Isoflurane causes greater neurodegeneration than an equivalent exposure of sevoflurane in the developing brain of neonatal mice.
BACKGROUND
We hypothesized that isoflurane has a greater potency to induce neurodegeneration than sevoflurane in the developing brains of neonatal mice based on our previous studies in cell culture.


METHODS
We treated 7-day-old mice with either 0.75% isoflurane or 1.1% sevoflurane ( approximately 0.5 minimum alveolar concentration) for 6 h and then obtained blood and brain samples at 2 h after the anesthesia treatment for determination of neuroapoptosis in different brain regions and the neurodegenerative biomarker S100beta in the blood. The mechanisms of neurodegeneration induced by isoflurane or sevoflurane were also compared by determining protein expressions of the cell cycle and apoptosis-related proteins. In separate groups, memory and learning ability were evaluated through the use of Morris Water Maze testing in mice at postnatal day 42 after anesthesia treatment at postnatal day 7.


RESULTS
Isoflurane but not sevoflurane significantly increased the neurodegenerative biomarker S100beta in the blood. Isoflurane treatments significantly increased apoptosis indicated by the activation of caspase-3 and elevation of poly-(ADP-ribose) polymerase in different brain regions. An equipotent exposure of sevoflurane tended to increase apoptosis in hippocampal and cortex areas but was significantly less potent than isoflurane. Neither isoflurane nor sevoflurane significantly changed protein levels of glyceraldehyde-3-phosphate dehydrogenase, beta-site amyloid beta-precursor protein-cleaving enzyme, and cell cycle regulatory proteins (CDK4, cyclin D1). Isoflurane and sevoflurane at the selected exposures did not significantly alter memory and learning ability.


CONCLUSIONS
At equipotent exposures, isoflurane has a greater potency than sevoflurane to cause neurodegeneration in the developing brains of neonatal mice.
Liang
Ge
G
Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Ward
Christopher
C
Peng
Jun
J
Zhao
Yifan
Y
Huang
Baosheng
B
Wei
Huafeng
H
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers / Q000097:blood; D001921:Brain / Q000187:drug effects / Q000254:growth & development* / Q000473:pathology*; D005260:Female; D007530:Isoflurane / Q000633:toxicity*; D008297:Male; D008738:Methyl Ethers / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000097:blood / Q000139:chemically induced* / Q000473:pathology*; D009414:Nerve Growth Factors / Q000097:blood; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000097:blood; D000077149:Sevoflurane
D015415:Biomarkers; D008738:Methyl Ethers; D009414:Nerve Growth Factors; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; D000077149:Sevoflurane; D007530:Isoflurane
Anesthesiology. 2008 Aug;109(2):243-50
18648233
Am J Physiol Renal Physiol. 2008 Jul;295(1):F128-36
18434384
Toxicol Sci. 2007 Jul;98(1):145-58
17426105
Nature. 1994 Sep 22;371(6495):346-7
8090205
Anesth Analg. 2007 Mar;104(3):509-20
17312200
Neurosci Lett. 2007 Sep 20;425(1):59-62
17723266
Anesthesiology. 2009 Mar;110(3):628-37
19212262
Anesthesiology. 2009 Apr;110(4):813-25
19293698
J Neurosci. 2003 Feb 1;23(3):876-82
12574416
Anesthesiology. 2009 Apr;110(4):796-804
19293700
Anesth Analg. 2003 Apr;96(4):1004-1009
12651650
Science. 1999 Jan 1;283(5398):70-4
9872743
Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):715-20
12522260
Anesthesiology. 2008 Feb;108(2):251-60
18212570
Pain. 2009 May;143(1-2):138-46
19307058
J Neurosci. 2007 Feb 7;27(6):1247-54
17287498
Anesthesiology. 2009 Apr;110(4):805-12
19293699
J Neurochem. 2000 Jul;75(1):81-90
10854250
Annu Rev Pharmacol Toxicol. 2005;45:269-90
15822178
Anesthesiology. 2009 Apr;110(4):849-61
19293696
Anesth Analg. 2007 Aug;105(2):381-5
17646494
Pediatr Res. 2009 Oct;66(4):435-40
20016413
Anesthesiology. 2007 Apr;106(4):746-53
17413912
Anesthesiology. 2009 Apr;110(4):826-33
19293697
Anesthesiology. 2004 Feb;100(2):309-14
14739805
Neurocrit Care. 2007;6(2):121-38
17522796
J Neurosurg Anesthesiol. 2008 Jan;20(1):21-8
18157021
Clin Chim Acta. 2003 Sep;335(1-2):1-7
12927678
Exp Neurol. 1999 Mar;156(1):1-15
10192773
Trends Pharmacol Sci. 2004 Mar;25(3):135-9
15019268
Pediatr Res. 2007 Sep;62(3):283-90
17551412
Brain Res. 2005 Mar 10;1037(1-2):139-47
15777762
Anesth Analg. 2008 Feb;106(2):492-500, table of contents
18227305
Int Immunopharmacol. 2002 Jan;2(1):95-104
11789673
Neuropharmacology. 2007 Dec;53(8):942-50
17959201
Arch Neurol. 2009 May;66(5):620-31
19433662