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

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.

• Authors: Zhili Ji, Kayin Liu, Lipeng Cai, Changya Peng, Ruiqiang Xin, Zhi Gao, Ethan Zhao, Radhika Rastogi, Wei Han, Jose A Rafols, Xiaokun Geng, Yuchuan Ding
• Journal: Brain research (Brain Res) Vol. 1627 Pg. 31-40 (Nov 19 2015) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 26319679 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015. Published by Elsevier B.V.

Chemical References

• Apoptosis Inducing Factor
• Central Nervous System Depressants
• Fibrinolytic Agents
• Proto-Oncogene Proteins c-bcl-2
• bcl-2-Associated X Protein
• Ethanol
• Tissue Plasminogen Activator
• Caspase 3

Topics

• Animals
• Apoptosis Inducing Factor (metabolism)
• Brain Ischemia (complications)
• Caspase 3 (metabolism)
• Cell Death (drug effects)
• Central Nervous System Depressants (pharmacology, therapeutic use)
• DNA Fragmentation (drug effects)
• Disease Models, Animal
• Ethanol (therapeutic use)
• Fibrinolytic Agents (pharmacology, therapeutic use)
• Hypothermia, Induced
• Male
• Oxygen Inhalation Therapy
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Rats
• Rats, Sprague-Dawley
• Stroke (drug therapy, etiology, therapy)
• Time Factors
• Tissue Plasminogen Activator (therapeutic use)
• bcl-2-Associated X Protein (metabolism)