Skip to main content

Advertisement

SpringerLink
Log in

Statins and ischemic stroke severity: Cytoprotection

  • Published:
Current Atherosclerosis Reports Aims and scope Submit manuscript

Abstract

Cytoprotective or neuroprotective interventions would be of value if they could block the processes leading to delayed neuronal death or if they could delay the period between the onset of ischemia and irreversible necrotic injury, thereby lengthening the period for effective reperfusion therapy. Experimental studies in cell culture systems and laboratory animals show that statins have several potential cytoprotective actions, including promotion of angiogenesis, reduction of clot formation and facilitation of clot lysis, upregulation of endothelial nitric oxide synthase, downregulation of inducible nitric oxide synthase, reduction of excitotoxicity, and modulation of the inflammatory response. Clinically, statins appear to protect against vasospasm-related ischemic injury after subarachnoid hemorrhage. There have been no prospective randomized trials aimed at determining whether statins reduce acute stroke severity, and observational studies have had inconsistent results. Although a prospective, randomized trial assessing the effect of pre-or poststroke statin treatment on initial stroke severity would be the most appropriate study design to test for this type of effect, it is unlikely that such a trial will be conducted given the benefits of these drugs in reducing the risk of cardiovascular events and stroke in high-risk populations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Ginsberg MD, Belayev L, Zhao W: Recruitment of the ischemic penumbra into the necrotic core. Cerebrovasc Dis 1997, 7(Suppl 5):14–18.

    Article  Google Scholar 

  2. O’Collins VE, Macleod MR, Donnan GA, et al.: 1,026 experimental treatments in acute stroke. Ann Neurol 2006, 59:467–477.

    Article  PubMed  Google Scholar 

  3. Donnan GA: The 2007 Feinberg lecture: a new road map for neuroprotection. Stroke 2008, 39:242.

    Article  PubMed  Google Scholar 

  4. Nishimura N, Schaffer CB, Friedman B, et al.: Penetrating arterioles are a bottleneck in the perfusion of neocortex. Proc Natl Acad Sci U S A 2007, 104:365–370.

    Article  PubMed  CAS  Google Scholar 

  5. Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults: Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001, 285:2486–2497.

    Article  Google Scholar 

  6. Goldstein LB, Adams R, Alberts MJ, et al.: Primary Prevention of Ischemic Stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council. Stroke 2006, 37:1583–1633.

    PubMed  Google Scholar 

  7. Adams RJ, Albers G, Alberts MJ, et al.: Update to the AHA/ASA recommendations for the prevention of stroke in patients with stroke and transient ischemic attack. Stroke 2008, 39:1647–1652.

    Article  PubMed  Google Scholar 

  8. Henderson RD, Eliasziw M, Fox AJ, et al.: Angiographically defined collateral circulation and risk of stroke in patients with severe carotid artery stenosis. Stroke 2000, 31:128–132.

    PubMed  CAS  Google Scholar 

  9. Kureishi Y, Luo Z, Shiojima I, et al.: The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med 2000, 6:1004–1010.

    Article  PubMed  CAS  Google Scholar 

  10. Chen JL, Zhang ZG, Li Y, et al.: Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke. Ann Neurol 2003, 53:743–751.

    Article  PubMed  CAS  Google Scholar 

  11. Pourati I, Kimmelstiel C, Rand W, Karas RH: Statin use is associated with enhanced collateralization of severely diseased coronary arteries. Am Heart J 2003, 146:876–881.

    Article  PubMed  CAS  Google Scholar 

  12. Ovbiagele B, Saver JL, Starkman S, et al.: Statin enhancement of collateralization in acute stroke. Neurology 2007, 68:2129–2131.

    Article  PubMed  CAS  Google Scholar 

  13. Laufs U, Gertz K, Huang P, et al.: Atorvastatin upregulates type III nitric oxide synthase in thrombocytes, decreases platelet activation, and protects from cerebral ischemia in normocholesterolemic mice. Stroke 2000, 31:2442–2449.

    PubMed  CAS  Google Scholar 

  14. Asahi M, Huang Z, Thomas S, et al.: Protective effects of statins involving both eNOS and tPA in focal cerebral ischemia. J Cereb Blood Flow Metab 2005, 25:722–729.

    Article  PubMed  CAS  Google Scholar 

  15. Yamada M, Huang Z, Dalkara T, et al.: Endothelial nitric oxide synthase-dependent cerebral blood flow augmentation by L-arginine after chronic statin treatment. J Cereb Blood Flow Metab 2000, 20:709–717.

    Article  PubMed  CAS  Google Scholar 

  16. Laufs U, Gertz K, Dirnagl U, et al.: Rosuvastatin, a new HMG-CoA reductase inhibitor, upregulates endothelial nitric oxide synthase and protects from ischemic stroke in mice. Brain Res 2002, 942:23–30.

    Article  PubMed  CAS  Google Scholar 

  17. Gertz K, Laufs U, Lindauer U, et al.: Withdrawal of statin treatment abrogates stroke protection in mice. Stroke 2003, 34:551–557.

    Article  PubMed  CAS  Google Scholar 

  18. McGirt MJ, Lynch JR, Parra A, et al.: Simvastatin increases endothelial nitric oxide synthase and ameliorates cerebral vasospasm resulting from subarachnoid hemorrhage. Stroke 2002, 33:2950–2956.

    Article  PubMed  CAS  Google Scholar 

  19. McGirt MJ, Pradilla G, Legnani FG, et al.: Systemic administration of simvastatin after the onset of experimental subarachnoid hemorrhage attenuates cerebral vasospasm. Neurosurgery 2006, 58:945–951.

    Article  PubMed  Google Scholar 

  20. Sillberg VA, Wells GA, Perry JJ: Do statins improve outcomes and reduce the incidence of vasospasm after aneurysmal subarachnoid hemorrhage: a meta-analysis. Stroke 2008, 39:2622–2626.

    Article  PubMed  CAS  Google Scholar 

  21. 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.

    Article  PubMed  CAS  Google Scholar 

  22. Amin-Hanjani S, Stagliano NE, Yamada M, et al.: Mevastatin, an HMG-CoA reductase inhibitor, reduces stroke damage and upregulates endothelial nitric oxide synthase in mice. Stroke 2001, 32:980–986.

    PubMed  CAS  Google Scholar 

  23. Prinz V, Laufs U, Gertz K, et al.: Intravenous rosuvastatin for acute stroke treatment: an animal study. Stroke 2008, 39:433–438.

    Article  PubMed  CAS  Google Scholar 

  24. Choi DW: Calcium-mediated neurotoxicity: relationship to specific channel types and role in ischemic damage. Trend Neurosci 1988, 11:465–469.

    Article  PubMed  CAS  Google Scholar 

  25. 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.

    PubMed  CAS  Google Scholar 

  26. Bosel J, Gandor F, Harms C, et al.: Neuroprotective effects of atorvastatin against glutamate-induced excitotoxicity in primary cortical neurones. J Neurochem 2005, 92:1386–1398.

    Article  PubMed  Google Scholar 

  27. Johnson-Anuna LN, Eckert GP, Franke C, et al.: Simvastatin protects neurons from cytotoxicity by up-regulating Bcl-2 mRNA and protein. J Neurochem 2007, 101:77–86.

    Article  PubMed  CAS  Google Scholar 

  28. Ortego M, Bustos C, Hernandez-Presa MA, et al.: Atorvastatin reduces NF-kappaB activation and chemokine expression in vascular smooth muscle cells and mononuclear cells. Atherosclerosis 1999, 147:253–261.

    Article  PubMed  CAS  Google Scholar 

  29. Pahan K, Sheikh FG, Nam S, Singh I: Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat primary astrocytes, microglia, and macrophages. J Clin Invest 1997, 100:2671–2679.

    Article  PubMed  CAS  Google Scholar 

  30. Sandani AF, Dawson TM, Dawson VL: Nitric oxide synthase in models of focal ischemia. Stroke 1997, 28:1283–1288.

    Google Scholar 

  31. Kawashima S, Yamashita T, Miwa Y, et al.: HMG-CoA reductase inhibitor has protective effects against stroke events in stroke-prone spontaneously hypertensive rats. Stroke 2003, 34:157–163.

    Article  PubMed  CAS  Google Scholar 

  32. Blanco M, Nombela F, Castellanos M, et al.: Statin treatment withdrawal in ischemic stroke: a controlled randomized study. Neurology 2007, 69:904–910.

    Article  PubMed  CAS  Google Scholar 

  33. Elkind MS, Flint AC, Sciacca RR, Sacco RL: Lipid-lowering agent use at ischemic stroke onset is associated with decreased mortality. Neurology 2005, 65:253–258.

    Article  PubMed  CAS  Google Scholar 

  34. Marti-Fabregas J, Gomis M, Arboix A, et al.: Favorable outcome of ischemic stroke in patients pretreated with statins. Stroke 2004, 35:1117–1121.

    Article  PubMed  CAS  Google Scholar 

  35. Aslanyan S, Weir CJ, McInnes GT, et al.: Statin administration prior to ischaemic stroke onset and survival: exploratory evidence from matched treatment-control study. Eur J Neurol 2005, 12:493–498.

    Article  PubMed  CAS  Google Scholar 

  36. Bushnell CD, Griffin J, Newby LK, et al.: Statin use and sex-specific stroke outcomes in patients with vascular disease. Stroke 2006, 37:1427–1431.

    Article  PubMed  CAS  Google Scholar 

  37. Moonis M, Kane K, Schwiderski U, et al.: HMG-CoA reductase inhibitors improve acute ischemic stroke outcome. Stroke 2005, 36:1298–1300.

    Article  PubMed  CAS  Google Scholar 

  38. Reeves MJ, Gargano JW, Luo Z, et al.: Effect of pretreatment with statins on ischemic stroke outcomes. Stroke 2008, 39:1779–1785.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine (Neurology), Duke Stroke Center, Duke University Medical Center, Room 201A, Bryan Research Building, Durham, NC, 27710, USA

    Larry B. Goldstein

Authors
  1. Larry B. Goldstein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Larry B. Goldstein.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Goldstein, L.B. Statins and ischemic stroke severity: Cytoprotection. Curr Atheroscler Rep 11, 296–300 (2009). https://doi.org/10.1007/s11883-009-0045-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11883-009-0045-3

Keywords

Search

Navigation