title: Developmental neurotoxicity of alcohol and anesthetic drugs is augmented by co-exposure to caffeine.
abstract: Anesthetic and anti-epileptic drugs used in pediatric and obstetric medicine and several drugs, including alcohol, that are abused by pregnant women, trigger widespread neuroapoptosis in the developing brain of several animal species, including non-human primates. Caffeine (CAF) is often administered to premature infants to stimulate respiration, and these infants are also exposed simultaneously to anesthetic drugs for procedural sedation and/or surgical procedures. Pregnant women who abuse alcohol or other apoptogenic drugs also may heavily consume CAF. We administered CAF to infant mice alone or in combination with alcohol, phencyclidine, diazepam, midazolam, ketamine, or isoflurane, which are drugs of abuse and/or drugs frequently used in pediatric medicine, and found that CAF weakly triggers neuroapoptosis by itself and markedly potentiates the neuroapoptogenic action of each of these other drugs. Exposure of infant mice to CAF + phencyclidine resulted in long-term impairment in behavioral domains relevant to attention deficit/hyperactivity disorder, whereas exposure to CAF + diazepam resulted in long-term learning/memory impairment. At doses used in these experiments, these behavioral impairments either did not occur or were substantially less pronounced in mice exposed to CAF alone or to phencyclidine or diazepam alone. CAF currently enjoys the reputation of being highly beneficial and safe for use in neonatal medicine. Our data suggest the need to consider whether CAF may have harmful as well as beneficial effects on the developing brain, and the need for research aimed at understanding the full advantage of its beneficial effects while avoiding its potentially harmful effects.
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA; yuedec@neuro.wustl.edu.
authors.forename: Carla M
authors.initials: CM
authors.lastname: Yuede
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Olney
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Creeley
keywords: CAF; alcohol; anesthetic drugs; developing brain; neuroapoptosis
references.citation: Ther Drug Monit. 2008 Dec;30(6):709-16
references.pmid: 19057373
references.citation: Anesthesiology. 2009 Apr;110(4):834-48
references.pmid: 19293705
references.citation: Behav Pharmacol. 2006 Jun;17(4):295-302
references.pmid: 16914947
references.citation: Anesthesiology. 2009 Mar;110(3):628-37
references.pmid: 19212262
references.citation: J Neurosurg Anesthesiol. 2008 Jan;20(1):21-8
references.pmid: 18157021
references.citation: Cell Death Differ. 2003 Oct;10(10):1148-55
references.pmid: 14502238
references.citation: Anesthesiology. 2011 Mar;114(3):578-87
references.pmid: 21293251
references.citation: Ann Neurol. 2006 Dec;60(6):696-705
references.pmid: 17044013
references.citation: Neurobiol Dis. 2010 Oct;40(1):200-6
references.pmid: 20580929
references.citation: Stroke. 2010 Feb;41(2):363-7
references.pmid: 20044532
references.citation: Am J Psychiatry. 2005 Dec;162(12):2344-51
references.pmid: 16330600
references.citation: Neurobiol Dis. 2004 Dec;17(3):403-14
references.pmid: 15571976
references.citation: Pediatrics. 2012 Sep;130(3):e476-85
references.pmid: 22908104
references.citation: Brain Res. 2009 Oct 19;1294:1-11
references.pmid: 19647724
references.citation: Int Rev Cytol. 1980;68:251-306
references.pmid: 7014501
references.citation: Toxicol Sci. 2007 Jul;98(1):145-58
references.pmid: 17426105
references.citation: Neuroreport. 2002 Oct 28;13(15):1945-50
references.pmid: 12395097
references.citation: Curr Opin Pharmacol. 2003 Feb;3(1):101-9
references.pmid: 12550750
references.citation: Acta Neuropathol Commun. 2013 Jun 12;1:23
references.pmid: 24252271
references.citation: Pediatrics. 2009 Feb;123(2):e289-96
references.pmid: 19171582
references.citation: Anesthesiology. 2009 May;110(5):1077-85
references.pmid: 19352168
references.citation: Neurobiol Dis. 2008 Sep;31(3):355-60
references.pmid: 18595723
references.citation: Anesth Analg. 2008 Jun;106(6):1708-11
references.pmid: 18499598
references.citation: N Engl J Med. 2009 Apr 16;360(16):1597-605
references.pmid: 19369666
references.citation: Invest Ophthalmol Vis Sci. 2003 Jul;44(7):2809-17
references.pmid: 12824217
references.citation: Brain Res Dev Brain Res. 2002 Feb 28;133(2):115-26
references.pmid: 11882342
references.citation: Anesthesiology. 2010 Apr;112(4):834-41
references.pmid: 20234312
references.citation: Pediatrics. 2011 Nov;128(5):e1053-61
references.pmid: 21969289
references.citation: Ann N Y Acad Sci. 2007 Dec;1122:69-82
references.pmid: 18077565
references.citation: Anesthesiology. 2012 Feb;116(2):372-84
references.pmid: 22222480
references.citation: Neurobiol Dis. 2001 Jun;8(3):359-79
references.pmid: 11447994
references.citation: Neurosci Lett. 2008 Dec 12;447(2-3):109-14
references.pmid: 18852026
references.citation: Int J Dev Neurosci. 2009 Nov;27(7):727-31
references.pmid: 19580862
references.citation: Early Hum Dev. 1979 Mar;3(1):79-83
references.pmid: 118862
references.citation: Neurobiol Dis. 2005 Nov;20(2):608-14
references.pmid: 15927478
references.citation: Neurology. 2012 Apr 17;78(16):1207-14
references.pmid: 22491865
references.citation: Exp Biol Med (Maywood). 2005 Jun;230(6):357-65
references.pmid: 15956765
references.citation: J Neurosurg Anesthesiol. 2009 Oct;21(4):286-91
references.pmid: 19955889
references.citation: Neurotoxicol Teratol. 2011 Mar-Apr;33(2):220-30
references.pmid: 21241795
references.citation: Neurobiol Dis. 2002 Mar;9(2):205-19
references.pmid: 11895372
references.citation: Anesth Analg. 2011 Nov;113(5):1143-51
references.pmid: 21415431
references.citation: Neurotoxicol Teratol. 2011 Sep-Oct;33(5):592-7
references.pmid: 21708249
references.citation: Pediatrics. 2007 May;119(5):936-40
references.pmid: 17473094
references.citation: Eur J Clin Pharmacol. 1981;21(2):121-6
references.pmid: 7341280
references.citation: Brain Pathol. 2008 Apr;18(2):198-210
references.pmid: 18241241
references.citation: Neurobiol Dis. 2006 Mar;21(3):522-30
references.pmid: 16289675
references.citation: Anesthesiology. 2007 Apr;106(4):746-53
references.pmid: 17413912
references.citation: N Engl J Med. 2007 Nov 8;357(19):1893-902
references.pmid: 17989382
references.citation: Anesth Analg. 2008 Jun;106(6):1712-4
references.pmid: 18499599
references.citation: Mayo Clin Proc. 2012 Feb;87(2):120-9
references.pmid: 22305025
references.citation: Ann Neurol. 2012 Oct;72(4):525-35
references.pmid: 23109147
references.citation: J Lab Clin Med. 1983 Jun;101(6):826-34
references.pmid: 6854123
references.citation: J Neurosci. 2003 Feb 1;23(3):876-82
references.pmid: 12574416
references.citation: Br J Pharmacol. 2005 Sep;146(2):189-97
references.pmid: 15997239
references.citation: Semin Clin Neuropsychiatry. 2000 Jul;5(3):177-90
references.pmid: 11291013
references.citation: Drug Saf. 2010 Jan 1;33(1):73-9
references.pmid: 20000869
references.citation: J Toxicol Clin Toxicol. 1984;22(5):473-83
references.pmid: 6530705
references.citation: Anesthesiology. 2007 Sep;107(3):427-36
references.pmid: 17721245
references.citation: Anesth Analg. 2006 Jan;102(1):75-80
references.pmid: 16368807
references.citation: Neurotox Res. 2004;6(6):435-56
references.pmid: 15639778
references.citation: Cochrane Database Syst Rev. 2001;(4):CD000048
references.pmid: 11687065
references.citation: Can J Anaesth. 2008 Jul;55(7):429-36
references.pmid: 18591700
references.citation: J Comp Neurol. 1999 Jun 14;408(4):461-76
references.pmid: 10340498
references.citation: Acta Anaesthesiol Scand. 2010 Jul;54(6):710-6
references.pmid: 20003127
references.citation: Anesthesiology. 2009 Apr;110(4):796-804
references.pmid: 19293700
references.citation: Science. 2000 Feb 11;287(5455):1056-60
references.pmid: 10669420
references.citation: Hum Mol Genet. 2010 Nov 15;19(22):4515-28
references.pmid: 20826448
references.citation: Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):15089-94
references.pmid: 12417760
references.citation: Brain Res Dev Brain Res. 2005 Mar 22;155(1):1-13
references.pmid: 15763270
references.citation: Dev Med Child Neurol. 2010 Dec;52(12):1133-8
references.pmid: 21175467
references.citation: Lakartidningen. 1998 Dec 16;95(51-52):5878-83
references.pmid: 9889511
references.citation: Anesthesiology. 2009 Apr;110(4):862-8
references.pmid: 19293695
references.citation: J Matern Fetal Neonatal Med. 2010 Oct;23 Suppl 3:20-3
references.pmid: 20873976
references.citation: Ann N Y Acad Sci. 2010 Jun;1199:43-51
references.pmid: 20633108
references.citation: Am J Psychiatry. 1998 Apr;155(4):552-4
references.pmid: 9546004
references.citation: Am J Obstet Gynecol. 2004 Sep;191(3):1037-43
references.pmid: 15467586
references.citation: Science. 1999 Jan 1;283(5398):70-4
references.pmid: 9872743
references.citation: Am J Perinatol. 2007 Jan;24(1):39-47
references.pmid: 17195151
references.citation: Anesthesiology. 2012 Sep;117(3):494-503
references.pmid: 22801049