Drug Repurposing for Vascular Protection After Acute Ischemic Stroke
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 improv
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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. Keywords Stroke · Drug repurposing · Hemorrhagic transformation
Introduction Drug repurposing has emerged as an antidote to the sluggish drug development pipeline [1–3], where marketed drugs are exploited for their secondary activity. This strategy is particularly well-suited to the public sector, where off-patent agents can undergo high throughput screening for their ability to interact with identified molecular targets both in vitro and in vivo [1]. Since neuroprotection has failed for stroke therapy, we have focused on vascular protection with an eye toward better success. Promising targets for vascular protection after stroke have been identified and include the inhibition of endogenous mediators of vascular damage (superoxide, endothelin, matrix metalloproteases, cytokines and caspases) and the stimulation of endogenous protectors (nitric oxide, angiopoietin 1, vascular endothelial growth factor-VEGF and superoxide dismutases) [4]. Several of these targets can be approached with “repurposed” old drugs, including statins, angiotensin receptor blockers (ARBs) and minocycline [5]. The purpose of this investigation was to compare the vascular protective properties of these agents in experimental stroke both with and without premorbid vascular disease.
Methods W. Guan and A. Kozak Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Charlie Norwood VA Medical Center, Augusta, GA, USA S.C. Fagan (*) Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Charlie Norwood VA Medical Center, Augusta, GA, USA and University of Georgia College of Pharmacy, Charlie Norwood VA Medical Center, HM-1220 Medical College of Georgia, 1120 15th St., Augusta, GA, USA e-mail: [email protected]
The Institutional Animal Care
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