Synthesis of Lipoxin A4 by 5-Lipoxygenase Mediates PPARγ-Dependent, Neuroprotective Effects of Rosiglitazone in Experimental Stroke

Peroxisome proliferator-activated receptorsgamma(PPAR gamma) are nuclear receptors with essential roles as transcriptional regulators of glucose and lipid homeostasis. PPAR gamma are also potent anti-inflammatory receptors, a property that contributes to the neuroprotective effects of PPAR gamma 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 gamma 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 A(4) (LXA(4)) levels and inhibited MCAO-induced production of leukotriene B-4 (LTB4). Furthermore, pharmacological inhibition and/or genetic deletion of 5-LO inhibited rosiglitazone-induced neuroprotection and downregulation of inflammatory gene expression, LXA(4) synthesis and PPAR gamma transcriptional activity in rodents. Finally, LXA(4) caused neuroprotection, which was partly inhibited by the PPAR gamma antagonist T0070907, and increased PPAR gamma transcriptional activity in isolated nuclei, showing for the first time that LXA(4) has PPAR gamma 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 LXA(4). 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.