title: Normobaric Hyperoxia Extends Neuro- and Vaso-Protection of N-Acetylcysteine in Transient Focal Ischemia.
abstract: N-acetylcysteine (NAC), a precursor of glutathione that reduces reperfusion-induced injury, has been shown protection when it was administered pre-ischemia. However, less is known about the effect when it was given post-ischemia and there is no positive result associated with anti-oxidant in clinical trials. This study investigated the neuro- and vaso-protection of post-ischemia NAC administration as well as combining NAC with normobaric hyperoxia (NBO). Male Sprague-Dawley rats were exposed to NBO or normoxia during 2-h occlusion of the middle cerebral artery, followed by 48-h reperfusion. NAC or vehicle was intraperitoneally administered to rats immediately before reperfusion onset. NAC and NBO treatments produced 1.2 and 30 % reduction of infarction volume, respectively, and combination treatment showed greater reduction (59.8 %) as well as more decrease of hemispheric swelling volume. Of note, combination therapy showed improved neurological assessment and motor function which were sustained for 7 days after reperfusion. We also determined that the combination therapy showed greater inhibitory effects on tight junction protein degradation accompanied by Evan's blue extravasation, hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) induction, and poly ADP-ribose polymerase (PARP)-1 activation in ischemic brain tissue. Our results showed that although post-ischemia NAC administration had limited protection, combination treatment of NAC plus NBO effectively prevented blood-brain barrier (BBB) damage and significantly improved the outcome of brain injury, providing new evidence to support the concept that "cocktail" treatment targeting different stages provides better neuro- and vaso-protection than current individual treatment that has all failed in their clinical trials.
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215004, China.
authors.forename: Yushan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Emergency, Shanxi Provincial People's Hospital, Taiyuan, 030001, China.
authors.forename: Wen-Cao
authors.initials: WC
authors.lastname: Liu
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215004, China.
authors.forename: Yanyun
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215004, China.
authors.forename: Xianzhi
authors.initials: X
authors.lastname: Shen
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215004, China.
authors.forename: Xiaona
authors.initials: X
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215004, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Shu
authors.affiliation: Department of Pharmaceutical Sciences, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Pan
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215004, China.|Department of Neurology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215004, China.
authors.forename: Chun-Feng
authors.initials: CF
authors.lastname: Liu
authors.affiliation: The Central Laboratory, Shenzhen Second People's Hospital, Shenzhen University 1st Affiliated Hospital, Shenzhen, 518035, China.
authors.forename: Wenlan
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutical Sciences, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131, USA.
authors.forename: Ke Jian
authors.initials: KJ
authors.lastname: Liu
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215004, China. xinchunjin@gmail.com.
authors.forename: Xinchun
authors.initials: X
authors.lastname: Jin
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D018496:Hyperoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D000066829:Neuroprotection / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D013481:Superoxides / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D013481:Superoxides; D011065:Poly(ADP-ribose) Polymerases; D000111:Acetylcysteine
keywords: Hemispheric swelling; Infarction; Ischemic stroke; N-acetylcysteine; Oxygen; Rat