Therapeutic time window and dose dependence of xenon delivered via echogenic liposomes for neuroprotection in stroke.

AimsNeurologic impairment following ischemic injury complicates the quality of life for stroke survivors. Xenon (Xe) has favorable neuroprotective properties to modify stroke. Xe delivery is hampered by a lack of suitable administration strategies. We have developed Xe-containing echogenic liposomes (Xe-ELIP) for systemic Xe delivery. We investigated the time window for Xe-ELIP therapeutic effect and the most efficacious dose for neuroprotection. Molecular mechanisms for Xe neuroprotection were investigated. MethodsXenon-containing echogenic liposomes were created by a previously developed pressurization-freezing method. Following right middle cerebral artery occlusion (2h), animals were treated with Xe-ELIP at 2, 3, or 5h to determine time window of therapeutic effect. The neuroprotectant dosage for optimal effect was evaluated 3h after stroke onset. Expression of brain-derived neurotrophic factor (BDNF), protein kinase B (Akt), and mitogen-activated protein kinases (MAPK) was determined. ResultsXenon-containing echogenic liposomes administration for up to 5h after stroke onset reduced infract size. Treatment groups given 7 and 14mg/kg of Xe-ELIP reduced infarct size. Behavioral outcomes corresponded to changes in infarct volume. Xe-ELIP treatment reduced ischemic neuronal cell death via activation of both MAPK and Akt. Elevated BDNF expression was shown following Xe-ELIP delivery. ConclusionThis study demonstrates the therapeutic efficacy of Xe-ELIP administered within 5h after stroke onset with an optimal dosage range of 7-14mg/kg for maximal neuroprotection.