Abstract 41: Targeting the Neurovascular Bed by Co-delivery of Therapeutics for Synergic Stroke Treatments
BACKGROUND: Due to the multifaceted pathology of neurovascular damage in stroke, providing combined therapies aimed at underline different mechanisms may be a promising strategy. We have demonstrated that echogenic liposomes (ELIP) can effectively deliver xenon (Xe), a N-methyl-D-aspartate receptor antagonist, into brain tissue for dose-dependent neuroprotection. This study evaluates the synergic therapeutic effects of ELIP delivering Xe with an anti-inflammatory gas, hydrogen sulfide (H2S), or a free radical scavenger, hydrogen (H2), in a rat stroke model.
METHODS: A gas mixture of 1% H2S with 99% Xe or 30% H2 with 70% Xe was loaded into ELIP by a pressurization-freeze method. Rats (n=25) undergoing 2-hour middle cerebral artery occlusion were then treated with low-dose Xe-ELIP, H2S/Xe-ELIP, or H2/Xe-ELIP, respectively, at 3 hours after stroke onset. One MHz low-amplitude (0.18 MPa) ultrasound was directed over the internal carotid artery to trigger gas release. Behavioral tests were conducted for three days following surgery. After sacrifice, brain sections were evaluated for infarction and apoptotic neuronal death using triphenyltetrazolium chloride (TTC) and TUNEL staining. Infarct size was evaluated as normalized infarct volume (%).
RESULTS: Strokes without treatment had an infarct size of 27± 6%. Strokes with Xe-ELIP treatment exhibited an infarct size of 20±4% (p=0.232 vs. no treatment). Strokes with H2S/Xe-ELIP and H2/Xe-ELIP treatments demonstrated a further infarct size reduction to 7.1±1.6% (p=0.017 vs. no treatment) and 8.8±1.9% (p=0.032 vs. no treatment), respectively. Neurologic behavior tests reflected infarct size.
CONCLUSIONS: In this study, using echogenic immunoliposomes as a vehicle, co-delivery of therapeutics targeting different mechanisms of neurovascular damage results in a synergic therapeutic effect. This methodology provides an avenue for evaluation of other synergic agents for use in acute stroke.
- © 2012 by American Heart Association, Inc.