Abstract T MP70: Genetic Deletion of the Prostaglandin E2 EP3 Receptor Improves Outcomes after Experimental Intracerebral Hemorrhage in Young and Old Mice
Intracerebral hemorrhage (ICH) is a type of hemorrhagic stroke associated with high mortality and morbidity rates. Prolonged and unbalanced inflammatory responses after hemorrhagic stroke may negatively contribute to secondary brain injury. Prostaglandin E2 (PGE2) is an important mediator of inflammation and plays a role in several neurologic disorders. PGE2 has selective high affinity toward its membrane-bound G-protein-coupled receptors EP1, EP2, EP3, and EP4, which together arbitrate its neuromodulatory effects. We have previously shown in a middle cerebral artery occlusion model of ischemia/reperfusion-induced brain injury and a striatal NMDA-induced excitotoxicity model that mice pretreated intracerebroventricularly with a selective EP3 receptor agonist have larger brain lesions when compared to control mice. In the present study, we investigated whether EP3 receptor deletion (EP3-/-) would lead to improved anatomical and functional outcomes in young (2-4mo) and aged (22-24mo) C57BL/6 mice after inducing a hemorrhagic stroke using the collagenase model of ICH (n=8-10 for all groups). Neurobehavioral testing, including video-recording of home cage activity and neurological deficit scoring was performed at 24h, 48h, and 72h post-ICH. At 72h, mice were transcardially perfused and brains isolated for Cresyl Violet staining and lesion volume quantification. In both young and aged mice, smaller brain lesion volumes were seen for the EP3-/- when compared to age-matched wildtype controls (p<0.05). Further, the aged EP3-/- displayed significantly better neurologic recovery at 72h, as identified by both behavioral tests (p<0.01). Interestingly, the aged EP3-/- showed significantly reduced ambulatory and stereotypic activity at 24h post-ictus (p<0.005). No significant behavioral differences were seen in the young cohort. Collectively, these results indicate a dynamic role of the EP3 receptor in mediating anatomical and functional outcomes following ICH. Additional studies are needed in order to clarify the mechanisms involved and identify potential therapeutic paradigms for alleviating the initial PGE2-EP3 receptor associated toxicity and promoting its later beneficial effects.
Author Disclosures: J.L. Leclerc: None. M. Diller: None. A. Lampert: None. S. Doré: None.
- © 2015 by American Heart Association, Inc.