A Combination of Three Repurposed Drugs Administered at Reperfusion as a Promising Therapy for Postischemic Brain Injury
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ORIGINAL ARTICLE
A Combination of Three Repurposed Drugs Administered at Reperfusion as a Promising Therapy for Postischemic Brain Injury I-Chen Yu 1 & Ping-Chang Kuo 2 & Jui-Hung Yen 2 & Hallel C. Paraiso 3 & Eric T. Curfman 1 & Benecia C. Hong-Goka 1 & Robert D. Sweazey 1 & Fen-Lei Chang 4
Received: 26 September 2016 / Revised: 17 April 2017 / Accepted: 24 May 2017 # Springer Science+Business Media New York 2017
Abstract Cerebral ischemia leads to multifaceted injury to the brain. A polytherapeutic drug that can be administered immediately after reperfusion may increase protection to the brain by simultaneously targeting multiple deleterious cascades. This study evaluated efficacy of the combination of three clinically approved drugs: lamotrigine, minocycline, and lovastatin, using two mouse models: global and focal cerebral ischemia induced by transient occlusion of the common carotid arteries or the middle cerebral artery, respectively. In vitro, the combination drug, but not single drug, protected neurons against oxygen-glucose deprivation (OGD)-induced cell death. The combination drug simultaneously targeted cell apoptosis and DNA damage induced by ischemia. Besides acting on neurons, the combination drug suppressed inflammatory processes in microglia and brain endothelial cells induced by ischemia. In a transient global ischemia model, the Electronic supplementary material The online version of this article (doi:10.1007/s12975-017-0543-5) contains supplementary material, which is available to authorized users. * I-Chen Yu [email protected] * Fen-Lei Chang [email protected] 1
Department of Anatomy and Cell Biology, Indiana University School of Medicine, 2101 E. Coliseum Boulevard, Fort Wayne, IN 46805, USA
2
Department of Microbiology and Immunology, Indiana University School of Medicine, 2101 E. Coliseum Boulevard, Fort Wayne, IN 46805, USA
3
Department of Biology, Indiana University-Purdue University Fort Wayne, 2101 E. Coliseum Boulevard, Fort Wayne, IN 46805, USA
4
Department of Neurology, Indiana University School of Medicine, 2101 E. Coliseum Boulevard, Fort Wayne, IN 46805, USA
combination drug, but not single drug, suppressed microglial activation and inflammatory cytokine production, and reduced neuronal damage. In a transient focal ischemia model, the combination drug, but not single drug, attenuated brain infarction, suppressed infiltration of peripheral neutrophils, and reduced neurological deficits following ischemic stroke. In summary, the combination drug confers a broad-spectrum protection against ischemia/reperfusion (I/R) injury and could be a promising approach for early neuroprotection after out-ofhospital cardiac arrest or ischemic stroke. Keywords Cerebral ischemia . Neuroinflammation . Neuroprotection . Brain infarction
Introduction Cerebral ischemia caused by disruption of blood supply to the brain is a leading cause of disability and death worldwide. Despite advanced interventions in cardiopulmonary resuscitation, many patients who experienced sudden cardiac arrest remain unconscio
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