title: Sex-specific effects of N-acetylcysteine in neonatal rats treated with hypothermia after severe hypoxia-ischemia.
abstract: Approximately half of moderate to severely hypoxic-ischemic (HI) newborns do not respond to hypothermia, the only proven neuroprotective treatment. N-acetylcysteine (NAC), an antioxidant and glutathione precursor, shows promise for neuroprotection in combination with hypothermia, mitigating post-HI neuroinflammation due to oxidative stress. As mechanisms of HI injury and cell death differ in males and females, sex differences must be considered in translational research of neuroprotection. We assessed the potential toxicity and efficacy of NAC in combination with hypothermia, in male and female neonatal rats after severe HI injury. NAC 50mg/kg/d administered 1h after initiation of hypothermia significantly decreased iNOS expression and caspase 3 activation in the injured hemisphere versus hypothermia alone. However, only females treated with hypothermia +NAC 50mg/kg showed improvement in short-term infarct volumes compared with saline treated animals. Hypothermia alone had no effect in this severe model. When NAC was continued for 6 weeks, significant improvement in long-term neuromotor outcomes over hypothermia treatment alone was observed, controlling for sex. Antioxidants may provide insufficient neuroprotection after HI for neonatal males in the short term, while long-term therapy may benefit both sexes.
authors: Center for Biomedical Imaging, Medical University of South Carolina, 165 Ashley Ave, Charleston, SC 29425, United States. Electronic address: niexi@musc.edu.
authors: Xingju
authors: X
authors: Nie
authors: Department of Pediatrics, Medical University of South Carolina, 165 Ashley Ave, Charleston, SC 29425, United States. Electronic address: clarkdw@musc.edu.
authors: Danielle W
authors: DW
authors: Lowe
authors: Department of Psychology, University of Massachusetts, 100 Morrissey Blvd, Boston, MA 02125, United States. Electronic address: lgrollins@gmail.com.
authors: Laura Grace
authors: LG
authors: Rollins
authors: Department of Pediatrics, Medical University of South Carolina, 165 Ashley Ave, Charleston, SC 29425, United States. Electronic address: perkel@musc.edu.
authors: Jessica
authors: J
authors: Bentzley
authors: Medical Genetics Training Program, National Human Genome Research Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892-2152, United States. Electronic address: jamie.fraser@nih.gov.
authors: Jamie L
authors: JL
authors: Fraser
authors: Department of Biostatistics and Epidemiology, Medical University of South Carolina, 165 Ashley Ave, Charleston, SC 29425, United States. Electronic address: hebertrl@musc.edu.
authors: Renee
authors: R
authors: Martin
authors: Department of Pediatrics, Medical University of South Carolina, 165 Ashley Ave, Charleston, SC 29425, United States. Electronic address: singhi@musc.edu.
authors: Inderjit
authors: I
authors: Singh
authors: Department of Pediatrics, Medical University of South Carolina, 165 Ashley Ave, Charleston, SC 29425, United States. Electronic address: jenkd@musc.edu.
authors: Dorothea
authors: D
authors: Jenkins
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000008:administration & dosage / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020520:Brain Infarction / Q000473:pathology / Q000628:therapy; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005260:Female; D007036:Hypothermia, Induced; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D009048:Motor Skills / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D013997:Time Factors
chemical_list: D000975:Antioxidants; D018836:Inflammation Mediators; D052247:Nitric Oxide Synthase Type II; D053148:Caspase 3; D000111:Acetylcysteine
keywords: N-acetylcysteine; Neonatal hypoxia ischemia; Neuroprotection; Redox regulation; Sex