Hannah J Schiffman1, Zachariah P G Olufs1, Michael R Lasarev2, David A Wassarman3, Misha Perouansky4. 1. Department of Anesthesiology. 2. Department of Biostatistics and Medical Informatics. 3. Department of Medical Genetics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA. 4. Department of Anesthesiology. Electronic address: mperouansky@wisc.edu.
Abstract
BACKGROUND: General anaesthetics interact with the pathophysiological mechanisms of traumatic brain injury (TBI). We used a Drosophila melanogaster (fruit fly) model to test the hypothesis that ageing and genetic background modulate the effect of anaesthetics and hyperoxia on TBI-induced mortality in the context of blunt trauma. METHODS: We exposed flies to isoflurane or sevoflurane under normoxic or hyperoxic conditions and TBI, and subsequently quantified the effect on mortality 24 h after injury. To determine the effect of age on anaesthetic-induced mortality, we analysed flies at 1-8 and 43-50 days old. To determine the effect of genetic background, we performed a genome-wide association study (GWAS) analysis on a collection of young inbred, fully sequenced lines. RESULTS: Exposure to anaesthetics and hyperoxia differentially affected mortality in young and old flies. Pre-exposure of young but not old flies to anaesthetics reduced mortality. Post-exposure selectively increased mortality. For old but not young flies, hyperoxia enhanced the effect on mortality of post-exposure to isoflurane but not to sevoflurane. Post-exposure to isoflurane in hyperoxia increased the mortality of young fly lines in the Drosophila Genetic Reference Panel collection to different extents. GWAS analysis of these data identified single nucleotide polymorphisms in genes involved in cell water regulation and oxygen sensing as being associated with the post-exposure effect on mortality. CONCLUSIONS: Ageing and genetic background influence the effects of volatile general anaesthetics and hyperoxia on mortality in the context of traumatic brain injury. Polymorphisms in specific genes are identified as potential causes of ageing and genetic effects.
BACKGROUND: General anaesthetics interact with the pathophysiological mechanisms of traumatic brain injury (TBI). We used a Drosophila melanogaster (fruit fly) model to test the hypothesis that ageing and genetic background modulate the effect of anaesthetics and hyperoxia on TBI-induced mortality in the context of blunt trauma. METHODS: We exposed flies to isoflurane or sevoflurane under normoxic or hyperoxic conditions and TBI, and subsequently quantified the effect on mortality 24 h after injury. To determine the effect of age on anaesthetic-induced mortality, we analysed flies at 1-8 and 43-50 days old. To determine the effect of genetic background, we performed a genome-wide association study (GWAS) analysis on a collection of young inbred, fully sequenced lines. RESULTS: Exposure to anaesthetics and hyperoxia differentially affected mortality in young and old flies. Pre-exposure of young but not old flies to anaesthetics reduced mortality. Post-exposure selectively increased mortality. For old but not young flies, hyperoxia enhanced the effect on mortality of post-exposure to isoflurane but not to sevoflurane. Post-exposure to isoflurane in hyperoxia increased the mortality of young fly lines in the Drosophila Genetic Reference Panel collection to different extents. GWAS analysis of these data identified single nucleotide polymorphisms in genes involved in cell water regulation and oxygen sensing as being associated with the post-exposure effect on mortality. CONCLUSIONS: Ageing and genetic background influence the effects of volatile general anaesthetics and hyperoxia on mortality in the context of traumatic brain injury. Polymorphisms in specific genes are identified as potential causes of ageing and genetic effects.
Authors: R Sterling Haring; Kunal Narang; Joseph K Canner; Anthony O Asemota; Benjamin P George; Shalini Selvarajah; Adil H Haider; Eric B Schneider Journal: J Surg Res Date: 2015-01-15 Impact factor: 2.192
Authors: José A Matta; Paul M Cornett; Rosa L Miyares; Ken Abe; Niaz Sahibzada; Gerard P Ahern Journal: Proc Natl Acad Sci U S A Date: 2008-06-23 Impact factor: 11.205
Authors: Geoff Appelboom; Sam Bruce; Andrew Duren; Matt Piazza; Aimee Monahan; Brandon Christophe; Steve Zoller; Melissa LoPresti; E Sander Connolly Journal: Neurol Res Date: 2015-05-22 Impact factor: 2.448
Authors: Julie A Fischer; Zachariah P G Olufs; Rebeccah J Katzenberger; David A Wassarman; Misha Perouansky Journal: Anesth Analg Date: 2018-06 Impact factor: 5.108
Authors: Trudy F C Mackay; Stephen Richards; Eric A Stone; Antonio Barbadilla; Julien F Ayroles; Dianhui Zhu; Sònia Casillas; Yi Han; Michael M Magwire; Julie M Cridland; Mark F Richardson; Robert R H Anholt; Maite Barrón; Crystal Bess; Kerstin Petra Blankenburg; Mary Anna Carbone; David Castellano; Lesley Chaboub; Laura Duncan; Zeke Harris; Mehwish Javaid; Joy Christina Jayaseelan; Shalini N Jhangiani; Katherine W Jordan; Fremiet Lara; Faye Lawrence; Sandra L Lee; Pablo Librado; Raquel S Linheiro; Richard F Lyman; Aaron J Mackey; Mala Munidasa; Donna Marie Muzny; Lynne Nazareth; Irene Newsham; Lora Perales; Ling-Ling Pu; Carson Qu; Miquel Ràmia; Jeffrey G Reid; Stephanie M Rollmann; Julio Rozas; Nehad Saada; Lavanya Turlapati; Kim C Worley; Yuan-Qing Wu; Akihiko Yamamoto; Yiming Zhu; Casey M Bergman; Kevin R Thornton; David Mittelman; Richard A Gibbs Journal: Nature Date: 2012-02-08 Impact factor: 49.962
Authors: Dena Johnson-Schlitz; Julie A Fischer; Hannah J Schiffman; Amanda R Scharenbrock; Zachariah P G Olufs; David A Wassarman; Misha Perouansky Journal: J Pharmacol Exp Ther Date: 2022-03-28 Impact factor: 4.402
Authors: Amanda R Scharenbrock; Hannah J Schiffman; Zachariah P G Olufs; David A Wassarman; Misha Perouansky Journal: Int J Mol Sci Date: 2020-09-21 Impact factor: 5.923