{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T05:38:28Z","timestamp":1769837908225,"version":"3.49.0"},"reference-count":103,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2013,7,31]],"date-time":"2013-07-31T00:00:00Z","timestamp":1375228800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Maternal ingestion of alcohol during pregnancy can cause a disability syndrome termed Fetal Alcohol Spectrum Disorder (FASD), which may include craniofacial malformations, structural pathology in the brain, and a variety of long-term neuropsychiatric disturbances. There is compelling evidence that exposure to alcohol during early embryogenesis (4th week of gestation) can cause excessive death of cell populations that are essential for normal development of the face and brain. While this can explain craniofacial malformations and certain structural brain anomalies that sometimes accompany FASD, in many cases these features are absent, and the FASD syndrome manifests primarily as neurobehavioral disorders. It is not clear from the literature how alcohol causes these latter manifestations. In this review we will describe a growing body of evidence documenting that alcohol triggers widespread apoptotic death of neurons and oligodendroglia (OLs) in the developing brain when administered to animals, including non-human primates, during a period equivalent to the human third trimester of gestation. This cell death reaction is associated with brain changes, including overall or regional reductions in brain mass, and long-term neurobehavioral disturbances. We will also review evidence that many drugs used in pediatric and obstetric medicine, including general anesthetics (GAs) and anti-epileptics (AEDs), mimic alcohol in triggering widespread apoptotic death of neurons and OLs in the third trimester-equivalent animal brain, and that human children exposed to GAs during early infancy, or to AEDs during the third trimester of gestation, have a significantly increased incidence of FASD-like neurobehavioral disturbances. These findings provide evidence that exposure of the developing human brain to GAs in early infancy, or to alcohol or AEDs in late gestation, can cause FASD-like neurodevelopmental disability syndromes. We propose that the mechanism by which alcohol, GAs and AEDs produce neurobehavioral deficit syndromes is by triggering apoptotic death and deletion of neurons and OLs (or their precursors) from the developing brain. Therefore, there is a need for research aimed at deciphering mechanisms by which these agents trip the apoptosis trigger, the ultimate goal being to learn how to prevent these agents from causing neurodevelopmental disabilities.<\/jats:p>","DOI":"10.3390\/brainsci3031153","type":"journal-article","created":{"date-parts":[[2013,7,31]],"date-time":"2013-07-31T12:11:46Z","timestamp":1375272706000},"page":"1153-1181","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Drug-Induced Apoptosis: Mechanism by which Alcohol and Many Other Drugs Can Disrupt Brain Development"],"prefix":"10.3390","volume":"3","author":[{"given":"Catherine","family":"Creeley","sequence":"first","affiliation":[{"name":"Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Olney","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2013,7,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1126\/science.283.5398.70","article-title":"Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain","volume":"283","author":"Ikonomidou","year":"1999","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1126\/science.287.5455.1056","article-title":"Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome","volume":"287","author":"Ikonomidou","year":"2000","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"15089","DOI":"10.1073\/pnas.222550499","article-title":"Antiepileptic drugs and apoptotic neurodegeneration in the developing brain","volume":"99","author":"Bittigau","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.devbrainres.2004.11.005","article-title":"Ethanol-induced neuroapoptosis in the developing rodent cerebellum and related brain stem structures","volume":"155","author":"Dikranian","year":"2005","journal-title":"Dev. Brain Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1097\/ALN.0b013e3182084a70","article-title":"Comparison of the neuroapoptotic properties of equipotent anesthetic concentrations of desflurane, isoflurane, or sevoflurane in neonatal mice","volume":"114","author":"Istaphanous","year":"2011","journal-title":"Anesthesiology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1523\/JNEUROSCI.23-03-00876.2003","article-title":"Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits","volume":"23","author":"Hartman","year":"2003","journal-title":"J. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/S0165-3806(02)00279-1","article-title":"Ethanol-induced apoptotic neurodegeneration in the developing C57BL\/6 mouse brain","volume":"133","author":"Olney","year":"2002","journal-title":"Dev. Brain Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1111\/j.1750-3639.2007.00116.x","article-title":"Clinical anesthesia causes permanent damage to the fetal guinea pig brain","volume":"18","author":"Rizzi","year":"2008","journal-title":"Brain Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1111\/j.1749-6632.2009.05173.x","article-title":"Timing versus duration: determinants of anesthesia-induceddevelopmental apoptosis in the young mammalian brain","volume":"1199","author":"Rizzi","year":"2010","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2809","DOI":"10.1167\/iovs.02-0982","article-title":"Ethanol-induced apoptosis in the visual system during synaptogenesis","volume":"44","author":"Tenkova","year":"2003","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1038\/sj.bjp.0706301","article-title":"Potential of ketamine and midazolam, individually or in combination, to induce apoptotic neurodegeneration in the infant mouse brain","volume":"146","author":"Young","year":"2005","journal-title":"Br. J. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1097\/ALN.0b013e3181d049cd","article-title":"Isoflurane-induced neuroapoptosis in the neonatal rhesus macaque brain","volume":"112","author":"Brambrink","year":"2010","journal-title":"Anesthesiology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1097\/ALN.0b013e318242b2cd","article-title":"Ketamine-induced neuroapoptosis in the fetal and neonatal rhesus macaque brain","volume":"116","author":"Brambrink","year":"2012","journal-title":"Anesthesiology"},{"key":"ref_14","unstructured":"Brambrink, A.M., Dissen, G.A., Martin, L.D., Creeley, C.E., and Olney, J.W. (2012, January 13\u201317). Propofol-Induced Apoptosis of Neurons and Oligodendrocytes in Neonatal Macaque Brain. Proceedings of the American Society of Anesthesiologists, Washington, DC, USA. Abstract Number A103."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.nbd.2010.05.025","article-title":"Alcohol-induced neuroapoptosis in the fetal macaque brain","volume":"40","author":"Farber","year":"2010","journal-title":"Neurobiol. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.ntt.2011.01.001","article-title":"Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys","volume":"33","author":"Paule","year":"2011","journal-title":"Neurotoxicol. Teratol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1093\/toxsci\/kfm084","article-title":"Ketamine-induced neuronal cell death in the perinatal rhesus monkey","volume":"98","author":"Slikker","year":"2007","journal-title":"Toxicol. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1016\/j.ntt.2011.06.003","article-title":"Inhalation anesthetic-induced neuronal damage in the developing rhesus monkey","volume":"33","author":"Zou","year":"2011","journal-title":"Neurotoxicol. Teratol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1016\/j.ijdevneu.2009.06.010","article-title":"Prolonged exposure to ketamine increases neurodegeneration in the developing monkey brain","volume":"27","author":"Zou","year":"2009","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1002\/ana.23652","article-title":"Isoflurane-induced apoptosis of oligodendrocytes in the neonatal primate brain","volume":"72","author":"Brambrink","year":"2012","journal-title":"Ann. Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/2051-5960-1-23","article-title":"Alcohol-induced apoptosis of oligodendrocytes in the fetal macaque brain","volume":"1","author":"Creeley","year":"2013","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1007\/BF03033280","article-title":"Neurobehavioural deficits associated with apoptotic neurodegeneration and vulnerability for ADHD","volume":"6","author":"Fredriksson","year":"2004","journal-title":"Neurotox. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1097\/01.anes.0000278892.62305.9c","article-title":"Neonatal exposure to a combination of N-methyl-d-aspartate and \u03b3-aminobutyric acid type A receptor anesthetic agents potentiates apoptotic neurodegeneration and persistent behavioral deficits","volume":"107","author":"Fredriksson","year":"2007","journal-title":"Anesthesiology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1097\/ALN.0b013e3181974fa2","article-title":"Neonatal exposure to sevoflurane induces abnormal social behaviors and deficits in fear conditioning in mice","volume":"110","author":"Satomoto","year":"2009","journal-title":"Anesthesiology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1038\/jcbfm.2009.274","article-title":"Isoflurane anesthesia induced persistent, progressive memory impairment, caused a loss of neural stem cells, and reduced neurogenesis in young, but not adult, rodents","volume":"30","author":"Zhu","year":"2010","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.nbd.2004.08.006","article-title":"Apoptotic neurodegeneration induced by ethanol in neonatal mice is associated with profound learning\/memory deficits in juveniles followed by progressive functional recovery in adults","volume":"17","author":"Wozniak","year":"2004","journal-title":"Neurobiol. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1006\/nbdi.2001.0411","article-title":"Apoptosis in the in vivo mammalian forebrain","volume":"8","author":"Dikranian","year":"2001","journal-title":"Neurobiol. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1196\/annals.1403.005","article-title":"Early exposure to general anesthesia causes significant neuronal deletion in the developing rat brain","volume":"1122","author":"Nikizad","year":"2007","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1007\/s12640-009-9088-z","article-title":"General anesthesia causes long-lasting disturbances in the ultrastructural properties of developing synapses in young rats","volume":"17","author":"Lunardi","year":"2010","journal-title":"Neurotox. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1708","DOI":"10.1213\/ane.0b013e3181733fdb","article-title":"General anesthetics induce apoptotic neurodegeneration in the neonatal rat spinal cord","volume":"106","author":"Sanders","year":"2008","journal-title":"Anesth. Analg."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1038\/sj.cdd.4401277","article-title":"Ethanol-induced neuronal apoptosis in the in vivo developing mouse brain is BAX dependent","volume":"10","author":"Young","year":"2003","journal-title":"Cell Death Differ."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.nbd.2008.05.009","article-title":"Ethanol causes and lithium prevents neuroapoptosis and suppression of pERK in the infant mouse brain","volume":"31","author":"Young","year":"2008","journal-title":"Neurobiol. Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1097\/ALN.0b013e31819b5eab","article-title":"Lithium protects against anesthesia-induced developmental neuroapoptosis","volume":"110","author":"Straiko","year":"2009","journal-title":"Anesthesiology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1111\/j.1399-6576.2009.02177.x","article-title":"Dexmedetomidine provides cortical neuroprotection: Impact on anaesthetic-induced neuroapoptosis in the rat developing brain","volume":"54","author":"Sanders","year":"2010","journal-title":"Acta Anaesthesiol. Scand."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1016\/j.nbd.2005.08.011","article-title":"Melatonin reduces the severity of anesthesia-induced apoptotic neurodegeneration in the developing rat brain","volume":"21","author":"Yon","year":"2006","journal-title":"Neurobiol. Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1006\/nbdi.2001.0475","article-title":"Ethanol-induced caspase-3 activation in the in vivo developing mouse brain","volume":"9","author":"Olney","year":"2002","journal-title":"Neurobiol. Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/j.nbd.2005.04.014","article-title":"Role of caspase-3 in ethanol-induced developmental neurodegeneration","volume":"20","author":"Young","year":"2005","journal-title":"Neurobiol. Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1016\/j.neuroscience.2005.03.064","article-title":"Anesthesia induces suicide in the developing rat brain via the intrinsic and extrinsic apoptotic pathways","volume":"135","author":"Yon","year":"2005","journal-title":"Neuroscience"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1712","DOI":"10.1213\/ane.0b013e318172ba0a","article-title":"Sub-anesthetic doses of propofol induce neuroapoptosis in the infant mouse brain","volume":"106","author":"Cattano","year":"2008","journal-title":"Anesth. Analg."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1097\/01.anes.0000264762.48920.80","article-title":"Xenon mitigates isoflurane-induced neuronal apoptosis in the developing rodent brain","volume":"106","author":"Ma","year":"2007","journal-title":"Anesthesiology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1097\/ANA.0b013e3181271850","article-title":"Isoflurane-induced neuroapoptosis in the developing brain of non-hypoglycemic mice","volume":"20","author":"Johnson","year":"2008","journal-title":"J. Neurosurg. Anesth."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"11077","DOI":"10.1097\/ALN.0b013e31819daedd","article-title":"Dexmedetomidine attenuates isoflurane-induced neurocognitive impairment in neonatal rats","volume":"110","author":"Sanders","year":"2009","journal-title":"Anesthesiology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.neulet.2008.09.083","article-title":"Subclinical concentration of sevoflurane potentiates neuronal apoptosis in the developing C57BL\/6 mouse brain","volume":"447","author":"Zhang","year":"2008","journal-title":"Neurosci. Lett."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1007\/BF03016309","article-title":"Potential of xenon to induce or to protect against neuroapoptosis in the developing mouse brain","volume":"55","author":"Cattano","year":"2008","journal-title":"Can. J. Anesth."},{"key":"ref_45","unstructured":"Brambrink, A.M., Back, S.A., Avidan, M.S., Creeley, C.E., and Olney, J.W. (2010, January 16\u201320). Ketamine and Isoflurane Anesthesia Triggers Neuronal and Glial Apoptosis in the Neonatal Macaque. Proceedings of the American Society of Anesthesiologists, San Diego, CA, USA. Abstract Number A375."},{"key":"ref_46","first-page":"494","article-title":"Neuronal and glial apoptosis observed after intravenous propofol anesthesia in neonatal macaques","volume":"24","author":"Brambrink","year":"2012","journal-title":"J. Neurosurg. Anesthesiol."},{"key":"ref_47","unstructured":"Brambrink, A.M., Dikranian, K., Evers, A.S., Creeley, C.E., and Olney, J.W. (2012, January 13\u201317). Isoflurane-Induced Apoptosis of Neurons and Oligodendrocytes in the Fetal Rhesus Macaque Brain. Proceedings of the American Society of Anesthesiologists, Washington, DC, USA. Abstract Number LBB10."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1002\/ana.23600","article-title":"Neonatal exposure to antiepileptic drugs disrupts striatal synaptic development","volume":"72","author":"Forcelli","year":"2012","journal-title":"Ann. Neurol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1016\/j.nbd.2011.12.022","article-title":"The abolishment of anesthesia-induced cognitive impairment by timely protection of mitochondria in the developing rat brain: The importance of free oxygen radicals and mitochondrial integrity","volume":"45","author":"Boscolo","year":"2012","journal-title":"Neurobiol. Dis."},{"key":"ref_50","first-page":"e101","article-title":"Nicoinamide protects against ethanol-induced apoptotic neurodegeneration in the developing mouse brain","volume":"4","author":"Leraci","year":"2006","journal-title":"PLoS Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/j.expneurol.2005.01.006","article-title":"Sulthiame but not levetiracetam exerts neurotoxic effect in the developing rat brain","volume":"193","author":"Manthey","year":"2005","journal-title":"Exp. Neurol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejpn.2010.10.003","article-title":"Levetiracetam: Safety and efficacy in neonatal seizures","volume":"15","author":"Ramantani","year":"2011","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1093\/jnen\/61.2.197","article-title":"Arrested oligodendrocyte lineage progression during human cerebral white matter development: Dissociation between the timing of progenitor differentiation and myelinogenesis","volume":"61","author":"Back","year":"2002","journal-title":"J. Neuropath. Exp. Neurol."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Creeley, C.E., Dikranian, K.T., Back, S.A., Olney, J.W., and Brambrink, A.M. (2013). Isoflurane-induced apoptosis of neurons and oligodendrocytes in the fetal rhesus macaque brain. Anesthesiology, in press.","DOI":"10.1093\/bja\/aet173"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1126\/science.6474175","article-title":"Regressive events in neurogenesis","volume":"225","author":"Cowan","year":"1984","journal-title":"Science"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1146\/annurev.ne.14.030191.002321","article-title":"Cell death during development of the nervous system","volume":"14","author":"Oppenheim","year":"1991","journal-title":"Ann. Rev. Neurosci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1126\/science.8235590","article-title":"Programmed cell death and the control of survival: Lessons from the nervous system","volume":"262","author":"Raff","year":"1993","journal-title":"Science"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0301-0082(92)90029-E","article-title":"Cell death and removal in the cerebral cortex during development","volume":"39","author":"Ferrer","year":"1992","journal-title":"Prog. Neurobiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1242\/dev.122.4.1165","article-title":"Widespread programmed cell death in proliferative and postmitotic regions of the fetal cerebral cortex","volume":"122","author":"Blaschke","year":"1996","journal-title":"Development"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1523\/JNEUROSCI.17-03-01075.1997","article-title":"Apoptosis and its relation to the cell cycle in the developing cerebral cortex","volume":"17","author":"Thomaidou","year":"1997","journal-title":"J. Neurosci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1177\/15353702-0323006-04","article-title":"Genesis of alcohol-induced craniofacial dysmorphism","volume":"230","author":"Sulik","year":"2005","journal-title":"Exp. Biol. Med."},{"key":"ref_62","first-page":"1523","article-title":"Selective vulnerability of embryonic cell populations to ethanol-induced apoptosis: Implications for alcohol-related birth defects and neurodevelopmental disorder","volume":"25","author":"Dunty","year":"2001","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3767","DOI":"10.1113\/jphysiol.2008.158436","article-title":"Synapses on NG2-expressing progenitors in the brain: Multiple functions?","volume":"16","author":"Gallo","year":"2008","journal-title":"J. Physiol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/0736-5748(90)90080-L","article-title":"GABA mediated excitation in immature rat CA3 hippocampal neurons","volume":"8","author":"Cherubini","year":"1990","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1093\/toxsci\/kfs296","article-title":"Ketamine-induced neuronal damage and altered NMDA receptor function in rat primary forebrain culture","volume":"131","author":"Liu","year":"2013","journal-title":"Toxicol. Sci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/j.neuro.2008.03.007","article-title":"Protective effects of 7-nitroindazole on ketamine-induced neurotoxicity in rat forebrain culture","volume":"29","author":"Wang","year":"2008","journal-title":"Neurtoxicology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3147","DOI":"10.1523\/JNEUROSCI.20-09-03147.2000","article-title":"Slow death of postnatal hippocampal neurons by GABAA receptor overactivation","volume":"20","author":"Xu","year":"2000","journal-title":"J. Neurosci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1006\/exnr.1999.7126","article-title":"N-Methyl-daspartate receptor blockade induces neuronal apoptosis in cortical culture","volume":"159","author":"Hwang","year":"1999","journal-title":"Exp. Neurol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.neulet.2008.12.002","article-title":"NMDAR blockade-induced neonatal brain injury: Reversal by the calcium channel agonist BayK 8644","volume":"450","author":"Turner","year":"2009","journal-title":"Neurosci. Lett."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1002\/(SICI)1096-9861(19990614)408:4<461::AID-CNE2>3.0.CO;2-9","article-title":"Distinguishing excitotoxic from apoptotic neurodegeneration in the developing rat brain","volume":"408","author":"Ishimaru","year":"1999","journal-title":"J. Comp. Neurol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2073","DOI":"10.1111\/j.1530-0277.2007.00528.x","article-title":"Persistent impairment of hippocampal neurogenesis in young adult rats following early postnatal alcohol exposure","volume":"31","author":"Klintsova","year":"2007","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1097\/ALN.0b013e31819c463d","article-title":"Isoflurane differentially affects neurogenesis and long-term neurocognitive function in 60-day-old and 7-day-old rats","volume":"110","author":"Stratmann","year":"2009","journal-title":"Anesthesiology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1002\/ana.21463","article-title":"Sedative and anticonvulsant drugs suppress postnatal neurogenesis","volume":"64","author":"Stefovska","year":"2008","journal-title":"Ann. Neurol."},{"key":"ref_74","first-page":"1","article-title":"Anesthesia-induced developmental neurodegeneration: The role of neuronal organelles","volume":"3","author":"Boscolo","year":"2012","journal-title":"Front. Neurol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1945","DOI":"10.1097\/00001756-200210280-00023","article-title":"Caffeine-induced neuronal death in neonatal rat brain and cortical cell cultures","volume":"13","author":"Kang","year":"2002","journal-title":"Neuroreport"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.brainres.2008.04.066","article-title":"Effect of caffeine and morphine on the developing pre-mature brain","volume":"1219","author":"Black","year":"2008","journal-title":"Brain Res."},{"key":"ref_77","unstructured":"Yuede, C.M., Creeley, C.E., and Olney, J.W. (2011, January 12\u201316). Long-Term Behavioral Effects of the Interaction between NMDA Antagonists and Caffeine in the Developing Mouse Brain. Proceedings of the Society for Neuroscience, Washington, DC, USA. Abstract Number 33.01."},{"key":"ref_78","unstructured":"Creeley, C.E., Yuede, C.M., and Olney, J.W. (2011, January 12\u201316). Long-Term Behavioral Effects of the Interaction between GABA Agonists and Caffeine in the Developing Mouse Brain. Proceedings of the Society for Neuroscience, Washington, DC, USA. Abstract Number 33.02."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1124\/jpet.107.123133","article-title":"Effects of lamotrigine alone and in combination with MK-801, phenobarbital, or phentoin on cell death on the neonatal rat brain","volume":"322","author":"Katz","year":"2002","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1111\/j.1469-8749.2010.03743.x","article-title":"Cognitive profile in young adults born preterm at very low birthweight","volume":"52","author":"Lohaugen","year":"2010","journal-title":"Dev. Med. Child Neurol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1097\/00000542-200408000-00033","article-title":"Anesthetic agents and the immature brain: Are these toxic or therapeutic?","volume":"101","author":"Anand","year":"2004","journal-title":"Anesthesiology"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1016\/j.nbd.2011.10.021","article-title":"Nociceptive stimuli enhance anesthetic-induced neuroapoptosis in the rat developing brain","volume":"45","author":"Shu","year":"2012","journal-title":"Neurobiol. Dis."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1053\/scnp.2000.6729","article-title":"Neuropsychiatric implications and long-term consequences of fetal alcohol spectrum disorders","volume":"5","author":"Streissguth","year":"2000","journal-title":"Semin. Clin. Neuropsychiatry"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1177\/15353702-0323006-03","article-title":"Fetal alcohol spectrum disorders: an overview with emphasis on changes in brain and behavior","volume":"230","author":"Riley","year":"2005","journal-title":"Exp. Biol. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1176\/ajp.155.4.552","article-title":"Mental illness in adults with fetal alcohol syndrome or fetal alcohol effects","volume":"155","author":"Famy","year":"1998","journal-title":"Am. J. Psychiatry"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1111\/j.1469-8749.2001.tb00179.x","article-title":"Brain dysmorphology in individuals with severe prenatal alcohol exposure","volume":"43","author":"Archibald","year":"2001","journal-title":"Dev. Med. Child Neurol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/0741-8329(90)90070-S","article-title":"A single day of alcohol exposure during the brain growth spurt induces brain weight restriction and cerebellar Purkinje cell loss","volume":"7","author":"Goodlett","year":"1990","journal-title":"Alcohol"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/1096-9926(200101)63:1<15::AID-TERA1003>3.0.CO;2-Q","article-title":"Effect of prenatal alcohol exposure on midsagittal commissure size in rats","volume":"63","author":"Livy","year":"2001","journal-title":"Teratology"},{"key":"ref_89","unstructured":"Creeley, C.E., Olney, J.W., and Brambrink, A.M. (2013). Acute apoptosis of neurons and oligodendrocytes induced in the developing rhesus macaque brain by anti-epileptic drugs. Soc. Neurosci. Abstr., in press."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.ejpn.2007.02.006","article-title":"Brain morphology alterations in the basal ganglia and the hypothalamus following prenatal exposure to antiepileptic drugs","volume":"11","author":"Ikonomidou","year":"2007","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1056\/NEJM199002083220604","article-title":"Phenbarbital for febrile seizures\u2014effects on intelligence and on seizure recurrence","volume":"322","author":"Farwell","year":"1990","journal-title":"N. Engl. J. Med."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1177\/000992289903800702","article-title":"Late cognitive effects of early treatment with phenobarbital","volume":"38","author":"Sulzbacher","year":"1999","journal-title":"Clin. Pediatr."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1056\/NEJMoa0803531","article-title":"Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs","volume":"360","author":"Meador","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1212\/WNL.0b013e318250d824","article-title":"Effects of fetal antiepileptic drug exposure: Outcomes at age 4.5 years","volume":"78","author":"Meador","year":"2012","journal-title":"Neurology"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1124\/jpet.111.188862","article-title":"Effects of neonatal antiepileptic drug exposure on cognitive, emotional and motor function in adult rats","volume":"340","author":"Forcelli","year":"2012","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1097\/ANA.0b013e3181a71f11","article-title":"A retrospective cohort study of the association of anesthesia and hernia repair surgery with behavioral and developmental disorders in young children","volume":"4","author":"DiMaggio","year":"2009","journal-title":"J. Neurosurg. Anesthesiol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1213\/ANE.0b013e3182147f42","article-title":"Early childhood exposure to anesthesia and risk of developmental and behavioral disorders in a sibling birth cohort","volume":"113","author":"DiMaggio","year":"2011","journal-title":"Anesth. Analg."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1097\/01.anes.0000344728.34332.5d","article-title":"Early exposure to anesthesia and learning disabilities in a population-based birth cohort","volume":"110","author":"Wilder","year":"2009","journal-title":"Anesthesiology"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1542\/peds.2011-0351","article-title":"Cognitive and behavioral outcomes after early exposure to anesthesia and surgery","volume":"128","author":"Flick","year":"2011","journal-title":"Pediatrics"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.mayocp.2011.11.008","article-title":"Attention-deficit\/hyperactivity disorder after early exposure to procedures requiring general anesthesia","volume":"87","author":"Sprung","year":"2012","journal-title":"Mayo Clin. Proc."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1542\/peds.2011-3822","article-title":"Long-term differences in language and cognitive function after childhood exposure to anesthesia","volume":"130","author":"Ing","year":"2012","journal-title":"Pediatrics"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1097\/ALN.0b013e3182644684","article-title":"Are anesthesia and surgery during infancy associated with altered academic performance during childhood?","volume":"117","author":"Block","year":"2012","journal-title":"Anesthesiology"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1097\/GRF.0b013e3181c11f60","article-title":"Anesthesia for nonobstetric surgery: Maternal and fetal considerations","volume":"52","author":"Cheek","year":"2009","journal-title":"Clin. Obstet. Gynecol."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/3\/3\/1153\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:48:19Z","timestamp":1760219299000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/3\/3\/1153"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,7,31]]},"references-count":103,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2013,9]]}},"alternative-id":["brainsci3031153"],"URL":"https:\/\/doi.org\/10.3390\/brainsci3031153","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,7,31]]}}}