gw-3965 and Stroke

GW3965, a synthetic liver X receptor agonist, elevates high-density lipoprotein cholesterol and has antiatherosclerosis and anti-inflammation properties. We tested the hypothesis that GW3965 treatment of stroke increases vascular remodeling, promotes synaptic protein expression and axonal growth in the ischemic brain, and improves functional outcome in mice.. Mice were subjected to transient middle cerebral artery occlusion and treated without or with different doses of GW3965 (5, 10, or 20 mg/kg) starting 24 hours after middle cerebral artery occlusion daily for 14 days. Neurological functional tests, blood high-density lipoprotein cholesterol measurement, and immunostaining were performed. Mouse brain endothelial cells, primary cultured artery explants, and primary cortical neurons cultures were also used in vitro.. GW3965 treatment of stroke significantly increased blood high-density lipoprotein cholesterol level, synaptic protein expression, axonal density, angiogenesis and arteriogenesis, and Angiopoietin1, Tie2, and occludin expression in the ischemic brain and improved functional outcome compared with middle cerebral artery occlusion control animals (n=10; P<0.05). In vitro, GW3965 and high-density lipoprotein cholesterol also significantly increased capillary-like tube formation and artery explant cell migration as well as neurite outgrowth. Inhibition of Angiopoietin-1 attenuated GW3965-induced tube-formation, artery cell migration, and neurite outgrowth (n=6 per group; P<0.05).. These data indicate, for the first time, that GW3965 promotes synaptic protein expression and axonal growth and increases vascular remodeling, which may contribute to improvement of functional outcome after stroke. Increasing Angiopoietin-1/Tie2 signaling activity may play an important role in GW3965-induced brain plasticity and neurological recovery from stroke.

Topics: Animals; Axons; Benzoates; Benzylamines; Cells, Cultured; Cholesterol, HDL; Ligands; Liver X Receptors; Male; Mice; Mice, Inbred C57BL; Organ Culture Techniques; Orphan Nuclear Receptors; Random Allocation; Recovery of Function; Stroke; Treatment Outcome

The liver X receptors (LXRs) belong to the nuclear receptor superfamily and act as transcriptional regulators of cholesterol metabolism in several tissues. Recent work also has identified LXRs as potent antiinflammatory molecules in macrophages and other immune cells. Combined changes in lipid and inflammatory profiles are likely mediating the protective role of LXRs in models of chronic injury like atherosclerosis. These beneficial actions, however, have not been illustrated in other models of acute injury such as stroke in which inflammation is an important pathophysiological feature.. We have studied LXR expression and function in the course of experimental stroke caused by permanent middle cerebral artery occlusion in rats and mice. Here, we show that administration of the synthetic LXR agonists GW3965 or TO901317 after the ischemic occlusion improves stroke outcome as shown by decreased infarct volume area and better neurological scores in rats. Neuroprotection observed with LXR agonists correlated with decreased expression of proinflammatory genes in the brain and with reduced nuclear factor-kappaB transcriptional activity. Loss of function studies using LXRalpha,beta(-/-) mice demonstrated that the effect of LXR agonists is receptor specific. Interestingly, infarcted brain area and inflammatory signaling were significantly extended in LXRalpha,beta(-/-) mice compared with control animals, indicating that endogenous LXR signaling mediates neuroprotection in this setting.. This work highlights the transcriptional action of LXR as a protective pathway in brain injury and the potential use of LXR agonists as therapeutic agents in stroke.

Topics: Animals; Benzoates; Benzylamines; Brain; Brain Ischemia; DNA-Binding Proteins; Inflammation; Liver X Receptors; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Neuroprotective Agents; Orphan Nuclear Receptors; Rats; Rats, Inbred F344; Receptors, Cytoplasmic and Nuclear; Stroke