LXR receptors mediate endogenous neuroprotection in acute experimental stroke

Abstract

Background and purpose: Liver X receptors (LXR ) and (LXR ), also known asNR1H3andNR1H2, respectively, are ligand-activated transcription factors that belong to the nuclearreceptor superfamily. Recent work has also identified LXRs as potent anti-inflammatorymolecules in macrophages and other immune cells. We have explored the endogenous role ofLXR receptors in acute stroke with genetic loss of LXR function by using LXR , -/- mice.Methods: Experimental ischemia was carried out by middle cerebral artery occlusion (MCAO)in wild type controls and Nr1h3-/-Nr1h2-/-double mutant (LXR , -/-) mice on a Sv129/C57BL/6background, obtained through a collaboration with Drs. David Mangelsdorf and Peter Tontonoz.Infarct size was determined by 2,3,5-triphenyltetrazolium chloride (TTC) staining. The effect ofexogenous LXR activation was studied by administration of the LXR agonists GW3965 (20mg/kg) 10 min after the ischemic occlusion. Neurological assesment was performed aspreviously described (Caso et al. Circulation 2007).Results: Administration of GW3965 reducedinfarct lesion in WT animals, whereas no significant changes were observed in LXR-deficientmice under the same experimental conditions. Interestingly, larger infarcted areas wereobserved in mice lacking both LXR isoforms when compared to control mice. Moreover, whenthe neurological test was applied to this set of mice, lower scores demonstrated a protectiveaction in WT mice treated with GW compound, whereas LXR , -/- mice showed poorneurological statusConclusion: These data show that an endogenous LXR activatory pathwayduring experimental stroke mediates a potent and natural protection, which could be causedby physiological LXR agonists such as oxysterols. This evidence also suggests that levels ofendogenous LXR agonists might serve as prognostic markers in stroke patients.