GW0742

GW0742 is a synthetic, potent and selective PPAR-β/δ agonist. PPARs are ligand-dependent transcription factors which are involved in many physiological processes, such as inflammation and energy homeostasis. PPAR-β/δ is one of three PPARs in the nuclear hormone receptor superfamily that are collectively involved in the control of lipid homoeostasis among other functions. GW0742 can attenuate the increase of PARP activity that caused by SAO shock. GW0742 is also able to prevent radiation-induced brain injury in C57Bl/6 wild-type (WT) and PPARδ knockout (KO) mice. Dietary GW0742 can prevent the acute increase in IL-1β mRNA and ERK phosphorylation measured at 3 h after a single 10-Gy dose of WBI as well as the increase in the number of activated hippocampal microglia 1 week after WBI.

Reference

Rosanna Di Paola, Emanuela Esposito, Emanuela Mazzon, Irene Paterniti, Maria Galuppo, Salvatore Cuzzocrea. GW0742, a selective PPAR-β/δ agonist, contributes to the resolution of inflammation after gut ischemia/reperfusion injury. August 2010. Journal of Leukocyte Biology. vol. 88 no. 2 291-301

Caroline I. Schnegg, Dana Greene-Schloesser, Mitra Kooshki, Valerie S. Payne, Fang-Chi Hsud, Mike E. Robbins. hippocampal-dependent cognitive impairment after whole-brain irradiation. Free Radical Biology and Medicine. Volume 61, August 2013, Pages 1–9.

Pulmonary Administration of GW0742, a High-Affinity Peroxisome Proliferator-Activated Receptor Agonist, Repairs Collapsed Alveoli in an Elastase-Induced Mouse Model of Emphysema.[Pubmed:27150147]

Biol Pharm Bull. 2016;39(5):778-85.

Pulmonary emphysema is a disease in which lung alveoli are irreversibly damaged, thus compromising lung function. Our previous study revealed that all-trans-retinoic acid (ATRA) induces the differentiation of human lung alveolar epithelial type 2 progenitor cells and repairs the alveoli of emphysema model mice. ATRA also reportedly has the ability to activate peroxisome proliferator-activated receptor (PPAR) beta/delta. A selective PPARbeta/delta ligand has been reported to induce the differentiation of human keratinocytes during wound repair. Here, we demonstrate that treatment using a high-affinity PPARbeta/delta agonist, GW0742, reverses the lung tissue damage induced by elastase in emphysema-model mice and improves respiratory function. Mice treated with elastase, which collapsed their alveoli, were then treated with either 10% dimethyl sulfoxide (DMSO) in saline (control group) or GW0742 (1.0 mg/kg twice a week) by pulmonary administration. Treatment with GW0742 for 2 weeks increased the in vivo expression of surfactant proteins A and D, which are known alveolar type II epithelial cell markers. GW0742 treatment also shortened the average distance between alveolar walls in the lungs of emphysema model mice, compared with a control group treated with 10% DMSO in saline. Treatment with GW0742 for 3 weeks also improved tissue elastance (cm H2O/mL), as well as the ratio of the forced expiratory volume in the fi rst 0.05 s to the forced vital capacity (FEV 0.05/FVC). In each of these experiments, GW0742 treatment reversed the damage caused by elastase. In conclusion, PPARbeta/delta agonists are potential therapeutic agents for pulmonary emphysema.

PPARdelta agonist GW0742 ameliorates Abeta1-42-induced hippocampal neurotoxicity in mice.[Pubmed:26864581]

Metab Brain Dis. 2016 Jun;31(3):663-71.

Amyloid-beta deposition is thought to be associated with memory deficits, neuroinflammation, apoptotic responses, and progressive neuronal death manifested in Alzheimer's disease. Peroxisome proliferator-activated receptor delta (PPARdelta) is a transcription factor with potent anti-inflammatory effect. In the current study, the effect of GW0742, a selective PPARdelta agonist, on Abeta1-42-induced neurotoxicity was investigated in the hippocampus of mice. Intra-hippocampal infusion of aggregated Abeta1-42 oligomer (410pmol/mouse) remarkably damaged learning and memory in the Morris water maze (MWM) and Y-maze tests, accompanied by decreased expression of PPARdelta in the hippocampus as confirmed by Western blot. Intra-hippocampal infusion of GW0742 (1.06 mM/mouse) significantly improved Abeta1-42-induced memory deficits in mice, reversed Abeta1-42-induced hippocampal PPARdelta down-regulation and repressed Abeta1-42-triggered neuroinflammatory and apoptotic responses, indicated by decreased nuclear NF-kappaB p65, TNF-alpha, IL-1beta as well as a decrease in cleaved caspase-3 and increased ratio of Bcl-2/Bax in the hippocampus. These results suggest that PPARdelta activation ameliorates Abeta1-42-induced hippocampal neurotoxicity, and it might play a crucial role in Alzheimer's disease.

Effect of PPAR-beta/delta agonist GW0742 treatment in the acute phase response and blood-brain barrier permeability following brain injury.[Pubmed:27818230]

Transl Res. 2017 Apr;182:27-48.

The systemic response to ischemic stroke is associated with the hepatic acute phase response (APR) that modulates leukocytes recruitment to the injured brain. The inappropriate recruitment of leukocytes to the brain parenchyma can result in blood-brain barrier (BBB) breakdown. Emerging data suggest that peroxisome proliferator-activated receptor beta/delta (PPAR-beta/delta) activation has a potential neuroprotective role in ischemic stroke. However, mechanisms of PPAR-beta/delta mediated protection in ischemic insults remain unclear. In the present study, we determined for the first time, the effects of GW0742, a PPAR-beta/delta agonist on the APR following brain injury and assessed the effects on BBB permeability and tight junction integrity via claudin-5, occludin, and zona occludens-1 expression. C57/BL6 mice were exposed to 1 hour of ischemia and received 10 minutes before reperfusion either a vehicle solution or GW0742. Hepatic expression of chemokines (C-X-C motif ligand: CXCL1, CXCL2, and CXCL10), serum amyloid A-1, tumor necrosis factor alpha, interleukin-1beta, and interleukin-6 was measured, and the extent of brain and hepatic neutrophil infiltration was determined. The results showed that GW0742 treatment decreased infarct volume and edema, reactant production and neutrophil recruitment to the brain and liver, which is a hallmark of the APR. GW0742 significantly reduced BBB leakage and metalloproteinase 9 expression and upregulated the expression of tight junction proteins. These findings may help to guide the experimental and clinical therapeutic use of PPAR-beta/delta agonists against brain injury.

The Non-Genomic Effects of the PPARbetagamma Agonist GW0742 on Streptozotocin Treated Rat Aorta.[Pubmed:28034288]

Curr Mol Pharmacol. 2018;11(2):149-154.

BACKGROUND: The ubiquitous nuclear receptor PPARbeta/delta is increasingly being studied in regards to numerous diseases including diabetes following on the finding that PPARbeta/delta agonist GW0742 controls Type 1 Diabetes in rats. Studies have shown that GW0742 has off target, non- PPARbeta/delta effects in the cell although there are some key questions that remain to be addressed in respect to the significance of this control on vascular tone. METHODS: Using isometric organ baths, rat aorta rings were exposed to ROCK inhibitors and the changes in contraction and dilation measured. RESULTS: Our data shows that the PPARbeta/delta agonist GW0742 (10-7M) inhibits contractile responses to U46619 and phenylephrine, and that these responses are similar in normal and Streptozotocin (STZ) diabetic rat aorta. ROCK inhibitors Fasudil and Y27632 significantly reduced GW0742 mediated dilation of naive rat aorta, but Fasudil had no effect on GW0742 dilation in STZ diabetic rat aorta. In contrast, STZ diabetic rat aorta pre-contracted with high [K+] Krebs lacked a dilatory response to GW0742, which taken together indicates that the mechanism of action of GW0742 mediated dilation changes in the diabetic state compared to non-diabetic state. CONCLUSION: This is the first direct evidence demonstrating the non- PPARbeta/delta effect of GW0742 on contraction is irrespective to the diabetic state, and that GW0742 has the potential to induce vasodilation via multiple off-target mechanisms.

Effect of the peroxisome proliferator-activated receptor beta activator GW0742 in rat cultured cerebellar granule neurons.[Pubmed:15211590]

J Neurosci Res. 2004 Jul 15;77(2):240-9.

The ligand-activated transcription factor peroxisome proliferator-activated receptor beta (PPARbeta) is present in the brain and is implicated in the regulation of genes with potential roles in neurotoxicity. We sought to examine the role of PPARbeta in neuronal cell death by using the PPARbeta ligand GW0742. Primary cultures of rat cerebellar granule neurons were prepared from 7-day-old pups. Reverse transcriptase-polymerase chain reaction and in situ hybridization were used to verify that PPARbeta mRNA was present in neurons. After 10-12 days in culture, the neuronal cells were incubated in the presence of GW0742, and cell death was measured with a lactate dehydrogenase release (LDH) assay. After 24 hr of exposure, PPARbeta activation by GW0742 was not inherently toxic to cerebellar granule neurons. However, toxicity was observed after 48 hr, with cell death mediated via an apoptotic mechanism. In an effect opposite to that observed with PPARalpha-activating ligands, PPARbeta activation exhibited neuroprotective properties. Treatment with GW0742 significantly reduced cell death during a 12-hr exposure to low-KCl media. These results clearly reinforce very specific roles for the PPAR isoforms in neurons and suggest that PPARbeta is worthy of further investigation regarding its potential role as a therapeutic target in neurodegenerative states.

Novel selective small molecule agonists for peroxisome proliferator-activated receptor delta (PPARdelta)--synthesis and biological activity.[Pubmed:12699745]

Bioorg Med Chem Lett. 2003 May 5;13(9):1517-21.

We report the synthesis and biological activity of a new series of small molecule agonists of the human Peroxisome Proliferator-Activated Receptor delta (PPARdelta). Several hits were identified from our original libraries containing lipophilic carboxylic acids. Optimization of these hits by structure-guided design led to 7k (GW501516) and 7l (GW0742), which shows an EC(50) of 1.1 nM against PPARdelta with 1000-fold selectivity over the other human subtypes.

GW0742 is a potent PPARβ and PPARδ agonist, with an IC50 of 1 nM for human PPARδ in binding assay, and EC50s of 1 nM, 1.1 μM and 2 μM for human PPARδ, PPARα, and PPARγ, respectively.

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