PPARs as new therapeutic targets for the treatment of cerebral ischemia/reperfusion injury.

Stroke is a leading cause of death and long-term disability in industrialized countries. Despite advances in understanding its pathophysiology, little progress has been made in the treatment of stroke. The currently available therapies have proven to be highly unsatisfactory (except thrombolysis) and attempts are being made to identify and characterize signaling proteins which could be exploited to design novel therapeutic modalities. The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that control lipid and glucose metabolism. PPARs regulate gene expression by binding with the retinoid X receptor (RXR) as a heterodimeric partner to specific DNA sequences, termed PPAR response elements. In addition, PPARs may modulate gene transcription also by directly interfering with other transcription factor pathways in a DNA-binding independent manner. To date, three different PPAR isoforms, designated α, β/ δ, and γ, have been identified. Recently, they have been found to play an important role for the pathogenesis of various disorders of the central nervous system and accumulating data suggest that PPARs may serve as potential targets for treating ischemic stroke. Activation of all PPAR isoforms, but especially of PPAR γ, was shown to prevent post-ischemic inflammation and neuronal damage in several in vitro and in vivo models, negatively regulating the expression of genes induced by ischemia/ reperfusion (I/R). This paper reviews the evidence and recent developments relating to the potential therapeutic effects of PPAR-agonists in the treatment of cerebral I/R injury

Editorial: Translational insights into mechanisms and therapy of organ dysfunction in sepsis and trauma

Multiple organ dysfunction or even failure after sepsis or trauma is due to a dysregulated host response. Currently, besides (surgical) source control (e.g., control of bleeding or drainage of abscesses) and administration of antimicrobial drugs, therapeutic approaches are limited to supportive care. Advances in our understanding of the key pathophysiological pathways involved in the excessive inflammation triggered by trauma, sepsis and/or ischemia-reperfusion have had limited impact. The 28 article in this Research Topic focus on the molecular mechanisms behind (hyper) inflammation after sepsis or trauma, with special emphasis on preclinical and translational studies that target potential organ-protective and/or -resuscitative therapeutic strategies. Most studies report rodent models of trauma and elective surgery (three articles), non-microbial hyper-inflammation induced with endotoxin exposure (LPS; seven articles) and chemical pancreatitis (one article), and cecal ligation and puncture-induced sepsis (six articles). Additional papers summarize investigations of human material (six articles) or fully-resuscitated large animal models (two articles). These article are complimented by four reviews and a commentary

Role of PPAR-δ in the development of zymosan-induced multiple organ failure: an experiment mice study

<p>Abstract</p> <p>Background</p> <p>Peroxisome proliferator-activated receptor (PPAR)-beta/delta is a nuclear receptor transcription factor that regulates gene expression in many important biological processes. It is expressed ubiquitously, especially white adipose tissue, heart, muscle, intestine, placenta and macrophages but many of its functions are unknown. Saturated and polyunsaturated fatty acids activate PPAR-beta/delta, but physiological ligands have not yet been identified. In the present study, we investigated the anti-inflammatory effects of PPAR-beta/delta activation, through the use of GW0742 (0,3 mg/kg 10% Dimethyl sulfoxide (DMSO) i.p), a synthetic high affinity ligand, on the development of zymosan-induced multiple organ failure (MOF).</p> <p>Methods</p> <p>Multiple organ failure (MOF) was induced in mice by administration of zymosan (given at 500 mg/kg, i.p. as a suspension in saline). The control groups were treated with vehicle (0.25 ml/mouse saline), while the pharmacological treatment was the administration of GW0742 (0,3 mg/kg 10% DMSO i.p. 1 h and 6 h after zymosan administration). MOF and systemic inflammation in mice was assessed 18 hours after administration of zymosan.</p> <p>Results</p> <p>Treatment with GW0742 caused a significant reduction of the peritoneal exudate formation and of the neutrophil infiltration caused by zymosan resulting in a reduction in myeloperoxidase activity. The PPAR-beta/delta agonist, GW0742, at the dose of 0,3 mg/kg in 10% DMSO, also attenuated the multiple organ dysfunction syndrome caused by zymosan. In pancreas, lung and gut, immunohistochemical analysis of some end points of the inflammatory response, such as inducible nitric oxide synthase (iNOS), nitrotyrosine, poly (ADP-ribose) (PAR), TNF- and IL-1as well as FasL, Bax, Bcl-2 and apoptosis, revealed positive staining in sections of tissue obtained from zymosan-injected mice. On the contrary, these parameters were markedly reduced in samples obtained from mice treated with GW0742</p> <p>Conclusions</p> <p>In this study, we have shown that GW0742 attenuates the degree of zymosan-induced non-septic shock in mice.</p