Abstract TP100: PGE2 EP1-4 Receptor Expression Levels After Intracerebral Hemorrhage in Young, Aged, and EP1 Deficient Mice

Abstract

Intracerebral hemorrhage (ICH) is the most severe form of stroke and is associated with high mortality and morbidity. Neuroinflammation significantly contributes to ICH-induced brain injury and upregulation of prostaglandin E 2 (PGE 2 ) has been implicated in modulating these deleterious neuroinflammatory pathways. PGE 2 acts on mainly the four G-protein-coupled E prostanoid (EP) receptors, EP1-4, which each have different downstream signaling pathways, tissue distributions, and expression profiles. We have previously demonstrated that EP1 receptor deletion promotes injury following ICH, whereas deletion of EP2 and EP3 is neuroprotective in an equivalent experimental approach. Here, we aimed to investigate the time course, brain sub-region expression profile, and relative level of EP1-4 mRNA expression in young (5-7mo) and aged (12-13mo) wildtype (WT) and EP1 receptor knockout (EP1 -/- ) mice. Following ICH or sham surgery, EP1-4 mRNA levels were assessed by RT-qPCR. Minimal EP1-4 expression changes are seen at 24h after ICH; although, EP2 (p=0.0.36) and EP4 (p=0.066) are 1.6X increased in the cortex of young WT mice. At 72h post-ICH, EP1 is 3.9x elevated in the cortex (p=0.0003) and 4.6x in the striatum (p=0.012). EP3 is also 1.6x elevated in the cortex (p=0.044). In the contralateral hemisphere, a mean 2.4x increase of EP1-4 (p<0.01) expression is seen. In contrast, at 72h after ICH, EP1 -/- mice have 0.53x reduced EP3 in the cortex (p=0.030) and 0.68x and 0.71x decreased EP3 (p=0.016) and EP4 (p=0.049), respectively, in the contralateral hemisphere. Aged EP1 -/- mice show significantly decreased expression levels of EP2-4 in nearly all areas (cortex, striatum, and contralateral hemisphere). Due to the contralateral differences, basal expression levels of EP2-4 were investigated in the EP1 -/- mice, where EP2 is 2.6x, 3.4x, and 3.8x increased in the cortex, hippocampus, and cerebellum; whereas, EP3 trended oppositely. These data indicate a cross-talk interaction between EP1 and the other EP receptors pre- and post-ICH and an association between age and EP receptor expression levels. A better understanding of EP receptor localization and dynamic expression levels after ICH will facilitate the development of effective pharmacological treatments.