title: Alpha 1-antitrypsin therapy mitigated ischemic stroke damage in rats.
abstract: 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 < .0001 and P < .05, respectively) compared with control rats. Human AAT significantly limited sensory motor system deficits. Human AAT could be a potential novel therapeutic drug for the protection against neurodegeneration after ischemic stroke, but more studies are needed to investigate the protective mechanisms and efficacy in other animal models.
authors.affiliation: Department of Pharmaceutics, University of Florida College of Pharmacy, Gainesville, Florida.
authors.forename: Huong L
authors.initials: HL
authors.lastname: Moldthan
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, Florida.
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Hirko
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, Florida.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Thinschmidt
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, Florida.
authors.forename: Maria B
authors.initials: MB
authors.lastname: Grant
authors.affiliation: Department of Pharmacodynamics, University of Florida College of Pharmacy, Gainesville, Florida.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Pharmacodynamics, University of Florida College of Pharmacy, Gainesville, Florida.
authors.forename: Joanna
authors.initials: J
authors.lastname: Peris
authors.affiliation: Department of Pharmaceutics, University of Florida College of Pharmacy, Gainesville, Florida.
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Pharmaceutics, University of Florida College of Pharmacy, Gainesville, Florida; Department of Pharmaceutics, Faculty of Pharmacy, Zagazig University, Zagazig, Sharkia, Egypt.
authors.forename: Ahmed S
authors.initials: AS
authors.lastname: Elshikha
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, Florida; Department of Veterans Affairs Medical Center, Gainesville, Florida.
authors.forename: Michael A
authors.initials: MA
authors.lastname: King
authors.affiliation: Monsanto Co., Chemistry, St Louis, Missouri.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Hughes
authors.affiliation: Department of Pharmaceutics, University of Florida College of Pharmacy, Gainesville, Florida. Electronic address: shsong@ufl.edu.
authors.forename: Sihong
authors.initials: S
authors.lastname: Song
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D019610:Cytoprotection; D004195:Disease Models, Animal; D019332:Endothelin-1; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000139:chemically induced / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D007275:Injections, Intravenous; D008279:Magnetic Resonance Imaging; D008297:Male; D008845:Microinjections; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D012684:Sensory Thresholds / Q000187:drug effects; D013997:Time Factors; D000515:alpha 1-Antitrypsin / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D019332:Endothelin-1; D018696:Neuroprotective Agents; C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin
keywords: Ischemic stroke; alpha 1-antitrypsin; anti-inflammation; endothelin-1–induced MCAO; inflammation; neuroprotection