Brain targeted xenon protects cerebral vasculature after traumatic brain injury

Cerebrovascular dysfunction following traumatic brain injury (TBI) is a well characterized phenomenon. Given the therapeutic potential of xenon, we aimed to study its effects after localized delivery to the brain using microbubbles. We designed xenon containing microbubbles stabilized by dibehenoylphosphatidylcholine (DBPC) and polyethylene glycol (PEG) attached to saturated phospholipid (DPSE-PEG5000). Using a pig model of TBI, these microbubbles were intravenously injected, and ultrasound was used release xenon at the level of the carotid artery. Control group received perfluorobutane containing microbubbles. Diffusion tensor imaging (DTI) showed higher fractional anisotropy for pigs receiving xenon microbubbles compared to control group at 1 day after injury. Radial diffusivity analysis showed that this effect was mainly due acute edema. Pigs were sacrificed at 5 days, and the brain tissues of xenon treated animals showed reduction of perivascular inflammation and blood-brain barrier disruption. Endothelial cell culture experiment showed that glutamate reduces tight junction protein zona occludens-1 (ZO-1), but treatment with xenon microbubbles attenuates this effect. Xenon treatment protects cerebrovasculature and astroglial reactivity after TBI. Furthermore, these data support the future use of localized delivery of various therapeutic agents for brain injury using microbubbles in order to limit systemic side effects and reduce costs. .