Published Online
on September 15, 2008

A more recent version of this article appeared on September 30, 2008

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Submitted on June 8, 2007
Accepted on July 29, 2008

Activation of Liver X Receptors Promotes Neuroprotection and Reduces Brain Inflammation in Experimental Stroke

Jesús R. Morales BPharm, Iván Ballesteros BSc, José Manuel Deniz BSc, Olivia Hurtado PhD, José Vivancos MD, PhD, Florentino Nombela MD, Ignacio Lizasoain MD, PhD, Antonio Castrillo PhD, and María A. Moro PhD^*

From the Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Madrid (J.R.M., I.B., O.H., I.L., M.A.M.); School of Medicine, Universidad de Las Palmas, Las Palmas de Gran Canaria (J.M.D., A.C.); and Hospital Universitario La Princesa, Madrid (J.V., F.N.), Spain.

^* To whom correspondence should be addressed. E-mail: neurona{at}med.ucm.es.

Background—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.

Methods and Results—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-B transcriptional activity. Loss of function studies using LXR,^-/- mice demonstrated that the effect of LXR agonists is receptor specific. Interestingly, infarcted brain area and inflammatory signaling were significantly extended in LXR,^-/- mice compared with control animals, indicating that endogenous LXR signaling mediates neuroprotection in this setting.

Conclusion—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.

Key words: cerebral ischemia • inflammation • nervous system • nuclear receptors

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Clinical Summaries
Circulation 2008 118: 1403-1404. [Extract] [Full Text]

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