Abstract TP321: Role of PGE 2 EP1 Receptor Antagonist on Stroke Outcomes in Alzheimer Disease Mouse Models

Abstract

Background: AD is the most common memory disorder and its prevalence is expected to triple by the year 2050. Neuroinflammation is recognized as an important player in the pathogenesis of AD. One of the most recognized pathways in mediating the neuroinflammation is of prostaglandin E 2 (PGE 2 ) EP1 receptor pathway. Role of PGE 2 EP1 receptor in AD mouse models following stroke has not been studied. In this study, we examined the efficacy of a selective EP1 antagonist, ONO-8713, on lesion volumes and behavioral indexes in AD mouse models after stroke. Methods: Two cohorts of transgenic, APP/PS1 and 3xTg, and wildtype (WT) mice were subjected to permanent distal middle cerebral artery occlusion (pdMCAO) and sham surgeries. EP1 antagonist ONO-8713 or vehicle was then administered to analyze its effect on anatomical and functional outcomes. Results: The functional outcomes were significantly deteriorated in the APP/PS1 and the 3xTg mice after stroke. Interestingly, the ONO-8713-treated groups of WT mice performed significantly (p<0.001) better in open field test than the respective groups of 3xTg mice. For the passive avoidance test, APP/PS1+ONO-8713 mice exhibited significant (p<0.05) difference in retention as compared with the vehicle group; whereas, there was a significant difference in acquisition between WT+ONO-8713 and 3xTg+ONO-8713 (p<0.05). There was a significantly lower tissue injury in APP/PS1+Veh mice when compared to the APP/PS1+ONO-8713 mice (p<0.02). Percent tissue injury was significantly higher in APP/PS1+ONO-8713 mice when compared to WT+ONO-8713 mice (p<0.05). Similarly, in the 3xTg cohort, percent tissue injury and percent tissue loss were significantly higher in 3xTg+ONO-8713 mice than in WT+ONO-8713 mice (p<0.02). Conclusion: The EP1 receptor antagonist ONO-8713 shows some beneficial effects on functional and anatomical outcomes after stroke in APP/PS1 and 3xTg mice models of AD; though, the effects were not significant in all outcomes investigated. Further studies are needed to understand the role and optimal timing of EP1 receptor blockade in the context of AD etiopathology. Funding support: Grants from the São Paulo Research Foundation, FAPESP (FRM), NIH, and the Ed and Ethel Moore Alzheimer's Disease Research Program (SD).