Abstract T P225: Loss of Pregnane X Receptor Impairs Stroke Recovery

Abstract

Introduction: Inflammation plays an important role in exacerbating injury following stroke, but current understanding of the factors regulating this inflammation is incomplete. Pregnane X Receptor (PXR) is a nuclear receptor which binds many xenobiotic targets including many commonly prescribed medications. Recent work has shown that PXR is crucial for maintaining the integrity of the intestinal epithelial barrier as well repressing inflammatory responses mediated by NFκB. Since both these pathways can modify the peripheral immune response, we hypothesized that PXR would play an important role in limiting inflammation following stroke. Using PXR knockout mice, we show that loss of PXR is detrimental for stroke recovery. Materials & Methods: Male PXR knockout mice and littermate controls underwent sham surgery or 60min middle cerebral artery occlusion (MCAO). Weight loss was monitored post-stroke and mice were sacrificed after 7 days for splenic weights, infarct analysis by cresyl violet staining, and bacterial translocation as assessed by culture of homogenized mesenteric lymph nodes on blood agar plates. Results: Following MCAO, PXR-/- mice lost significantly more weight than wild type littermate controls (n=6 vs. 4 respectively; p<0.05) and also showed greater splenic atrophy 7 days following MCAO (2.14mg/g body weight vs. 3.40mg/g body weight; p<0.05). However, preliminary studies suggest PXR-/- mice do not have larger infarcts (n=3 vs. 2) and did not exhibit more bacterial translocation 7 days following MCAO (5.4 vs. 7 CFU). Discussion: PXR is known to negatively regulate NFκB signaling and maintain intestinal barrier integrity. Both of these mechanisms may contribute to delayed recovery following stroke with PXR acting as a master switch. In summary, this early work begins to explore the importance of a xenobiotic sensor, PXR, in stroke recovery.