Genetic variability affects absolute and relative potencies and kinetics of the anesthetics isoflurane and sevoflurane in Drosophila melanogaster

Olufs, Zachariah P. G.; Loewen, Carin A.; Ganetzky, Barry; Wassarman, David A.; Perouansky, Misha

doi:10.1038/s41598-018-20720-7

Cited by 40 publications

(70 citation statements)

References 63 publications

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“…One limitation of our study was the use of only female flies for behavioral experiments in adults. Sex-specific effects in Drosophila have been observed during recovery from anesthesia, 41,42 although these effects generalize to cold-shock and oxygen deprivation anesthesia, which are likely unrelated to the presynaptic mechanisms described in this study. Given the lack of sexual dimorphism in synaptic proteins, it is unlikely that the phenotypes we describe here would be different using male flies, although this remains to be tested experimentally.…”

Section: Perioperative Medicinementioning

confidence: 59%

Syntaxin1A Neomorphic Mutations Promote Rapid Recovery from Isoflurane Anesthesia in Drosophila melanogaster

et al. 2019

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Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Mutations in the presynaptic protein syntaxin1A modulate general anesthetic effects in vitro and in vivo. Coexpression of a truncated syntaxin1A protein confers resistance to volatile and intravenous anesthetics, suggesting a target mechanism distinct from postsynaptic inhibitory receptor processes. Hypothesizing that recovery from anesthesia may involve a presynaptic component, the authors tested whether syntaxin1A mutations facilitated recovery from isoflurane anesthesia in Drosophila melanogaster. Methods A truncated syntaxin1A construct was expressed in Drosophila neurons. The authors compared effects on isoflurane induction versus recovery in syntaxin1A mutant animals by probing behavioral responses to mechanical stimuli. The authors also measured synaptic responses from the larval neuromuscular junction using sharp intracellular recordings, and performed Western blots to determine whether the truncated syntaxin1A is associated with presynaptic core complexes. Results Drosophila expressing a truncated syntaxin1A (syx227, n = 40) were resistant to isoflurane induction for a behavioral responsiveness endpoint (ED50 0.30 ± 0.01% isoflurane, P < 0.001) compared with control (0.240 ± 0.002% isoflurane, n = 40). Recovery from isoflurane anesthesia was also faster, with syx227-expressing flies showing greater levels of responsiveness earlier in recovery (reaction proportion 0.66 ± 0.48, P < 0.001, n = 68) than controls (0.22 ± 0.42, n = 68 and 0.33 ± 0.48, n = 66). Measuring excitatory junction potentials of larvae coexpressing the truncated syntaxin1A protein showed a greater recovery of synaptic function, compared with controls (17.39 ± 3.19 mV and 10.29 ± 4.88 mV, P = 0.014, n = 8 for both). The resistance-promoting truncated syntaxin1A was not associated with presynaptic core complexes, in the presence or absence of isoflurane anesthesia. Conclusions The same neomorphic syntaxin1A mutation that confers isoflurane resistance in cell culture and nematodes also produces isoflurane resistance in Drosophila. Resistance in Drosophila is, however, most evident at the level of recovery from anesthesia, suggesting that the syntaxin1A target affects anesthesia maintenance and recovery processes rather than induction. The absence of truncated syntaxin1A from the presynaptic complex suggests that the resistance-promoting effect of this molecule occurs before core complex formation.

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Section: Perioperative Medicinementioning

confidence: 59%

Syntaxin1A Neomorphic Mutations Promote Rapid Recovery from Isoflurane Anesthesia in Drosophila melanogaster

et al. 2019

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“…We used a custom-built Serial Anesthesia Array to simultaneously expose up to eight samples of at least 20 flies each to precise doses of VGAs and oxygen [8,17]. VGAs were administered through the Array using a Datex-Ohmeda Aestiva/5 anesthesia machine equipped with commercial agent-specific vaporizers (Datex-Ohmeda Inc., Madison, WI, USA).…”

Section: Exposure To Vgas and Omentioning

confidence: 99%

“…We used a modification of the "rapid iterative negative geotaxis" (RING) [8] as a versatile and reproducible test of integrated neural activity. Gait speed correlates with impending cognitive impairment in humans [18], while in flies locomotor activity integrates multiple modalities indicative of health [19].…”

Section: Impairment Of Locomotionmentioning

confidence: 99%

“…Several lines of evidence indicate that mortality and impaired locomotion in this model are due to primary injuries to the brain. We used a serial anesthesia array to expose injured and uninjured flies to precise doses of the volatile general anesthetics (VGAs) isoflurane (ISO) and sevoflurane (SEVO) and the desired concentration of oxygen (O 2 ) [8]. We found that exposure to ISO or ISO and 100% O 2 (ISO/O 2 ) increases mortality after TBI in the w 1118 laboratory fly strain [8,9].…”

Section: Introductionmentioning

confidence: 99%

“…We used a serial anesthesia array to expose injured and uninjured flies to precise doses of the volatile general anesthetics (VGAs) isoflurane (ISO) and sevoflurane (SEVO) and the desired concentration of oxygen (O 2 ) [8]. We found that exposure to ISO or ISO and 100% O 2 (ISO/O 2 ) increases mortality after TBI in the w 1118 laboratory fly strain [8,9]. We also found that genetic background affects the extent to which exposure to ISO/O 2 increases mortality following TBI.…”

Section: Introductionmentioning

confidence: 99%

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Interactions among Genetic Background, Anesthetic Agent, and Oxygen Concentration Shape Blunt Traumatic Brain Injury Outcomes in Drosophila melanogaster

Scharenbrock

Schiffman

Olufs

et al. 2020

IJMS

Self Cite

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Following traumatic brain injury (TBI), the time window during which secondary injuries develop provides a window for therapeutic interventions. During this time, many TBI victims undergo exposure to hyperoxia and anesthetics. We investigated the effects of genetic background on the interaction of oxygen and volatile general anesthetics with brain pathophysiology after closed-head TBI in the fruit fly Drosophila melanogaster. To test whether sevoflurane shares genetic risk factors for mortality with isoflurane and whether locomotion is affected similarly to mortality, we used a device that generates acceleration–deceleration forces to induce TBI in ten inbred fly lines. After TBI, we exposed flies to hyperoxia alone or in combination with isoflurane or sevoflurane and quantified mortality and locomotion 24 and 48 h after TBI. Modulation of TBI–induced mortality and locomotor impairment by hyperoxia with or without anesthetics varied among fly strains and among combinations of agents. Resistance to increased mortality from hyperoxic isoflurane predicted resistance to increased mortality from hyperoxic sevoflurane but did not predict the degree of locomotion impairment under any condition. These findings are important because they demonstrate that, in the context of TBI, genetic background determines the latent toxic potentials of oxygen and anesthetics.

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Insights from Drosophila on mitochondrial complex I

Rhooms

Murari

Goparaju

et al. 2019

Cell. Mol. Life Sci.

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Genetic variability affects absolute and relative potencies and kinetics of the anesthetics isoflurane and sevoflurane in Drosophila melanogaster

Cited by 40 publications

References 63 publications

Syntaxin1A Neomorphic Mutations Promote Rapid Recovery from Isoflurane Anesthesia in Drosophila melanogaster

Syntaxin1A Neomorphic Mutations Promote Rapid Recovery from Isoflurane Anesthesia in Drosophila melanogaster

Interactions among Genetic Background, Anesthetic Agent, and Oxygen Concentration Shape Blunt Traumatic Brain Injury Outcomes in Drosophila melanogaster

Insights from Drosophila on mitochondrial complex I

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