title: Therapeutic time window and dose dependence of xenon delivered via echogenic liposomes for neuroprotection in stroke.
abstract: OBJECTIVE
  Neurologic 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.
  
  
  METHODS
  Xenon-containing echogenic liposomes were created by a previously developed pressurization-freezing method. Following right middle cerebral artery occlusion (2 h), animals were treated with Xe-ELIP at 2, 3, or 5 h to determine time window of therapeutic effect. The neuroprotectant dosage for optimal effect was evaluated 3 h after stroke onset. Expression of brain-derived neurotrophic factor (BDNF), protein kinase B (Akt), and mitogen-activated protein kinases (MAPK) was determined.
  
  
  RESULTS
  Xenon-containing echogenic liposomes administration for up to 5 h after stroke onset reduced infract size. Treatment groups given 7 and 14 mg/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.
  
  
  CONCLUSIONS
  This study demonstrates the therapeutic efficacy of Xe-ELIP administered within 5 h after stroke onset with an optimal dosage range of 7-14 mg/kg for maximal neuroprotection.
authors: Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors: Tao
authors: T
authors: Peng
authors: George L
authors: GL
authors: Britton
authors: Hyunggun
authors: H
authors: Kim
authors: Davide
authors: D
authors: Cattano
authors: Jaroslaw
authors: J
authors: Aronowski
authors: James
authors: J
authors: Grotta
authors: David D
authors: DD
authors: McPherson
authors: Shao-Ling
authors: SL
authors: Huang
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D008081:Liposomes; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000473:pathology / Q000517:prevention & control*; D013997:Time Factors; D014978:Xenon / Q000008:administration & dosage*
chemical_list: D008081:Liposomes; D018696:Neuroprotective Agents; D014978:Xenon
keywords: Cerebral ischemia; Liposomes; Neuroprotection; Stroke; Xenon
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