Abstract
The attempts to develop new treatments for acute ischemic stroke have been fraught with costly and spectacularly disappointing failures. Repurposing of safe, older drugs provides a lower risk alternative. Vascular protection is a novel strategy for improving stroke outcome. Promising targets for vascular protection after stroke have been identified, and several of these targets can be approached with “repurposed” old drugs, including statins, angiotensin receptor blockers (ARBs), and minocycline.
We tested the vascular protection (ability to reduce hemorrhagic transformation) of three marketed drugs (candesartan, minocycline, and atorvastatin) in the experimental stroke model using three different rat strains [Wistar, spontaneously hypertensive rats (SHR) and type 2 diabetic Goto-Kakizaki (GK) rats]. All agents decreased the infarct size, improved the neurological outcome and decreased bleeding. Mechanisms identified include inhibition of MMP-9, activation of Akt, and increased expression of proangiogenic growth factors. Premorbid vascular damage (presence of either diabetes or hypertension) increased the likelihood of vascular injury after ischemia and reperfusion and improved the response to vascular protection.
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References
Bisson WH, Cheltsov AV, Bruey-Sedano N, Lin B, Chen J, Goldberger N, May LT, Christopoulos A, Dalton JT, Sexton PM, Zhang XK, Abagyan R (2007) Discovery of antiandrogen activity of nonsteroidal scaffolds of marketed drugs. Proc Natl Acad Sci USA 104:11927–11932
Boguski MS, Mandl KD, Sukhatme VP (2009) Repurposing with a difference. Science 324:1394–1395
Duenas-Gonzalez A, Garcia-Lopez P, Herrera LA, Medina-Franco JL, Gonzalez-Fierro A, Candelaria M (2008) The prince and the pauper. A tale of anticancer targeted agents. Mol Cancer 7:82
Fagan SC, Hess DC, Pollock DM, Hohnadel EJ, Ergul A (2004) Targets for vascular protection after acute ischemic stroke. Stroke 35(9):2220–2225
Fagan SC, Hess DC, Machado LS, Hohnadel EJ, Pollock DM, Ergul A (2005) Tactics for vascular protection after acute ischemic stroke. Pharmacotherapy 25(3):387–395
Elewa HF, Kozak A, Johnson MH, Ergul A, Fagan SC (2007) Blood pressure lowering after experimental cerebral ischemia provides neurovascular protection. J Hypertens 25:855–859
Elewa HF, Kozak A, Frye RF, Johnson MH, Ergul A, Fagan SC (2009) Early atorvastatin reduces hemorrhage after acute cerebral ischemia in diabetic rats. J Pharmacol Exp Ther 330:532–540
Fagan SC, Kozak A, Hill WD, Pollock DM, Xu L, Johnson MH, Ergul A, Hess DC (2006) Hypertension after experimental cerebral ischemia: candesartan provides neurovascular protection. J Hypertens 24:535–539
Kozak A, El-Remessy AB, Ergul A, Machado LS, Elewa HF, Johnson MH, Abdelsaid M, Wiley DA, Fagan SC (2009) Candesartan augments ischemia-induced proangiogenic state and results in sustained functional improvement after stroke. Stroke 40:1870
Kozak W, Kozak A, Elewa HF, Johnson MH, Fagan SC (2008) Vascular protection with candesartan after experimental acute stroke in hypertensive rats: a dose-response study. J Pharmacol Exp Ther 326:773–782
Machado LS, Sazanova I, Kozak A, Wiley DC, El-Remessy AB, Ergul A, Hess DC, Fagan SC (2009) Minocycline and tissue plasminogen activator for stroke: assessment of interaction potential. Stroke 40:3028–3033
Longa EZ, Weinstein PR, Carlson S, Cummins R (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20:84–91
Hilali HM, Simpkins AN, Hill WD, Waller JL, Knight RA, Fagan SC (2004) Single slice method for quantification of hemorrhagic transformation using direct ELISA. Neurol Res 26:93–98
Conflict of interest statement
SCF is a consultant for Pfizer, Inc and Genentech, Inc. Candesartan was a gift from Astra Zeneca and tPA was a gift from Genentech, Inc.
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Guan, W., Kozak, A., Fagan, S.C. (2011). Drug Repurposing for Vascular Protection After Acute Ischemic Stroke. In: Zhang, J., Colohan, A. (eds) Intracerebral Hemorrhage Research. Acta Neurochirurgica Supplementum, vol 111. Springer, Vienna. https://doi.org/10.1007/978-3-7091-0693-8_49
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DOI: https://doi.org/10.1007/978-3-7091-0693-8_49
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