 2000;6:1399–1402. doi: 10.1038/82219. [DOI] [PubMed] [Google Scholar]
  • 12.Sadeghi MM, Tiglio A, Sadigh K, et al. Inhibition of interferon-gamma-mediated microvascular endothelial cell major histocom-patibility complex class II gene activation by HMG-CoA reductase inhibitors. Transplantation. 2001;71:1262–1268. doi: 10.1097/00007890-200105150-00014. [DOI] [PubMed] [Google Scholar]
  • 13.Dustin ML, Shaw AS. Costimulation: building an immunological synapse. Science. 1999;283:649–650. doi: 10.1126/science.283.5402.649. [DOI] [PubMed] [Google Scholar]
  • 14.Yilmaz A, Reiss C, Tantawi O, Weng A, Stumpf C, Raaz D, et al. HMG-CoA reductase inhibitors suppress maturation of human dendritic cells: new implications for atherosclerosis. Atherosclerosis. 2004;172:85–93. doi: 10.1016/j.atherosclerosis.2003.10.002. [DOI] [PubMed] [Google Scholar]
  • 15.Stuve O, Youssef S, Weber MS, et al. Immunomodulatory synergy by combination of atorvastatin and glatiramer acetate in treatment of CNS autoimmunity. J Clin Invest. 2006;116:1037–1044. doi: 10.1172/JCI25805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Waiczies S, Prozorovski T, Infante-Duarte C, et al. Atorvastatin induces T cell anergy via phosphorylation of ERK1. J Immunol. 2005;174:5630–5635. doi: 10.4049/jimmunol.174.9.5630. [DOI] [PubMed] [Google Scholar]
  • 17.Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature. 1996;383:787–793. doi: 10.1038/383787a0. [DOI] [PubMed] [Google Scholar]
  • 18.Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441:235–238. doi: 10.1038/nature04753. [DOI] [PubMed] [Google Scholar]
  • 19.Steinman L. A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat Med. 2007;13:139–145. doi: 10.1038/nm1551. [DOI] [PubMed] [Google Scholar]
  • 20.Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med. 2004;199:971–979. doi: 10.1084/jem.20031579. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Nath N, Giri S, Prasad R, Singh AK, Singh I. Potential targets of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor for multiple sclerosis therapy. J Immunol. 2004;172:1273–1286. doi: 10.4049/jimmunol.172.2.1273. [DOI] [PubMed] [Google Scholar]
  • 22.Ho IC, Glimcher LH. Transcription: tantalizing times for T cells. Cell. 2002;109:S109–120. doi: 10.1016/S0092-8674(02)00705-5. [DOI] [PubMed] [Google Scholar]
  • 23.Murphy KM, Reiner SL. The lineage decisions of helper T cells. Nat Rev Immunol. 2002;2:933–944. doi: 10.1038/nri954. [DOI] [PubMed] [Google Scholar]
  • 24.Robinson DS, O’Garra A. Further checkpoints in Thl development. Immunity. 2002;16:755–758. doi: 10.1016/S1074-7613(02)00331-X. [DOI] [PubMed] [Google Scholar]
  • 25.Gegg ME, Harry R, Hankey D, et al. Suppression of autoimmune retinal disease by lovastatin does not require Th2 cytokine induction. J Immunol. 2005;174:2327–2335. doi: 10.4049/jimmunol.174.4.2327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Leung BP, Sattar N, Crilly A, et al. A novel anti-inflammatory role for simvastatin in inflammatory arthritis. J Immunol. 2003;170:1524–1530. doi: 10.4049/jimmunol.170.3.1524. [DOI] [PubMed] [Google Scholar]
  • 27.Cannella B, Raine CS. The adhesion molecule and cytokine profile of multiple sclerosis lesions. Ann Neurol. 1995;37:424–435. doi: 10.1002/ana.410370404. [DOI] [PubMed] [Google Scholar]
  • 28.Weitz-Schmidt G, Weizenbach K, Brinkmann V, et al. Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat Med. 2001;7:687–692. doi: 10.1038/89058. [DOI] [PubMed] [Google Scholar]
  • 29.Weber C, Erl W, Weber KS, Weber PC. 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. 1997;30:1212–1217. doi: 10.1016/S0735-1097(97)00324-0. [DOI] [PubMed] [Google Scholar]
  • 30.Chung HK, Lee IK, Kang H, et al. Statin inhibits interferon-gamma-induced expression of intercellular adhesion molecule-1 (ICAM-1) in vascular endothelial and smooth muscle cells. Exp Mol Med. 2002;34:451–461. doi: 10.1038/emm.2002.63. [DOI] [PubMed] [Google Scholar]
  • 31.Doo YC, Han SJ, Han SW, et al. Effect of preexisting statin use on expression of C-reactive protein, adhesion molecules, interleukin-6, and antioxidized low-density lipoprotein antibody in patients with unstable angina undergoing coronary stenting. Clin Cardiol. 2005;28:72–76. doi: 10.1002/clc.4960280206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Prasad R, Giri S, Nath N, Singh I, Singh AK. Inhibition of phosphoinositide 3 kinase-Akt (protein kinase B)-nuclear factor-kappa B pathway by lovastatin limits endothelial-monocyte cell interaction. J Neurochem. 2005;94:204–214. doi: 10.1111/j.1471-4159.2005.03182.x. [DOI] [PubMed] [Google Scholar]
  • 33.Greenwood J, Steinman L, Zamvil S. Statin therapy in autoimmunity: From protein prenylation to immunomodulation. Nat Rev Immunol. 2006;6:358–358. doi: 10.1038/nri1839. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Etienne S, Adamson P, Greenwood J, Strosberg AD, Cazaubon S, Couraud PO. ICAM-1 signaling pathways associated with Rho activation in microvascular brain endothelial cells. J Immunol. 1998;161:5755–5761. [PubMed] [Google Scholar]
  • 35.Adamson P, Etienne S, Couraud PO, Calder V, Greenwood J. Lymphocyte migration through brain endothelial cell monolayers involves signaling through endothelial ICAM-1 via a rho-dependent pathway. J Immunol. 1999;162:2964–2973. [PubMed] [Google Scholar]
  • 36.Etienne-Manneville S, Manneville JB, Adamson P, Wilboum B, Greenwood J, Couraud PO. ICAM-1-coupled cytoskeletal rearrangements and transendothelial lymphocyte migration involve intracellular calcium signaling in brain endothelial cell lines. J Immunol. 2000;165:3375–3383. doi: 10.4049/jimmunol.165.6.3375. [DOI] [PubMed] [Google Scholar]
  • 37.Adamson P, Wilboum B, Etienne-Manneville S, et al. Lymphocyte trafficking through the blood-brain barrier is dependent on endothelial cell heterotrimeric G-protein signaling. Faseb J. 2002;16:1185–1194. doi: 10.1096/fj.02-0035com. [DOI] [PubMed] [Google Scholar]
  • 38.Walters CE, Pryce G, Hankey DJ, et al. Inhibition of Rho GTPases with protein prenyltransferase inhibitors prevents leukocyte recruitment to the central nervous system and attenuates clinical signs of disease in an animal model of multiple sclerosis. J Immunol. 2002;168:4087–4094. doi: 10.4049/jimmunol.168.8.4087. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Yong VW, Krekoski CA, Forsyth PA, Bell R, Edwards DR. Matrix metalloproteinases and diseases of the CNS. Trends Neurosci. 1998;21:75–80. doi: 10.1016/S0166-2236(97)01169-7. [DOI] [PubMed] [Google Scholar]
  • 40.Ganne F, Vasse M, Beaudeux JL, et al. Cerivastatin, an inhibitor of HMG-CoA reductase, inhibits urokinase/urokinase-receptor expression and MMP-9 secretion by peripheral blood monocytes—a possible protective mechanism against atherothrombosis. Thromb Haemost. 2000;84:680–688. [PubMed] [Google Scholar]
  • 41.Bellosta S, Via D, Canavesi M, et al. HMG-CoA reductase inhibitors reduce MMP-9 secretion by macrophages. Arterioscler Thromb Vasc Biol. 1998;18:1671–1678. doi: 10.1161/01.atv.18.11.1671. [DOI] [PubMed] [Google Scholar]
  • 42.Wong B, Lumma WC, Smith AM, Sisko JT, Wright SD, Cai TQ. Statins suppress THP-1 cell migration and secretion of matrix metalloproteinase 9 by inhibiting geranylgeranylation. J Leukoc Biol. 2001;69:959–962. [PubMed] [Google Scholar]
  • 43.Sena A, Pedrosa R, Graca Morais M. Therapeutic potential of lovastatin in multiple sclerosis. J Neurol. 2003;250:754–755. doi: 10.1007/s00415-003-1070-8. [DOI] [PubMed] [Google Scholar]
  • 44.Vollmer T, Key L, Durkalski V, et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet. 2004;363:1607–1608. doi: 10.1016/S0140-6736(04)16205-3. [DOI] [PubMed] [Google Scholar]
  • 45.McCarey DW, McInnes IB, Madhok R, et al. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet. 2004;363:2015–2021. doi: 10.1016/S0140-6736(04)16449-0. [DOI] [PubMed] [Google Scholar]
  • 46.Neuhaus O, Farina C, Wekerle H, Hohlfeld R. Mechanisms of action of glatiramer acetate in multiple sclerosis. Neurology. 2001;56:702–708. doi: 10.1212/wnl.56.6.702. [DOI] [PubMed] [Google Scholar]
  • 47.Duda PW, Schmied MC, Cook SL, Krieger JI, Hafler DA. Glatiramer acetate (Copaxone) induces degenerate, Th2-polarized immune responses in patients with multiple sclerosis. J Clin Invest. 2000;105:967–976. doi: 10.1172/JCI8970. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Kim HJ, Ifergan I, Antel JP, et al. Type 2 monocyte and microglia differentiation mediated by glatiramer acetate therapy in patients with multiple sclerosis. J Immunol. 2004;172:7144–7153. doi: 10.4049/jimmunol.172.11.7144. [DOI] [PubMed] [Google Scholar]
  • 49.Weber MS, Starck M, Wagenpfeil S, Meinl E, Hohlfeld R, Farina C. Multiple sclerosis: glatiramer acetate inhibits monocyte reactivity in vitro and in vivo. Brain. 2004;127:1370–1378. doi: 10.1093/brain/awh163. [DOI] [PubMed] [Google Scholar]
  • 50.Paintlia AS, Paintlia MK, Singh I, Singh AK. Immunomodulatory effect of combination therapy with lovastatin and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside alleviates neurode-generation in experimental autoimmune encephalomyelitis. Am J Pathol. 2006;169:1012–1025. doi: 10.2353/ajpath.2006.051309. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Birnbaum GA. A double-blind, placebo controlled trial of atorvastatin in combination with subcutaneous interferon-beat la in persons with multiple sclerosis. Neurology. 2007;68:A206–A206. doi: 10.1212/01.wnl.0000251300.24540.c4. [DOI] [Google Scholar]
  • 52.Zacco A, Togo J, Spence K, et al. 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors protect cortical neurons from excitotoxicity. J Neurosci. 2003;23:11104–11111. doi: 10.1523/JNEUROSCI.23-35-11104.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Paintlia AS, Paintlia MK, Khan M, Vollmer T, Singh AK, Singh I. HMG-CoA reductase inhibitor augments survival and differentiation of oligodendrocyte progenitors in animal model of multiple sclerosis. Faseb J. 2005;19:1407–1421. doi: 10.1096/fj.05-3861com. [DOI] [PubMed] [Google Scholar]
  • 54.Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol. 2000;57:1439–1443. doi: 10.1001/archneur.57.10.1439. [DOI] [PubMed] [Google Scholar]
  • 55.Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA. Statins and the risk of dementia. Lancet. 2000;356:1627–1631. doi: 10.1016/S0140-6736(00)03155-X. [DOI] [PubMed] [Google Scholar]
  • 56.Sparks DL, Sabbagh MN, Connor DJ, et al. Atorvastatin for the treatment of mild to moderate Alzheimer disease: preliminary results. Arch Neural. 2005;62:753–757. doi: 10.1001/archneur.62.5.753. [DOI] [PubMed] [Google Scholar]
  • 57.Sparks DL, Scheff SW, Hunsaker JC, Liu H, Landers T, Gross DR. Induction of Alzheimer-like beta-amyloid immunoreactivity in the brains of rabbits with dietary cholesterol. Exp Neurol. 1994;126:88–94. doi: 10.1006/exnr.1994.1044. [DOI] [PubMed] [Google Scholar]
  • 58.Refolo LM, Malester B, LaFrancois J, et al. Hypercholesterolemia accelerates the Alzheimer’s amyloid pathology in a transgenic mouse model. Neurobiol Dis. 2000;7:321–331. doi: 10.1006/nbdi.2000.0304. [DOI] [PubMed] [Google Scholar]
  • 59.Akiyama H, Barger S, Barnum S, et al. Inflammation and Alzheimer’s disease. Neurobiol Aging. 2000;21:383–421. doi: 10.1016/S0197-4580(00)00124-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Crisby M, Nordin-Fredriksson G, Shah PK, Yano J, Zhu J, Nilsson J. Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization. Circulation. 2001;103:926–933. doi: 10.1161/01.cir.103.7.926. [DOI] [PubMed] [Google Scholar]
  • 61.Endres M, Laufs U, Huang Z, et al. Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci U S A. 1998;95:8880–8885. doi: 10.1073/pnas.95.15.8880. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Notarbartolo A, Davi G, Avema M, et al. Inhibition of thromboxane biosynthesis and platelet function by simvastatin in type Ha hypercholesterolemia. Arterioscler Thromb Vasc Biol. 1995;15:2–1025. doi: 10.1161/01.atv.15.2.247. [DOI] [PubMed] [Google Scholar]
  • 63.Chen J, Zhang ZG, Li Y, et al. Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke. Ann Neurol. 2003;53:743–751. doi: 10.1002/ana.10555. [DOI] [PubMed] [Google Scholar]
  • 64.Amarenco P, Tonkin AM. Statins for stroke prevention: disappointment and hope. Circulation. 2004;109(Suppl 1):III44–49. doi: 10.1161/01.CIR.0000131518.25959.8F. [DOI] [PubMed] [Google Scholar]
  • 65.Sever PS, Dahlof B, Poulter NR, et al. 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 (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361:1149–1158. doi: 10.1016/S0140-6736(03)12948-0. [DOI] [PubMed] [Google Scholar]
  • 66.Amarenco P. Effect of statins in stroke prevention. Curr Opin Lipidol. 2005;16:614–618. doi: 10.1097/01.mol.0000194127.99968.ca. [DOI] [PubMed] [Google Scholar]
  • 67.Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383–1389. [PubMed]
  • 68.Jukema JW, Bruschke AV, van Boven AJ, et al. Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderately elevated serum cholesterol levels. The Regression Growth Evaluation Statin Study (REGRESS) Circulation. 1995;91:2528–2540. doi: 10.1161/01.cir.91.10.2528. [DOI] [PubMed] [Google Scholar]
  • 69.Begolka WS, Vanderlugt CL, Rahbe SM, Miller SD. Differential expression of inflammatory cytokines parallels progression of central nervous system pathology in two clinically distinct models of multiple sclerosis. J Immunol. 1998;161:4437–4446. [PubMed] [Google Scholar]
  • 70.Graham DJ, Staffa JA, Shatin D, et al. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA. 2004;292:2585–2590. doi: 10.1001/jama.292.21.2585. [DOI] [PubMed] [Google Scholar]
  • 71.Gaist D, Jeppesen U, Andersen M, Garcia Rodriguez LA, Hallas J, Sindrup SH. Statins and risk of polyneuropathy: a case-control study. Neurology. 2002;58:1333–1337. doi: 10.1212/wnl.58.9.1333. [DOI] [PubMed] [Google Scholar]
  • 72.Gaist D, Garcia Rodriguez LA, Huerta C, Hallas J, Sindrup SH. Are users of lipid-lowering drugs at increased risk of peripheral neuropathy? Eur J Clin Pharmacol. 2001;56:931–933. doi: 10.1007/s002280000248. [DOI] [PubMed] [Google Scholar]

Articles from Neurotherapeutics are provided here courtesy of Elsevier

RESOURCES