Zhili Ji1, Kayin Liu2, Lipeng Cai3, Changya Peng2, Ruiqiang Xin4, Zhi Gao5, Ethan Zhao2, Radhika Rastogi2, Wei Han6, Jose A Rafols7, Xiaokun Geng3, Yuchuan Ding8. 1. Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China. 2. Department of Neurological Surgery, Wayne State University School of Medicine, Detroit, MI, USA. 3. Department of Neurological Surgery, Wayne State University School of Medicine, Detroit, MI, USA; China-America Institute of Neuroscience, Department of Neurology, Luhe Hospital, Capital Medical University, Beijing, China. 4. Department of Neurological Surgery, Wayne State University School of Medicine, Detroit, MI, USA; China-America Institute of Neuroscience, Department of Neurology, Luhe Hospital, Capital Medical University, Beijing, China; Department of Radiology, Luhe Hospital, Capital Medical University, Beijing, China. 5. Cerebral Vascular Diseases Research Institute, Capital Medical University, Beijing, China. 6. Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China. Electronic address: dr-han@vip.sina.com. 7. Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI USA. 8. Department of Neurological Surgery, Wayne State University School of Medicine, Detroit, MI, USA; China-America Institute of Neuroscience, Department of Neurology, Luhe Hospital, Capital Medical University, Beijing, China. Electronic address: yding@med.wayne.edu.
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 1h 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 3h) in combination with NBO (60% for 3h). 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 24h 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<0.01) in the cell death by 71.1% and 73.6%, respectively. Similarly, NBO+EtOH or NBO+Hypo treatment in addition to t-PA enhanced beneficial effects on both pro- and anti-apoptotic protein expressions as compared to other options. CONCLUSIONS: Neuroprotection after stroke can be enhanced by combination treatment with either EtOH or hypothermia in the presence of t-PA and 60% NBO. Because the effects produced by EtOH and hypothermia are comparable, their mechanism of action may be not only similar but also could be interchangeable in future clinical trials.
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 ratstroke model in which reperfusion was established by tissue-type plasminogen activator (t-PA). METHODS: At 1h 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 3h) in combination with NBO (60% for 3h). 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 24h of reperfusion induced by t-PA administration. RESULTS: Compared to ischemicrats 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<0.01) in the cell death by 71.1% and 73.6%, respectively. Similarly, NBO+EtOH or NBO+Hypo treatment in addition to t-PA enhanced beneficial effects on both pro- and anti-apoptotic protein expressions as compared to other options. CONCLUSIONS: Neuroprotection after stroke can be enhanced by combination treatment with either EtOH or hypothermia in the presence of t-PA and 60% NBO. Because the effects produced by EtOH and hypothermia are comparable, their mechanism of action may be not only similar but also could be interchangeable in future clinical trials.
Authors: Anthony E Kline; Jacob B Leary; Hannah L Radabaugh; Jeffrey P Cheng; Corina O Bondi Journal: Prog Neurobiol Date: 2016-05-07 Impact factor: 11.685