Abstract W P235: The Nuclear Receptors FXR and Nur77 Exhibit Neuroprotective Effects in the Ischemic Mouse Brain

Introduction: FXR and Nur77, members of the nuclear hormone superfamily, have been shown to modulate pro- and anti-inflammatory responses by immune cells, such as macrophages or T cells. As ischemic stroke induces an inflammatory response accompanied by activation and recruitment of immune cells, the aim of this study was to investigate the influence of nuclear receptors Nur77, FXR as well as FXR activation by the agonist GW4064 in cerebral ischemia-reperfusion (I/R) injury. Methods: Transient middle cerebral ischemia (MCAO) was induced in adult mice assigned to 4 groups: placebo, Nur77-deficient, FXR-deficient and FXR-ligand GW4064-treated (each n=7-8). A priori survival-time was set to 72 hours. Mice underwent functional tests and histological studies were performed for evaluation of infarct volume, immune cell activation/immigration and neuronal apoptosis. Results: MCAO led to delayed (24-48h after I/R) but severely worsened functional outcome in Nur77 and FXR-ko mice compared to wildtype animals (p<0.001, ANOVA+Bonferroni post-hoc). FXR- and Nur77-ko mice developed increased infarct volumes (Nur77, p<0.05) and had elevated TUNEL+-cell counts within the ischemic lesion (FXR, p<0.05). In contrast, treatment with FXR-agonist GW4064 resulted in improved functional outcome compared to placebo-treated mice. Evaluation of microglia and monocytes/macrophages showed an increased F4/80+-cell count 72h following MCAO in GW4064-treated mice. Conclusion: Deficiency of nuclear receptors Nur77 and FXR significantly worsened functional outcome, increased infarct size and cell apoptosis, whereas treatment with nuclear receptor agonist GW4064 led to improved rotarod performance and altered F4/80+-immune cell response. These results suggest a crucial involvement of the nuclear receptors Nur77 and FXR in pathways relating to post-stroke inflammation and tissue damage development.