Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Drug Insight: using statins to treat neuroinflammatory disease

Abstract

Statins, a family of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are used primarily to reduce atherogenesis and cardiovascular morbidity. Surprisingly, they have also been shown to have immunomodulatory properties that might be of benefit for the treatment of autoimmune disorders. Statins can prevent and even reverse ongoing paralysis in experimental autoimmune encephalomyelitis—the mouse model for multiple sclerosis—and on the basis of these findings, statins are now being tested in patients with multiple sclerosis in clinical trials.

Key Points

  • Statins are cholesterol-lowering drugs with immunomodulatory properties that might be of benefit in the treatment of neuroinflammatory disorders such as multiple sclerosis (MS)

  • Most of the currently known statin-mediated immunomodulatory effects seem to be related to the inhibition of HMG-CoA reductase, a key enzyme in the cholesterol biosynthetic pathway

  • Studies in mice with experimental autoimmune encephalomyelitis have shown that statins interfere with multiple aspects of immune cell function

  • At present, there is insufficient epidemiological evidence to support the use of statins to treat MS in humans, but the initial results of clinical trials have been encouraging

  • Statins are also being tested in other inflammatory conditions, including rheumatoid arthritis and Alzheimer's disease

  • Although statins are perceived as safe and well-tolerated drugs, they have side effects that should be considered, particularly when they are administered in combination with other agents

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Cholesterol biosynthesis and isoprenylation of Ras and Rho.

References

  1. 1

    Ginsberg HN (1998) Effects of statins on triglyceride metabolism. Am J Cardiol 81: 32B–35B

  2. 2

    Kobashigawa JA et al. (1995) Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med 333: 621–627

    CAS  Article  Google Scholar 

  3. 3

    Steinman L (2004) Immune therapy for autoimmune diseases. Science 305: 212–216

    CAS  Article  Google Scholar 

  4. 4

    Weitz-Schmidt G et al. (2001) Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat Med 7: 687–692

    CAS  Article  Google Scholar 

  5. 5

    Youssef S et al. (2002) The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 420: 78–84

    CAS  Article  Google Scholar 

  6. 6

    Aktas O et al. (2003) Treatment of relapsing paralysis in experimental encephalomyelitis by targeting Th1 cells through atorvastatin. J Exp Med 197: 725–733

    CAS  Article  Google Scholar 

  7. 7

    Stanislaus R et al. (2002) Immunomodulation of experimental autoimmune encephalomyelitis in the Lewis rats by lovastatin. Neurosci Lett 333: 167–170

    CAS  Article  Google Scholar 

  8. 8

    Chang CH and Flavell RA (1995) Class II transactivator regulates the expression of multiple genes involved in antigen presentation. J Exp Med 181: 765–767

    CAS  Article  Google Scholar 

  9. 9

    Kwak B et al. (2000) Statins as a newly recognized type of immunomodulator. Nat Med 6: 1399–1402

    CAS  Article  Google Scholar 

  10. 10

    Dustin ML and Shaw AS (1999) Costimulation: building an immunological synapse. Science 283: 649–650

    CAS  Article  Google Scholar 

  11. 11

    Stüve O et al. (2004) Atorvastatin enhances the clinically beneficial effect of Glatiramer Acetate in Experimental Autoimmune Encephalomyelitis through Induction of a Th2 Phenotype [abstract #S50.003]. In Proceedings of the 56th Meeting of the American Academy of Neurology: 2004 April 24–May 1; San Francisco. St Paul: American Academy of Neurology Press

    Google Scholar 

  12. 12

    Abbas AK et al. (1996) Functional diversity of helper T lymphocytes. Nature 383: 787–793

    CAS  Article  Google Scholar 

  13. 13

    Panitch HS et al. (1987) Exacerbations of multiple sclerosis in patients treated with gamma interferon. Lancet 1: 893–895

    CAS  Article  Google Scholar 

  14. 14

    Khoury SJ et al. (1992) Oral tolerance to myelin basic protein and natural recovery from experimental autoimmune encephalomyelitis are associated with downregulation of inflammatory cytokines and differential upregulation of transforming growth factor beta, interleukin 4, and prostaglandin E expression in the brain. J Exp Med 176: 1355–1364

    CAS  Article  Google Scholar 

  15. 15

    Begolka WS et al. (1998) Differential expression of inflammatory cytokines parallels progression of central nervous system pathology in two clinically distinct models of multiple sclerosis. J Immunol 161: 4437–4446

    CAS  PubMed  Google Scholar 

  16. 16

    Neuhaus O et al. (2002) Statins as immunomodulators: comparison with interferon-beta 1b in MS. Neurology 59: 990–997

    CAS  Article  Google Scholar 

  17. 17

    Nath N et al. (2004) Potential targets of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor for multiple sclerosis therapy. J Immunol 172: 1273–1286

    CAS  Article  Google Scholar 

  18. 18

    Hakamada-Taguchi R et al. (2003) Inhibition of hydroxymethylglutaryl-coenzyme A reductase reduces Th1 development and promotes Th2 development. Circ Res 93: 948–956

    CAS  Article  Google Scholar 

  19. 19

    Waiczies S et al. (2005) Atorvastatin induces T cell anergy via phosphorylation of ERK1. J Immunol 174: 5630–5635

    CAS  Article  Google Scholar 

  20. 20

    Dunn SE et al. (2005) Atorvastatin prevents the Th1 differentiation of myelin-reactive T cells during CNS autoimmune disease by interfering with the prenylation of Ras and activation of ERK pathway [abstract #S64.001]. In Proceedings of the 57th Meeting of the American Academy of Neurology: 2005 April 9–16; Miami Beach. St Paul: American Academy of Neurology Press

    Google Scholar 

  21. 21

    Jorritsma et al. (2003) Role of TCR-induced extracellular signal-regulated kinase activation in the regulation of early IL-4 expression in naive CD4+ T cells. J Immunol 170: 2427–2434

    CAS  Article  Google Scholar 

  22. 22

    Cannella B and Raine CS (1995) The adhesion molecule and cytokine profile of multiple sclerosis lesions. Ann Neurol 37: 424–435

    CAS  Article  Google Scholar 

  23. 23

    Etienne S et al. (1998) ICAM-1 signaling pathways associated with Rho activation in microvascular brain endothelial cells. J Immunol 161: 5755–5761

    CAS  PubMed  Google Scholar 

  24. 24

    Adamson P et al. (1999) Lymphocyte migration through brain endothelial cell monolayers involves signaling through endothelial ICAM-1 via a rho-dependent pathway. J Immunol 162: 2964–2973

    CAS  PubMed  Google Scholar 

  25. 25

    Etienne-Manneville S et al. (2000) ICAM-1-coupled cytoskeletal rearrangements and transendothelial lymphocyte migration involve intracellular calcium signaling in brain endothelial cell lines. J Immunol 165: 3375–3383

    CAS  Article  Google Scholar 

  26. 26

    Adamson P et al. (2002) Lymphocyte trafficking through the blood–brain barrier is dependent on endothelial cell heterotrimeric G-protein signaling. Faseb J 16: 1185–1194

    CAS  Article  Google Scholar 

  27. 27

    Walters CE et al. (2002) 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 168: 4087–4094

    CAS  Article  Google Scholar 

  28. 28

    Greenwood J et al. (2003) Lovastatin inhibits brain endothelial cell Rho-mediated lymphocyte migration and attenuates experimental autoimmune encephalomyelitis. Faseb J 17: 905–907

    CAS  Article  Google Scholar 

  29. 29

    Yong VW et al. (1998) Matrix metalloproteinases and diseases of the CNS. Trends Neurosci 21: 75–80

    CAS  Article  Google Scholar 

  30. 30

    Ganne F et al. (2000) 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 84: 680–688

    CAS  Article  Google Scholar 

  31. 31

    Bellosta S et al. (1998) HMG-CoA reductase inhibitors reduce MMP-9 secretion by macrophages. Arterioscler Thromb Vasc Biol 18: 1671–1678

    CAS  Article  Google Scholar 

  32. 32

    Bonet S et al. (1999) When and how do we treat our hypercholesterolemic patients? Aten Primaria 24: 397–403

    CAS  PubMed  Google Scholar 

  33. 33

    Sena A et al. (2003) Therapeutic potential of lovastatin in multiple sclerosis. J Neurol 250: 754–755

    CAS  Article  Google Scholar 

  34. 34

    Vollmer T et al. (2004) Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet 363: 1607–1608

    CAS  Article  Google Scholar 

  35. 35

    Birnbaum G and Altafullah I (2005) A double blind, placebo controlled combination trial of interferon beta 1a (Rebif) and atorvastatin (Lipitor) in patients with relapsing remitting multiple sclerosis [abstract #P06.158]. In Proceedings of the 57th Meeting of the American Academy of Neurology: 2005 April 9–16; Miami Beach. St Paul: American Academy of Neurology Press

    Google Scholar 

  36. 36

    Neuhaus O et al. (2001) Mechanisms of action of glatiramer acetate in multiple sclerosis. Neurology 56: 702–708

    CAS  Article  Google Scholar 

  37. 37

    Duda PW et al. (2000) Glatiramer acetate (Copaxone) induces degenerate, Th2-polarized immune responses in patients with multiple sclerosis. J Clin Invest 105: 967–976

    CAS  Article  Google Scholar 

  38. 38

    Kim HJ et al. (2004) Type 2 monocyte and microglia differentiation mediated by glatiramer acetate therapy in patients with multiple sclerosis. J Immunol 172: 7144–7153

    CAS  Article  Google Scholar 

  39. 39

    Weber MS et al. (2004) Multiple sclerosis: glatiramer acetate inhibits monocyte reactivity in vitro and in vivo. Brain 127: 1370–1378

    Article  Google Scholar 

  40. 40

    McCarey DW et al. (2004) Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet 363: 2015–2021

    CAS  Article  Google Scholar 

  41. 41

    Wolozin B et al. (2000) Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol 57: 1439–1443

    CAS  Article  Google Scholar 

  42. 42

    Jick H et al. (2000) Statins and the risk of dementia. Lancet 356: 1627–1631

    CAS  Article  Google Scholar 

  43. 43

    Sparks DL et al. (2005) Atorvastatin for the treatment of mild to moderate Alzheimer disease: preliminary results. Arch Neurol 62: 753–757

    Article  Google Scholar 

  44. 44

    Sparks DL et al. (1994) Induction of Alzheimer-like beta-amyloid immunoreactivity in the brains of rabbits with dietary cholesterol. Exp Neurol 126: 88–94

    CAS  Article  Google Scholar 

  45. 45

    Refolo LM et al. (2000) Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model. Neurobiol Dis 7: 321–331

    CAS  Article  Google Scholar 

  46. 46

    Fassbender K et al. (2001) Simvastatin strongly reduces levels of Alzheimer's disease beta-amyloid peptides Aβ42 and Aβ40 in vitro and in vivo. Proc Natl Acad Sci USA 98: 5856–5861

    CAS  Article  Google Scholar 

  47. 47

    Akiyama H et al. (2000) Inflammation and Alzheimer's disease. Neurobiol Aging 21: 383–421

    CAS  Article  Google Scholar 

  48. 48

    [No authors listed] (1994) Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344: 1383–1389

  49. 49

    Jukema JW et al. (1995) 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 91: 2528–2540

    CAS  Article  Google Scholar 

  50. 50

    Graham DJ et al. (2004) Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 292: 2585–2590

    CAS  Article  Google Scholar 

  51. 51

    Staffa JA et al. (2002) Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med 346: 539–540

    Article  Google Scholar 

  52. 52

    Gaist D et al. (2002) Statins and risk of polyneuropathy: a case-control study. Neurology 58: 1333–1337

    CAS  Article  Google Scholar 

  53. 53

    Gaist D et al. (2001) Are users of lipid-lowering drugs at increased risk of peripheral neuropathy? Eur J Clin Pharmacol 56: 931–933.

    CAS  Article  Google Scholar 

  54. 54

    Pahan K et al. (1997) Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat primary astrocytes, microglia, and macrophages. J Clin Invest 100: 2671–2679

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Scott S Zamvil.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Weber, M., Prod'homme, T., Steinman, L. et al. Drug Insight: using statins to treat neuroinflammatory disease. Nat Rev Neurol 1, 106–112 (2005). https://doi.org/10.1038/ncpneuro0047

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing