Delivery of xenon-containing echogenic liposomes inhibits early brain injury following subarachnoid hemorrhage

David D Mcpherson,Shao-Ling Huang,Yi-Feng Miao,Hyunggun Kim,Melanie R Moody,Jaroslaw Aronowski,Melvin E Klegerman,James Grotta,Tao Peng

doi:10.1038/s41598-017-18914-6

Abstract

Xenon (Xe), a noble gas, has promising neuroprotective properties with no proven adverse side-effects. We evaluated neuroprotective effects of Xe delivered by Xe-containing echogenic liposomes (Xe-ELIP) via ultrasound-controlled cerebral drug release on early brain injury following subarachnoid hemorrhage (SAH). The Xe-ELIP structure was evaluated by ultrasound imaging, electron microscopy and gas chromatography-mass spectroscopy. Animals were randomly divided into five groups: Sham, SAH, SAH treated with Xe-ELIP, empty ELIP, or Xe-saturated saline. Treatments were administrated intravenously in combination with ultrasound application over the common carotid artery to trigger Xe release from circulating Xe-ELIP. Hematoma development was graded by SAH scaling and quantitated by a colorimetric method. Neurological evaluation and motor behavioral tests were conducted for three days following SAH injury. Ultrasound imaging and electron microscopy demonstrated that Xe-ELIP have a unique two-compartment structure, which allows a two-stage Xe release profile. Xe-ELIP treatment effectively reduced bleeding, improved general neurological function, and alleviated motor function damage in association with reduced apoptotic neuronal death and decreased mortality. Xe-ELIP alleviated early SAH brain injury by inhibiting neuronal death and bleeding. This novel approach provides a noninvasive strategy of therapeutic gas delivery for SAH treatment.

Highlights

Subarachnoid hemorrhage (SAH) is a medical emergency with high mortality
We have demonstrated the neuroprotective effect of Xe-containing echogenic liposomes (Xe-ELIP) in ischemic stroke following intravenous administration of Xe-ELIP in association with ultrasound application over the carotid arteries to trigger Xe release from Xe-ELIP15
Little acoustic reflectivity was found in traditional liposomes (Fig. 1a), while high acoustic reflectivity was shown in Xe-containing ELIP (Fig. 1b) demonstrating the existence of Xe bubbles in Xe-ELIP

Summary

Introduction

Subarachnoid hemorrhage (SAH) is a medical emergency with high mortality. Epidemiologic studies have shown that the overall mortality rates range from 32–67%, with 10–20% of these patients dying before reaching hospital, 33% dying within 48 hours, and 40–60% dying within 30 days following SAH onset[1]. A recent multicenter clinical trial indicates that prevention of delayed vasospasm does not improve mortality and morbility in SAH patients[4,5] This finding has focused the role of stabilization of early brain injury resulting from SAH. If a neuroprotective agent providing high diffusion into the hypoperfused brain with low systemic side effects in combination with a novel therapeutic delivery method for enhanced local release could be developed, it would have great potential for early treatment of SAH at the time of first response prior to neurological evaluation and treatment in the hospital setting. We investigated the neuroprotective effects of Xe-ELIP delivery in treatment of early brain injury following SAH

Methods

Results

Conclusion