Xenon As A Therapeutic in Experimental Intracerebral Hemorrhage

Duke University, Durham NC

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Abstract

? DESCRIPTION: Xenon (Xe) is an inert gas, which has undergone intensive preclinical investigation as a brain injury therapeutic. Xe is currently under investigation in humans as an adjunct to hypothermia for treatment of anoxic birth and adult cardiac arrest brain insults. Xe offers major advantages to injured brain: 1) Rapid blood-brain barrier penetration and therapeutic onset, 2) modulation of the NMDA glycine recognition site and TREK-1 channels without psychotomimetic effects, and 3) negligible effects on intracranial pressure and cardiovascular function. Neuroresuscitative Xe doses are sub-hypnotic and can be delivered by face mask or endotracheal tube. Xe is rapidly eliminated allowing full reversal of intervention within minutes and titration to effect. We investigated Xe in a rodent transient focal ischemic stroke model. While post-ischemic Xe improved short-term outcome, long-term outcome was improved only when Xe was combined with reduction of brain temperature to 36C. This offered sufficient clinical relevance to lead us to explore the effect of Xe in 2 different mouse intracerebral hemorrhage (ICH) models. The goal was to rule out potential adverse effects of Xe in ICH should treatment be initiated prior to diagnostic imaging for ischemic stroke allowing thromoblysis. To the contrary, Xe improved ICH functional outcome and decreased brain edema and microglial activation. We repeated the ICH experiments with MRI-defined lesion volume. Efficacy persisted along with the finding of decreased hydrocephalus. We have since provided preliminary efficacy data in aged rats. Medical grade Xe and toxicology analysis are complete. The work proposed herein will advance Xe through preclinical studies using RIGOR criteria to enable IND status for ICH. We will address the following essential questions: 1) Optimal dosing strategy (dose, treatment duration, and therapeutic window), 2) Efficacy in hypertensive rats, 3) Independence of efficacy from incidental hypothermia, 5) Efficacy in both males and females, 6) Efficacy in aged animals, 7) Durability of efficacy over extended recovery intervals, and 8) Explore biomarkers associated with Xe efficacy. We believe that should Xe continue to prove efficacious in the context of clinically relevant preclinical treatment ICH exposures, opportunity to rapidly advance Xe to clinical trials is major.