Anesthetic sevoflurane causes neurotoxicity differently in neonatal naïve and Alzheimer disease transgenic mice.
BACKGROUND
Recent studies have suggested that children undergoing surgery under anesthesia could be at an increased risk for the development of learning disabilities, but whether anesthetics contribute to this learning disability is unclear. Therefore, the authors set out to assess the effects of sevoflurane, the most commonly used inhalation anesthetic, on caspase activation, apoptosis, beta-amyloid protein levels, and neuroinflammation in the brain tissues of neonatal naïve and Alzheimer disease (AD) transgenic mice.


METHODS
Six-day-old naïve and AD transgenic (B6.Cg-Tg[amyloid precursor protein swe, PSEN1dE9]85Dbo/J) mice were treated with sevoflurane. The mice were killed at the end of the anesthesia, and the brain tissues were harvested and then subjected to Western blot, immunocytochemistry, enzyme-linked immunosorbent assay, and real-time polymerase chain reaction.


RESULTS
Herein, the authors show for the first time that sevoflurane anesthesia induced caspase activation and apoptosis, altered amyloid precursor protein processing, and increased beta-amyloid protein levels in the brain tissues of neonatal mice. Furthermore, sevoflurane anesthesia led to a greater degree of neurotoxicity in the brain tissues of the AD transgenic mice when compared with naïve mice and increased tumor necrosis factor-alpha levels in the brain tissues of only the AD transgenic mice. Finally, inositol 1,4,5-trisphosphate receptor antagonist 2-aminoethoxydiphenyl borate attenuated sevoflurane-induced caspase-3 activation and beta-amyloid protein accumulation in vivo.


CONCLUSIONS
These results suggest that sevoflurane may induce neurotoxicity in neonatal mice. AD transgenic mice could be more vulnerable to such neurotoxicity. These findings should promote more studies to determine the potential neurotoxicity of anesthesia in animals and humans, especially in children.
Lu
Yan
Y
Geriatric Anesthesia Research Unit, Departmentof Anesthesia, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129-2060, USA.
Wu
Xu
X
Dong
Yuanlin
Y
Xu
Zhipeng
Z
Zhang
Yiying
Y
Xie
Zhongcong
Z
D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D018685:Anesthetics, Inhalation / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D007859:Learning Disabilities / Q000139:chemically induced / Q000517:prevention & control; D008738:Methyl Ethers / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000077149:Sevoflurane
D018685:Anesthetics, Inhalation; D008738:Methyl Ethers; D000077149:Sevoflurane; D053148:Caspase 3
Anesthesiology. 2009 Apr;110(4):834-48
19293705
Science. 2001 Jul 6;293(5527):115-20
11441186
Am J Pathol. 1998 Dec;153(6):1687-93
9846958
Anesthesiology. 2009 Apr;110(4):849-61
19293696
Dev Cell. 2002 Jul;3(1):85-97
12110170
Br J Pharmacol. 2007 Aug;151(8):1176-86
17592515
Anesthesiology. 2009 Apr;110(4):796-804
19293700
Exp Gerontol. 2006 Apr;41(4):346-59
16564662
J Neuroimmunol. 2007 Mar;184(1-2):69-91
17222916
Twin Res Hum Genet. 2009 Jun;12(3):246-53
19456216
Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):715-20
12522260
Anesthesiology. 2008 Feb;108(2):251-60
18212570
J Biol Chem. 2004 Nov 19;279(47):49523-32
15347683
Nature. 2000 Sep 7;407(6800):48-54
10993067
Nature. 1991 Feb 21;349(6311):704-6
1671712
Proc Natl Acad Sci U S A. 2000 May 23;97(11):6138-43
10801983
Nat Med. 2006 Sep;12(9):1005-15
16960575
J Neurosci. 2008 Apr 23;28(17):4551-60
18434534
Proc Natl Acad Sci U S A. 1988 Oct;85(19):7341-5
3140239
Anesthesiology. 2009 Apr;110(4):805-12
19293699
Neurobiol Dis. 2006 Dec;24(3):516-24
17029828
Neuron. 2008 Dec 26;60(6):988-1009
19109907
Cell. 2009 Jun 12;137(6):1100-11
19524512
Proc Natl Acad Sci U S A. 1985 Jun;82(12):4245-9
3159021
J Biol Chem. 2002 Oct 18;277(42):39062-5
12198112
Nature. 2008 Aug 7;454(7205):706-8
18685694
Brain Res. 1998 Aug 10;801(1-2):1-8
9729236
Anesthesiology. 2009 Mar;110(3):628-37
19212262
Curr Alzheimer Res. 2009 Feb;6(1):30-5
19199872
Physiol Rev. 2001 Apr;81(2):741-66
11274343
Nature. 1993 Jan 28;361(6410):315-25
8381210
Ann Neurol. 2008 Dec;64(6):618-27
19006075
Neurology. 2007 May 29;68(22):1902-8
17536046
J Mol Neurosci. 2005;25(1):67-77
15781968
Science. 1998 Aug 28;281(5381):1312-6
9721091
Am J Pathol. 2007 Feb;170(2):680-92
17255335
Arch Neurol. 2009 May;66(5):620-31
19433662