Abstract TP346: Pge2 Ep1-4 Temporospatial Expression Level Changes in the Brain After Intracerebral Hemorrhage in Young, Aged, and Ep1 Deficient Mice Suggests Cross-talk Interactions

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Abstract

Intracerebral hemorrhage (ICH) is the most severe form of stroke with the highest mortality. Neuroinflammation contributes to ICH-induced brain injury and the upregulation of prostaglandin E2 (PGE2) has been implicated in modulating these deleterious pathways. PGE2 acts mainly on four G-protein-coupled E Prostanoid (EP) receptors, EP1-4, each having different downstream pathways, tissue distributions, and expression profiles. Our previous studies demonstrate that EP1 receptor deletion promotes injury following ICH; whereas, deletion of EP2 and EP3 is neuroprotective in an equivalent 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-/- mice. Following ICH or sham surgery, EP1-4 mRNA levels were assessed by RT-qPCR whereby the relative fold change of the gene of interest were determined using the reference gene Tbp and the 2-ΔΔCT method relative to the control. Minimal EP1-4 expression changes are seen at 24h after ICH; although, EP2 (p=0.036) 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. Aged EP1-/- mice show significantly decreased expression levels of EP2-4 in nearly all areas. 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 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 spark the development of effective pharmacological treatments.

Funding: NIH F31NS086441 (JLL) and R01NS046400 (SD)

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