Neuroprotection by noble gases in models of brain injury

Abstract

Background: There has been a growing interest in the use of noble gases as potential novel treatment agents against brain injury. This thesis investigates the neuroprotective properties of the inert gases xenon, argon, krypton and neon in two models – in vitro ischemic brain injury and in vivo blast brain injury. Methods: The in vitro ischemic model used mouse organotypic hippocampal brain slices subjected to oxygen-glucose deprivation. Injury was quantified using propidium iodide fluorescence. In the blast model rats were exposed to a single or multiple shock waves using a compressed-gas shock tube. Motor and neurologic function of animals was assessed at different time points after injury. Results: Xenon (0.5 atm) and argon (0.5 atm) are neuroprotective in ischemic injury (xenon 70 ± 4% protection at 24 h after injury [n = 95]; argon 75 ± 5% protection [n = 52]; mean ± SEM) in an in vitro model of ischemic brain injury. Neon and krypton lack neuroprotective properties. Glycine reversed the neuroprotective effect of xenon, but not argon. Combined treatment with argon (0.35 atm) and progesterone (0.5 μM) did not cause an injury reduction. To establish and characterize the novel in vivo blast TBI model a series of experiments with one or three shock waves were performed. Three shock waves (260 kPa peak overpressure, 1ms duration) resulted in a significant motor and neurological deficit. Treatment with 50% xenon for 3 hours after injury did not cause a significant improvement of motor and neurologic function. Conclusions: Xenon and argon are equally protective in an in vitro model of ischemic brain injury. Neon and krypton do not exhibit neuroprotective properties. Xenon neuroprotection can be reversed by increased concentration of glycine. Argon and xenon act via different mechanisms. Xenon did not improve motor or neurologic function in our in vivo blast TBI model.