Abstract WP105: Therapeutic Time Window for Conivaptan Treatment of Cerebral Edema and Blood-Brain Barrier Breakdown in Mice

Abstract

Introduction: Stroke is complicated by brain edema, blood-brain barrier (BBB) disruption, and is often accompanied by increased release of arginine-vasopressin (AVP). AVP, acting through V1a and V2 receptors can trigger hyponatremia, vasospasm, and platelet aggregation which can exacerbate brain edema. We recently reported that conivaptan, V1a and V2 receptor blocker, reduces stroke-evoked brain edema and blood-brain barrier (BBB) disruption in mice when administered immediately after reperfusion. However, these pre-clinical results can be translated into clinical applications if the therapeutic time window for conivaptan is explored. Hypothesis: We hypothesized that conivaptan will alleviate brain edema and BBB disruption even if the treatment is delayed. Methods: Mice underwent the filament model of middle cerebral artery occlusion (MCAO) with reperfusion. After 60 minutes occlusion, mice were recovered and randomly allocated into the following groups: conivaptan or vehicle-treated at 3 or 5 hours after MCAO. Treatments were administered via a jugular catheter and continued for 48 hours. Physiological variables, plasma and urine sodium and osmolality, brain water content (BWC) and Evans Blue (EB) extravasation were evaluated at the end point. Results: Conivaptan produced aquaresis as indicated by changes in plasma and urine sodium and osmolality. Conivaptan treatment, when initiated at 3 hours after MCAO reduced BWC in the ipsilateral hemisphere from 80.2 ± 0.2% (vehicle) to 78.1 ± 0.1% (p < 0.05 vs vehicle, n=10), and attenuated the EB extravasation index from 1.3 ± 0.2 (vehicle) to 1.01 ± 0.1 (p < 0.05, n=5-7). However, a 5-hour delay of conivaptan treatment after MCAO did not affect ipsilateral BWC (n=10). Conclusion: A 3-hour delay of conivaptan treatment after experimental stroke is effective at reducing brain edema and protecting BBB integrity. Further delay of treatment up to 5 hours after stroke abolishes the beneficial effect of conivaptan on postischemic brain edema. In conclusion, these results present an opportunity for potential use of conivaptan to treat post-ischemic brain edema in ICU patients.