Alpha 1-Antitrypsin Therapy Mitigated Ischemic Stroke Damage in Rats

• Published in: Journal of stroke and cerebrovascular diseases 2014-05, Vol.23 (5), p.e355-e363
• Main Authors: Moldthan, Huong L., PhD, Hirko, Aaron C., PhD, Thinschmidt, Jeffrey S., MSc, Grant, Maria B., MD, Li, Zhimin, PhD, Peris, Joanna, PhD, Lu, Yuanqing, MD, Elshikha, Ahmed S., MSc, King, Michael A., PhD, Hughes, Jeffrey A., PharmD, PhD, Song, Sihong, PhD
• Format: Article
• Language: English
• Subjects: alpha 1-antitrypsin; alpha 1-Antitrypsin - administration & dosage; alpha 1-Antitrypsin - pharmacology; Animals; anti-inflammation; Brain - blood supply; Brain - drug effects; Brain - pathology; Brain - physiopathology; Cardiovascular; Cytoprotection; Disease Models, Animal; Endothelin-1; endothelin-1–induced MCAO; Humans; Infarction, Middle Cerebral Artery - chemically induced; Infarction, Middle Cerebral Artery - diagnosis; Infarction, Middle Cerebral Artery - drug therapy; Infarction, Middle Cerebral Artery - physiopathology; inflammation; Injections, Intravenous; Ischemic stroke; Magnetic Resonance Imaging; Male; Microinjections; Motor Activity - drug effects; Neurology; neuroprotection; Neuroprotective Agents - administration & dosage; Neuroprotective Agents - pharmacology; Rats, Sprague-Dawley; Sensory Thresholds - drug effects; Time Factors
• ISSN: 1052-3057; 1532-8511
• DOI: 10.1016/j.jstrokecerebrovasdis.2013.12.029

Our objective is to develop a new therapy for the treatment of stroke. Currently, the only effective therapy for acute ischemic stroke is the thrombolytic agent recombinant tissue plasminogen activator. α1 -Antitrypsin (AAT), a serine proteinase inhibitor with potent anti-inflammatory, anti-apoptotic, antimicrobial, and cytoprotective activities, could be beneficial in stroke. The goal of this study is to test whether AAT can improve ischemic stroke outcome in an established rat model. Middle cerebral artery occlusion was induced in male rats via intracranial (i.c.) microinjection of endothelin-1. Five to 10 minutes after stroke induction, rats received either i.c. or intravenous delivery of human AAT. Cylinder and vibrissae tests were used to evaluate sensorimotor function before and 72 hours after middle cerebral artery occlusion. Infarct volumes were examined via either 2,3,5-triphenyltetrazolium chloride assay or magnetic resonance imaging 72 hours after middle cerebral artery occlusion. Despite equivalent initial strokes, at 72 hours, the infarct volumes of the human AAT treatment groups (local and systemic injection) were statistically significantly reduced by 83% and 63% ( P