Sequential Therapy with Minocycline and Candesartan Improves Long-Term Recovery After Experimental Stroke
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ORIGINAL ARTICLE
Sequential Therapy with Minocycline and Candesartan Improves Long-Term Recovery After Experimental Stroke Sahar Soliman 1,2 & Tauheed Ishrat 1,2 & Abdelrahman Y. Fouda 1,2 & Ami Patel 1,2 & Bindu Pillai 1,2 & Susan C. Fagan 1,2,3
Received: 24 June 2014 / Revised: 11 May 2015 / Accepted: 12 May 2015 / Published online: 26 May 2015 # Springer Science+Business Media New York 2015
Abstract Minocycline and candesartan have both shown promise as candidate therapeutics in ischemic stroke, with multiple, and somewhat contrasting, molecular mechanisms. Minocycline is an anti-inflammatory, antioxidant, and anti-apoptotic agent and a known inhibitor of matrix metalloproteinases (MMPs). Yet, minocycline exerts antiangiogenic effects both in vivo and in vitro. Candesartan promotes angiogenesis and activates MMPs. Aligning these therapies with the dynamic processes of injury and repair after ischemia is likely to improve success of treatment. In this study, we hypothesize that opposing actions of minocycline and candesartan on angiogenesis, when administered simultaneously, will reduce the benefit of candesartan treatment. Therefore, we propose a sequential combination treatment regimen to yield a better outcome and preserve the proangiogenic potential of candesartan. In vitro angiogenesis was assessed using human brain endothelial cells. In vivo, Wistar rats subjected to 90-min middle cerebral artery occlusion (MCAO) were randomized into four groups: saline, candesartan, minocycline, and sequential combination of minocycline and candesartan. Neurobehavioral tests were performed 1, 3, 7, and 14 days after stroke. Brain tissue was collected on day 14 for assessment of infarct size and vascular density. Minocycline, when added simultaneously, decreased
* Susan C. Fagan [email protected] 1
Charlie Norwood VA Medical Center, Augusta, GA, USA
2
Program in Clinical and Experimental Therapeutics, University of Georgia, Augusta, GA 30912, USA
3
Department of Neurology, Georgia Regents University, Augusta, GA, USA
the proangiogenic effect of candesartan treatment in vitro. Sequential treatment, however, preserved the proangiogenic potential of candesartan both in vivo and in vitro, improved neurobehavioral outcome, and reduced infarct size. Sequential combination therapy with minocycline and candesartan improves long-term recovery and maintains candesartan’s proangiogenic potential. Keywords ARBs . Candesartan . Minocycline . Stroke . Recovery . Angiogenesis
Abbreviations ARBs Angiotensin II type-1 receptor blockers hCMECs Human cerebral microvascular endothelial cells MCAO Middle cerebral artery occlusion MMPs Matrix metalloproteinases VEGF Vascular endothelial growth factor
Introduction Stroke is one of the most common and undertreated conditions worldwide. Each year, more than 700,000 stroke cases occur in the USA, resulting in significant disability and mortality as well as an estimated cost of $36 billion [1]. Tissue plasminogen activator (tPA) remains the only FDA-approved pharmacologic/biologic treatment op
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