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Statin Therapy in Ischemic Stroke Models: A Meta-Analysis

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Abstract

Statins, drugs known for lipid lowering capabilities and reduction of cardiovascular disease, have demonstrated neuroprotective effects following ischemic stroke in retrospective clinical and animal studies. However, dosing (methods, time, type of statin, and quantity) varies across studies, limiting the clinical applicability of these findings. Furthermore, a comprehensive review of statins in edema and blood-brain barrier (BBB) breakdown is needed to provide insight on diverse, less explored neuroprotective effects. In the present study, we conduct a meta-analysis of publications evaluating statin administration in animal models of ischemic stroke. We review statins’ most effective dosing regimen in four outcomes—infarct, edema, BBB breakdown, and functional outcome—to characterize several parameters of benefit associated with statin administration. A search term was constructed to identify experimental murine studies exploring statin use after transient middle cerebral artery occlusion (tMCAO) in PubMed, Web of Science, and Embase. Extracted data included statin type, dose, time and method of administration, and the four predetermined outcomes (functional outcome, edema, BBB breakdown, and infarction). A meta-analysis and stratified meta-regression were conducted using the standardized mean difference (SMD) method for continuous measurements. Included publications were assessed for bias using SYRCLE’s RoB tool for animal studies. A total of 24 studies were included. Statin administration significantly reduced infarct volume (p < 0.0001), edema volume (p < 0.002), and neurological deficit (p < 0.0001). Simvastatin and pravastatin were most effective in reducing infarct volume when compared with atorvastatin (p = 0.0475, p = 0.0004) and rosuvastatin (p = 0.0036, p < 0.0001). Pravastatin outperformed all others in functional outcome. Subcutaneous (SC) injection was most effective in all outcomes. Statin therapy reduced BBB breakdown according to our systematic review. Mean study quality was 4.6/10. While statin therapy evidently improves neurological outcome following ischemic stroke, this analysis adds to our understanding of dosing and statins’ effects on edema and BBB breakdown. These findings will aid the design of future studies investigating statin use and have larger implications for the clinical care of ischemic stroke patients.

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References

  1. Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, et al. Heart Disease and Stroke Statistics-2017 Update: a report from the American Heart Association. Circulation. 2017;135(10):e146–603.

  2. Fang J-x, et al. The efficacy and safety of high-dose statins in acute phase of ischemic stroke and transient ischemic attack: a systematic review. Intern Emerg Med. 2017;12(5):679–87.

    Article  PubMed  Google Scholar 

  3. Zhao J, Zhang X, Dong L, Wen Y, Cui L. The many roles of statins in ischemic stroke. Curr Neuropharmacol. 2014;12(6):564–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hooijmans CR, et al. SYRCLE’s risk of bias tool for animal studies. BMC Med Res Methodol. 2014;14:43–3.

  5. DiMaggio C. Introduction to meta-analysis.

  6. Nagaraja TN, Knight RA, Croxen RL, Konda KP, Fenstermacher JD Acute neurovascular unit protection by simvastatin in transient cerebral ischemia. Neurological Research 2013;28(8):826–830

  7. Prinz V, Laufs U, Gertz K, Kronenberg G, Balkaya M, Leithner C, et al. Intravenous Rosuvastatin for Acute Stroke Treatment. Stroke. 2008;39(2):433–8.

    Article  CAS  PubMed  Google Scholar 

  8. Xing H, Sun S, Mei Y, Dirk H. The protective effect of rosuvastatin on ischemic brain injury and its mechanism. Journal of Huazhong University of Science and Technology. 2006;26(6):667–9.

    Article  CAS  PubMed  Google Scholar 

  9. Endres M, Laufs U, Huang Z, Nakamura T, Huang P, Moskowitz MA, et al. Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proceedings of the National Academy of Sciences. 1998;95(15):8880–5.

    Article  CAS  Google Scholar 

  10. Berger C, Xia F, Maurer MH, Schwab S. Neuroprotection by pravastatin in acute ischemic stroke in rats. Brain Research Reviews. 2008;58(1):48–56.

    Article  CAS  PubMed  Google Scholar 

  11. Zhu M-x, Lu C, Xia C-m, Qiao Z-w, Zhu D-n. Simvastatin Pretreatment Protects Cerebrum from Neuronal Injury by Decreasing the Expressions of Phosphor-CaMK II and AQP4 in Ischemic Stroke Rats. Journal of Molecular Neuroscience. 2014;54(4):591–601.

    Article  CAS  PubMed  Google Scholar 

  12. Chen J, Xu C, Zacharek A, Chopp M. Increasing Ang1/Tie2 expression by simvastatin treatment induces vascular stabilization and neuroblast migration after stroke. Journal of Cellular and Molecular Medicine. 2009;13(7):1348–57.

    Article  CAS  PubMed  Google Scholar 

  13. Sabogal AM, Arango CA, Cardona GP, Rubio AEC. La atorvastatina protege las neuronas GABAérgicas y dopaminérgicas del sistema nigroestriatal en un modelo experimental de isquemia cerebral focal transitoria en ratas. Biomédica. 2013;34 (2)

  14. Saito T, Nito C, Ueda M, Inaba T, Kamiya F, Muraga K, et al. Continuous oral administration of atorvastatin ameliorates brain damage after transient focal ischemia in rats. Life Sciences. 2014;94(2):106–14.

    Article  CAS  PubMed  Google Scholar 

  15. Ouk T, Potey C, Laprais M, Gautier S, Hanf R, Darteil R, et al. PPARα is involved in the multitargeted effects of a pretreatment with atorvastatin in experimental stroke. Fundamental & Clinical Pharmacology. 2014;28(3):294–302.

    Article  CAS  Google Scholar 

  16. Xu C, Chopp M, Zacharek A, Roberts C, Lu M, Savant-Bhonsale S, et al. Chemokine, vascular and therapeutic effects of combination Simvastatin and BMSC treatment of stroke. Neurobiology of Disease. 2009;36(1):35–41.

    Article  Google Scholar 

  17. Trinkl A, Vosko MR, Wunderlich N, Dichgans M, Hamann GF. Pravastatin reduces microvascular basal lamina damage following focal cerebral ischemia and reperfusion. European Journal of Neuroscience. 2006;24(2):520–6.

    Article  PubMed  Google Scholar 

  18. Xu C, Chopp M, Shehadah A, Zacharek A, Kuzmin-Nichols N, Sanberg CD, et al. Therapeutic Benefit of Treatment of Stroke with Simvastatin and Human Umbilical Cord Blood Cells: Neurogenesis, Synaptic Plasticity, and Axon Growth. Cell Transplantation. 2012;21(5):845–56.

    Article  Google Scholar 

  19. Laufs U, Gertz K, Huang P, Nickenig G, Böhm M, Dirnagl U, 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(10):2442–9.

    Article  CAS  PubMed  Google Scholar 

  20. Engelhorn T, Doerfler A, Heusch G, Schulz R. Reduction of cerebral infarct size by the AT1-receptor blocker candesartan, the HMGCoA reductase inhibitor rosuvastatin and their combination. Neuroscience Letters. 2006;406(1-2):92–6.

    Article  CAS  PubMed  Google Scholar 

  21. Laufs U, Endres M, Stagliano N, Amin-Hanjani S, Chui D-S, Yang S-X, et al. Neuroprotection mediated by changes in the endothelial actin cytoskeleton. Journal of Clinical Investigation. 2000;106(1):15–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kilic Ü, Bassetti CL, Kilic E, Xing H, Wang Z, Hermann DM. Post-ischemic delivery of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor rosuvastatin protects against focal cerebral ischemia in mice via inhibition of extracellular-regulated kinase-1/-2. Neuroscience. 2005;134(3):901–6.

    Article  CAS  PubMed  Google Scholar 

  23. Hayashi T, Hamakawa K, Nagotani S, Jin G, Li F, Deguchi K, et al. HMG CoA reductase inhibitors reduce ischemic brain injury of Wistar rats through decreasing oxidative stress on neurons. Brain Research. 2005;1037(1-2):52–8.

    Article  CAS  PubMed  Google Scholar 

  24. Gertz K, Laufs U, Lindauer U, Nickenig G, Böhm M, Dirnagl U, et al. Withdrawal of Statin Treatment Abrogates Stroke Protection in Mice. Stroke. 2003;34(2):551–7.

    Article  CAS  PubMed  Google Scholar 

  25. Chen J, Zhang ZG, Li Y, Wang Y, Wang L, Jiang H, et al. Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke. Annals of Neurology. 2003;53(6):743–51.

    Article  CAS  PubMed  Google Scholar 

  26. Elewa HF, Kozak A, El-Remessy AB, Frye RF, Johnson MH, Ergul A, et al. Early Atorvastatin Reduces Hemorrhage after Acute Cerebral Ischemia in Diabetic Rats. Journal of Pharmacology and Experimental Therapeutics. 2009;330(2):532–40.

    Article  CAS  PubMed  Google Scholar 

  27. Hong H, Zeng J-S, Kreulen DL, Kaufman DI, Chen AF. Atorvastatin protects against cerebral infarction via inhibition of NADPH oxidase-derived superoxide in ischemic stroke. American Journal of Physiology-Heart and Circulatory Physiology. 2006;291(5):H2210–5.

    Article  CAS  PubMed  Google Scholar 

  28. Mayanagi K, Katakam PV, Gáspár T, Domoki F, Busija DW. Acute Treatment with Rosuvastatin Protects Insulin Resistant (C57BL/6J ob/ob) Mice against Transient Cerebral Ischemia. Journal of Cerebral Blood Flow & Metabolism. 2008;28(12):1927–35.

    Article  CAS  Google Scholar 

  29. Laufs U, Gertz K, Dirnagl U, Böhm M, Nickenig G, Endres M. Rosuvastatin, a new HMG-CoA reductase inhibitor, upregulates endothelial nitric oxide synthase and protects from ischemic stroke in mice. Brain Research. 2002;942(1-2):23–30.

    Article  CAS  PubMed  Google Scholar 

  30. Eliot L, Richardson SS. Sex in Context: Limitations of Animal Studies for Addressing Human Sex/Gender Neurobehavioral Health Disparities. The Journal of Neuroscience. 2016;36(47):11823–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wang RY, Wang PSG, Yang YR. Effect of Age in Rats following Middle Cerebral Artery Occlusion. Gerontology. 2003;49(1):27–32.

    Article  PubMed  Google Scholar 

  32. Macrae IM. Preclinical stroke research - advantages and disadvantages of the most common rodent models of focal ischaemia. British Journal of Pharmacology. 2011;164(4):1062–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. García-Bonilla L, Campos M, Giralt D, Salat D, Chacón P, Hernández-Guillamon M, et al. Evidence for the efficacy of statins in animal stroke models: a meta-analysis. Journal of Neurochemistry. 2012;122(2):233–43.

    Article  PubMed  Google Scholar 

  34. Danielle Ní Chróinín et al. Statin Therapy and Outcome After Ischemic Stroke

  35. Statin Treatment and Stroke Outcome in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Trial

  36. The THRombolysis and STatins (THRaST) study

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Authors and Affiliations

  1. Department of Neurological Surgery, Columbia University Medical Center, 630 West 168th Street, Physicians and Surgeons 5-454, New York, NY, 10032, USA

    Brandon Christophe, Maham Karatela, Joanly Sanchez, Josephine Pucci & E. Sander Connolly

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  1. Brandon Christophe
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  2. Maham Karatela
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  3. Joanly Sanchez
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Correspondence to Maham Karatela.

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Christophe, B., Karatela, M., Sanchez, J. et al. Statin Therapy in Ischemic Stroke Models: A Meta-Analysis. Transl. Stroke Res. 11, 590–600 (2020). https://doi.org/10.1007/s12975-019-00750-7

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