Anesthetic Preconditioning of Traumatic Brain Injury Is Ineffective in a Drosophila Model of Obesity.

We tested the hypothesis that obesity influences the pharmacodynamics of volatile general anesthetics (VGAs) by comparing effects of anesthetic exposure on mortality from traumatic brain injury (TBI) in lean and obese Drosophila melanogaster We induced TBI with a high-impact trauma device. Starvation-selection over multiple generations resulted in an obese phenotype (SS flies). Fed flies served as lean controls (FC flies). Adult (1-8-day-old) SS and FC flies were exposed to equianesthetic doses of isoflurane or sevoflurane either before or after TBI. The principal outcome was percent mortality 24 hours after injury, expressed as the Mortality Index at 24 hours (MI24). TBI resulted in a lower MI24 in FC than in SS flies [21 (2.35) and 57.8 (2.14), respectively n = 12, P = 0.0001]. Pre-exposure to isoflurane or sevoflurane preconditioned FC flies to TBI, reducing the risk of death to 0.53 (0.25 to 1.13) and 0.82 (0.43 to 1.58), respectively, but had no preconditioning effect in SS flies. Postexposure to isoflurane or sevoflurane increased the risk of death in SS flies, but only postexposure to isoflurane increased the risk in FC flies [1.39 (0.81 to 2.38)]. Thus, obesity affects the pharmacodynamics of VGAs, thwarting the preconditioning effect of isoflurane and sevoflurane in TBI. SIGNIFICANCE STATEMENT: Inadvertent preconditioning in models of traumatic brain injury (TBI) is a recognized confounder. The findings in a fruit fly (Drosophila melanogaster) model of closed-head TBI indicate that anesthetic pharmacodynamics are profoundly affected by obesity. Specifically, obesity thwarts the brain-protective effect of anesthetic preconditioning. This finding is important for experimental studies of TBI and supports the versatility of the fruit fly as a model for the exploration of anesthetic pharmacodynamics in a wide parameter space.

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

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.

Ageing and genetic background influence anaesthetic effects in a D. melanogaster model of blunt trauma with brain injury†.

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.