{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T01:27:06Z","timestamp":1788398826420,"version":"build-2803163510"},"reference-count":38,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T00:00:00Z","timestamp":1639958400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Perinatal hypoxia is a major cause of infant brain damage, lifelong neurological disability, and infant mortality. N-Acetyl-Cysteine (NAC) is a powerful antioxidant that acts directly as a scavenger of free radicals. We hypothesized that maternal-antenatal and offspring-postnatal NAC can protect offspring brains from hypoxic brain damage.Sixty six newborn rats were randomized into four study groups. Group 1: Control (CON) received no hypoxic intervention. Group 2: Hypoxia (HYP)-received hypoxia protocol. Group 3: Hypoxia-NAC (HYP-NAC). received hypoxia protocol and treated with NAC following each hypoxia episode. Group 4: NAC Hypoxia (NAC-HYP) treated with NAC during pregnancy, pups subject to hypoxia protocol. Each group was evaluated for: neurological function (Righting reflex), serum proinflammatory IL-6 protein levels (ELISA), brain protein levels: NF-\u03baB p65, neuronal nitric oxide synthase (nNOS), TNF-\u03b1, and IL-6 (Western blot) and neuronal apoptosis (histology evaluation with TUNEL stain). Hypoxia significantly increased pups brain protein levels compared to controls. NAC administration to dams or offspring demonstrated lower brain NF-\u03baB p65, nNOS, TNF-\u03b1 and IL-6 protein levels compared to hypoxia alone. Hypoxia significantly increased brain apoptosis as evidenced by higher grade of brain TUNEL reaction. NAC administration to dams or offspring significantly reduce this effect. Hypoxia induced acute sensorimotor dysfunction. NAC treatment to dams significantly attenuated hypoxia-induced acute sensorimotor dysfunction. Prophylactic NAC treatment of dams during pregnancy confers long-term protection to offspring with hypoxia associated brain injury, measured by several pathways of injury and correlated markers with pathology and behavior. This implies we may consider prophylactic NAC treatment for patients at risk for hypoxia during labor.<\/jats:p>","DOI":"10.3390\/ijms222413629","type":"journal-article","created":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T08:43:32Z","timestamp":1639989812000},"page":"13629","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Maternal N-Acetyl-Cysteine Prevents Neonatal Hypoxia-Induced Brain Injury in a Rat Model"],"prefix":"10.3390","volume":"22","author":[{"given":"Ola","family":"Gutziet","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Rambam Health Care Campus, Haifa 3525433, Israel"},{"name":"Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3525408, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roee","family":"Iluz","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Rambam Health Care Campus, Haifa 3525433, Israel"},{"name":"Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3525408, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hila","family":"Ben Asher","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Rambam Health Care Campus, Haifa 3525433, Israel"},{"name":"Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3525408, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linoy","family":"Segal","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Rambam Health Care Campus, Haifa 3525433, Israel"},{"name":"Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3525408, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dikla","family":"Ben Zvi","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Rambam Health Care Campus, Haifa 3525433, Israel"},{"name":"Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3525408, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1651-7501","authenticated-orcid":false,"given":"Yuval","family":"Ginsberg","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Rambam Health Care Campus, Haifa 3525433, Israel"},{"name":"Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3525408, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nizar","family":"Khatib","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Rambam Health Care Campus, Haifa 3525433, Israel"},{"name":"Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3525408, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osnat","family":"Zmora","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Shamir Medical Center, Tzrifin 7073001, Israel"},{"name":"Sackler School of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael G.","family":"Ross","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center and The Lundquist Institute, Torrance, CA 92270, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeev","family":"Weiner","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Rambam Health Care Campus, Haifa 3525433, Israel"},{"name":"Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3525408, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ron","family":"Beloosesky","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Rambam Health Care Campus, Haifa 3525433, Israel"},{"name":"Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3525408, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/j.clp.2018.01.015","article-title":"Perinatal brain injury: Mechanisms, prevention, and outcomes","volume":"45","author":"Novak","year":"2018","journal-title":"Clin. Perinatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1097\/00005072-199806000-00002","article-title":"Sustained hypoxia-ischemia results in reactive nitrogen and oxygen species production and injury in the premature fetal rabbit brain","volume":"57","author":"Tan","year":"1998","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1002\/1098-2779(200102)7:1<56::AID-MRDD1008>3.0.CO;2-A","article-title":"Perinatal brain injury: From pathogenesis to neuroprotection","volume":"7","author":"Volpe","year":"2001","journal-title":"Ment. Retard. Dev. Disabil. Res. Rev."},{"key":"ref_4","first-page":"10","article-title":"Mechanisms of brain injury of the premature baby","volume":"79","author":"Cerisola","year":"2019","journal-title":"Medicina"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1046\/j.1471-0528.2003.00063.x","article-title":"Intrauterine infection and the development of cerebral palsy","volume":"110","author":"Yoon","year":"2003","journal-title":"BJOG Int. J. Obstet. Gynaecol."},{"key":"ref_6","first-page":"11","article-title":"A review on various uses of N-acetyl cysteine","volume":"19","author":"Mokhtari","year":"2017","journal-title":"Cell J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"13248","DOI":"10.3109\/14767058.2011.632793","article-title":"Maternal N-acetyl-cysteine (NAC) protects the rat fetal brain from inflammatory cytokine responses to lipopolysaccharide (LPS)","volume":"25","author":"Beloosesky","year":"2012","journal-title":"J. Matern. Fetal Neonatal Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"213.e1","DOI":"10.1016\/j.ajog.2013.01.023","article-title":"Prophylactic maternal N-acetylcysteine in rats prevents maternal inflammation-induced offspring cerebral injury shown on magnetic resonance imaging","volume":"208","author":"Beloosesky","year":"2013","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/s41390-020-01106-w","article-title":"Antenatal N-acetylcysteine to improve outcomes of premature infants with intra-amniotic infection and inflammation (Triple I): Randomized clinical trial","volume":"89","author":"Buhimschi","year":"2021","journal-title":"Pediatric Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1159\/000447255","article-title":"N-acetylcysteine amide exerts possible neuroprotective effects in newborn pigs after perinatal asphyxia","volume":"111","author":"Benterud","year":"2017","journal-title":"Neonatology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/0887-8994(95)00223-5","article-title":"Immunohistochemical expression of tumor necrosis factor alpha in neonatal leukomalacia","volume":"14","author":"Deguchi","year":"1996","journal-title":"Pediatric Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/s00401-002-0633-6","article-title":"Cytokine immunoreactivity in cortical and subcortical neurons in periventricular leukomalacia: Are cytokines implicated in neuronal dysfunction in cerebral palsy?","volume":"105","author":"Kadhim","year":"2003","journal-title":"Acta Neuropathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1161\/01.STR.25.7.1481","article-title":"Tumor necrosis factor-alpha expression in ischemic neurons","volume":"25","author":"Liu","year":"1994","journal-title":"Stroke"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5763743","DOI":"10.1155\/2016\/5763743","article-title":"Immediate remote ischemic postconditioning reduces brain nitrotyrosine formation in a piglet asphyxia model","volume":"2016","author":"Rudge","year":"2016","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_15","first-page":"203","article-title":"A comparison of blood and cerebrospinal fluid cytokines (IL-1\u03b2, IL-6, IL-18, TNF-\u03b1) in neonates with perinatal hypoxia","volume":"17","author":"Konjevoda","year":"2017","journal-title":"Bosn. J. Basic Med Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1111\/j.1442-200X.2010.03290.x","article-title":"New insights into the pathogenesis of perinatal hypoxic-ischemic brain injury","volume":"53","author":"Vasiljevic","year":"2011","journal-title":"Pediatrics Int."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1111\/j.1471-4159.2004.02500.x","article-title":"Nitrosylation precedes caspase-3 activation and translocation of apoptosis-inducing factor in neonatal rat cerebral hypoxia-ischaemia","volume":"90","author":"Zhu","year":"2004","journal-title":"J. Neurochem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/0378-3782(79)90022-7","article-title":"Comparative aspects of the brain growth spurt","volume":"3","author":"Dobbing","year":"1979","journal-title":"Early Hum. Dev."},{"key":"ref_19","first-page":"261","article-title":"Comparisons and considerations on the new immunological pregnancy tests","volume":"46","author":"Aimone","year":"1964","journal-title":"Riv. D Ostetricia E Ginecol. Prat."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.bbr.2015.11.025","article-title":"Lipopolysaccharide Exposure during Late Embryogenesis Results in Diminished Locomotor Activity and Amphetamine Response in Females and Spatial Cognition Impairment in Males in Adult, but not Adolescent Rat Offspring","volume":"299","year":"2016","journal-title":"Behav. Brain Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"12785","DOI":"10.1002\/jcb.28548","article-title":"In utero transplantation of neural stem cells ameliorates maternal inflammation-induced prenatal white matter injury","volume":"120","author":"Mohamadi","year":"2019","journal-title":"J. Cell. Biochem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/j.bbi.2018.01.001","article-title":"Mild prenatal hypoxia-ischemia leads to social deficits and central and peripheral inflammation in exposed offspring","volume":"69","author":"Felice","year":"2018","journal-title":"Brain Behav. Immun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1038\/s41398-018-0112-z","article-title":"Gestational cytokine concentrations and neurocognitive development at 7 years","volume":"8","author":"Ghassabian","year":"2018","journal-title":"Transl. Psychiatry"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1186\/s12974-017-0981-8","article-title":"Acute in utero exposure to lipopolysaccharide induces inflammation in the pre- and postnatal brain and alters the glial cytoarchitecture in the developing amygdala","volume":"14","author":"Pakan","year":"2017","journal-title":"J. Neuroinflammation"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1159\/000327244","article-title":"Neuronal nitric oxide synthase inhibition prevents cerebral palsy following hypoxia-ischemia in fetal rabbits: Comparison between JI-8 and 7-nitroindazole","volume":"33","author":"Yu","year":"2011","journal-title":"Dev. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1093\/eurheartj\/ehr304","article-title":"Nitric oxide synthases: Regulation and function","volume":"33","author":"Sessa","year":"2012","journal-title":"Eur. Heart J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.niox.2009.03.001","article-title":"Neuronal nitric oxide synthase: Structure, subcellular localization, regulation, and clinical implications","volume":"20","author":"Zhou","year":"2009","journal-title":"Nitric Oxide"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1126\/science.1519065","article-title":"Inhibition of long-term potentiation by NMDA-mediated nitric oxide release","volume":"257","author":"Izumi","year":"1992","journal-title":"Science"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1126\/science.1720572","article-title":"A requirement for the intercellular messenger nitric oxide in long-term potentiation","volume":"254","author":"Schuman","year":"1991","journal-title":"Science"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"11285","DOI":"10.1073\/pnas.88.24.11285","article-title":"Tests of the roles of two diffusible substances in long-term potentiation: Evidence for nitric oxide as a possible early retrograde messenger","volume":"88","author":"Hawkins","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1067\/mob.2001.115745","article-title":"The effects of intrapartum magnesium sulfate therapy on fetal serum interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha at delivery: A randomized, placebo-controlled trial","volume":"184","author":"Blackwell","year":"2001","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1093\/molehr\/7.8.787","article-title":"Nuclear factor-kappa B is essential for up-regulation of interleukin-8 expression in human amnion and cervical epithelial cells","volume":"7","author":"Elliott","year":"2001","journal-title":"Basic Sci. Reprod. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/S0166-4328(03)00146-3","article-title":"Brain injury and neurofunctional deficit in neonatal mice with hypoxic-ischemic encephalopathy","volume":"145","author":"Ten","year":"2003","journal-title":"Behav. Brain Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1002\/brb3.208","article-title":"N-acetylcysteine (NAC) in Neurological Disorders: Mechanisms of Action and Therapeutic Opportunities","volume":"4","author":"Harrigan","year":"2014","journal-title":"Brain Behav."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1111\/aogs.14054","article-title":"Maternal N-acetyl-cysteine prevents neonatal brain injury associated with necrotizing enterocolitis in a rat model","volume":"100","author":"Zmora","year":"2021","journal-title":"Acta Obstet. Gynecol. Scand."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2010","DOI":"10.1016\/j.lfs.2006.06.040","article-title":"Post-treatment with N-acetylcysteine ameliorates endotoxin shock-induced organ damage in conscious rats","volume":"79","author":"Hsu","year":"2006","journal-title":"Life Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1067\/mob.2003.112","article-title":"Protective effect of N-acetylcysteine against fetal death and preterm labor induced by maternal inflammation","volume":"188","author":"Buhimschi","year":"2003","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.ntt.2010.01.010","article-title":"Preweaning behaviors, developmental landmarks, and acrylamide and glycidamide levels after pre- and postnatal acrylamide treatment in rats","volume":"32","author":"Ferguson","year":"2010","journal-title":"Neurotoxicol. Teratol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/24\/13629\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:52:22Z","timestamp":1760169142000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/24\/13629"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,20]]},"references-count":38,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["ijms222413629"],"URL":"https:\/\/doi.org\/10.3390\/ijms222413629","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,20]]}}}