Abstract
Minocycline—a tetracycline antibiotic with anti-inflammatory and MMP inhibitory effects—has been promising in stroke preclinical as well as phase I and II clinical trials. Candesartan- angiotensin II receptor blocker- improved outcome and enhanced neovascularization post stroke. Despite its failure to provide benefit in the SCAST trial, candesartan’s long history of success in preclinical studies leads us to further investigate the combination of candesartan with other promising agents in the management of ischemic stroke. Objective: We propose the combination of candesartan and minocycline as a potential treatment for ischemic stroke and we optimize the timing of administration for maximal benefit. We hypothesize that early minocycline administration- to reduce inflammation- followed by 7-day candesartan dosing- to stimulate angiogenesis- yields a better outcome than either alone. Due to opposing actions of both agents on MMPs, sequential rather than simultaneous administration maintains candesartan neovascularization potential. Methods: Wistar rats subjected to 90-minute middle cerebral artery occlusion (MCAO) were divided into 4 groups: Saline, Candesartan, Minocycline and combination. Neurobehavioral tests were performed 1, 3, 7 and 14 days after stroke. Brains were collected on day 14 for assessment of angiogenesis and infarct size. Human brain endothelial cell proliferation and tube formation were measured in vitro by BrdU incorporation and Matrigel tube formation assays. Results: Sequential therapy improved neurobehavioral outcome and infarct volume compared to saline or either treatment alone. When added after minocycline, candesartan was effective at stimulating angiogenesis. However, simultaneous treatment decreased endothelial cell proliferation and tube formation in vitro . Conclusion: Sequential rather than simultaneous treatment with candesartan and minocycline offers more benefit than either alone.
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