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The Journal of Neuroscience, March 25, 2009, 29(12):3875-3884; doi:10.1523/JNEUROSCI.5529-08.2009

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Cellular/Molecular
Synthesis of Lipoxin A₄ by 5-Lipoxygenase Mediates PPAR-Dependent, Neuroprotective Effects of Rosiglitazone in Experimental Stroke

Mónica Sobrado,^1 * Marta P. Pereira,^1 * Iván Ballesteros,¹ Olivia Hurtado,¹ David Fernández-López,¹ Jesús M. Pradillo,¹ Javier R. Caso,¹ José Vivancos,² Florentino Nombela,² Joaquín Serena,³ Ignacio Lizasoain,¹ and María A. Moro¹

¹Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, ²Departamento de Neurología, Hospital Universitario La Princesa, 28006 Madrid, and ³Unidad de Ictus, Hospital Dr. Josep Trueta, 17007 Girona, Spain

Correspondence should be addressed to Dr. Maria A. Moro, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain. Email: neurona{at}med.ucm.es

Peroxisome proliferator-activated receptors gamma (PPAR) are nuclear receptors with essential roles as transcriptional regulators of glucose and lipid homeostasis. PPAR are also potent anti-inflammatory receptors, a property that contributes to the neuroprotective effects of PPAR agonists in experimental stroke. The mechanism of these beneficial actions, however, is not fully elucidated. Therefore, we have explored further the actions of the PPAR agonist rosiglitazone in experimental stroke induced by permanent middle cerebral artery occlusion (MCAO) in rodents. Rosiglitazone induced brain 5-lipoxygenase (5-LO) expression in ischemic rat brain, concomitantly with neuroprotection. Rosiglitazone also increased cerebral lipoxin A₄ (LXA₄) levels and inhibited MCAO-induced production of leukotriene B4 (LTB₄). Furthermore, pharmacological inhibition and/or genetic deletion of 5-LO inhibited rosiglitazone-induced neuroprotection and downregulation of inflammatory gene expression, LXA₄ synthesis and PPAR transcriptional activity in rodents. Finally, LXA₄ caused neuroprotection, which was partly inhibited by the PPAR antagonist T0070907, and increased PPAR transcriptional activity in isolated nuclei, showing for the first time that LXA₄ has PPAR agonistic actions. Altogether, our data illustrate that some effects of rosiglitazone are attributable to de novo synthesis of 5-LO, able to induce a switch from the synthesis of proinflammatory LTB₄ to the synthesis of the proresolving LXA₄. Our study suggests novel lines of study such as the interest of lipoxin-like anti-inflammatory drugs or the use of these molecules as prognostic and/or diagnostic markers for pathologies in which inflammation is involved, such as stroke.

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Received Nov. 18, 2008; revised Feb. 14, 2009; accepted Feb. 19, 2009.

Correspondence should be addressed to Dr. Maria A. Moro, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain. Email: neurona{at}med.ucm.es

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