Therapeutic effect of tPA in ischemic stroke is enhanced by its combination with normobaric oxygen and hypothermia or ethanol

• Published in: Brain research 2015-11, Vol.1627, p.31-40
• Main Authors: Ji, Zhili, Liu, Kayin, Cai, Lipeng, Peng, Changya, Xin, Ruiqiang, Gao, Zhi, Zhao, Ethan, Rastogi, Radhika, Han, Wei, Rafols, Jose A, Geng, Xiaokun, Ding, Yuchuan
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis Inducing Factor - metabolism; Autologous embolus; bcl-2-Associated X Protein - metabolism; Brain Ischemia - complications; Caspase 3 - metabolism; Cell Death - drug effects; Central Nervous System Depressants - pharmacology; Central Nervous System Depressants - therapeutic use; Combination therapy; Disease Models, Animal; DNA Fragmentation - drug effects; Ethanol - therapeutic use; Fibrinolytic Agents - pharmacology; Fibrinolytic Agents - therapeutic use; Hypothermia, Induced; Ischemia/reperfusion injury; Male; Neurology; Oxygen Inhalation Therapy; Proto-Oncogene Proteins c-bcl-2 - metabolism; Rats; Rats, Sprague-Dawley; Stroke - drug therapy; Stroke - etiology; Stroke - therapy; Time Factors; Tissue Plasminogen Activator - therapeutic use
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2015.08.019

Abstract Background and Purpose : Our lab has previously elucidated the neuroprotective effects of normobaric oxygen (NBO) and ethanol (EtOH) in ischemic stroke. The present study further evaluated the effect of EtOH or hypothermia (Hypo) in the presence of low concentration of NBO and determined whether EtOH can substitute hypothermia in a more clinically relevant autologous embolus rat stroke model in which reperfusion was established by tissue-type plasminogen activator (t-PA). Methods : At 1 h of middle cerebral artery occlusion (MCAO) by an autologous embolus, rats received t-PA. In addition, at the same time, ischemic animals were treated with either EtOH (1.0 g/kg) or hypothermia (33 °C for 3 h) in combination with NBO (60% for 3 h). Extent of neuroprotection was assessed by apoptotic cell death measured by ELISA and Western immunoblotting analysis for pro- (AIF, activated Caspase-3, Bax) and anti-apoptotic (Bcl-2) protein expression at 3 and 24 h of reperfusion induced by t-PA administration. Results : Compared to ischemic rats treated only with t-PA, animals with NBO, hypothermia or EtOH had significantly reduced apoptotic cell death by 32.5%, 43.1% and 36.0% respectively. Furthermore, combination therapy that included NBO+EtOH or NBO+Hypo with t-PA exhibited a much larger decline ( p