GW1929

IC50: 5.0 μM

GW1929 is a nonthiazolidinedione PPARγ agonist. Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors with three isoforms: PPARα, PPARγ, and PPARβ/δ. Among these, PPARγ is highly expressed in various brain regions. A growing evidences have suggested that PPARγ play a key role in pathogenesis of cerebral IR injury

In vitro: GW1929 was tested on currents through L-type voltage-dependent calcium channels (VDCC) in freshly isolated smooth muscle cells. Using Ba2+ as the charge carrier through VDCC, the IC50s for GW1929 and pioglitazone were determined to be 5.0 +/- 0.7 and 10.0 +/- 0.8 μM, respectively. GW1929 and pioglitazone were both effective on inhibiting VDCC and relaxing pressurized arteries, indicating the vasodilation of resistance arteries might be explained by the inhibition of calcium entry through VDCC [1].

In vivo: GW1929 treatment attenuated the neurological damage in focal cerebral IR injury significantly. In addition, the neuroprotective effects of GW1929 were found to be associated with significant reduction in the levels of MMP-9, COX-2, iNOS, TNFα and IL-6. Neuroprotective effects of GW1929 related with significant reduction in TUNEL positive cells in IR challenged brain [2].

Clinical trial: N/A

References:
[1] Heppner TJ,Bonev AD,Eckman DM,Gomez MF,Petkov GV,Nelson MT. Novel PPARgamma agonists GI 262570, GW 7845, GW 1929, and pioglitazone decrease calcium channel function and myogenic tone in rat mesenteric arteries. Pharmacology.2005 Jan;73(1):15-22.
[2] Kaundal RK,Sharma SS.  Ameliorative effects of GW1929, a nonthiazolidinedione PPARγ agonist, on inflammation and apoptosis in focal cerebral ischemic-reperfusion injury. Curr Neurovasc Res.2011 Aug 1;8(3):236-45.

PPAR-gamma agonist GW1929 but not antagonist GW9662 reduces TBBPA-induced neurotoxicity in primary neocortical cells.[Pubmed:24132472]

Neurotox Res. 2014 Apr;25(3):311-22.

Tetrabromobisphenol A (2,2-bis(4-hydroxy-3,5-dibromophenyl)propane; TBBPA) is a widely used brominated flame retardant. TBBPA induces neuronal damage, but the mechanism by which this occurs is largely unknown. We studied the possible involvement of peroxisome proliferator-activated receptor gamma (PPAR-gamma) in TBBPA-induced apoptosis and toxicity in mouse primary neuronal cell cultures. TBBPA enhanced both, caspase-3 activity and lactate dehydrogenase (LDH) release in neocortical cells after 6 and 24 h of exposition. These data were supported at the cellular level with Hoechst 33342 staining. Immunoblot analyses showed that, compared with control cells, 10 muM TBBPA decreased the expression of PPAR-gamma protein in neocortical neurons after 1-24 h of exposure. Co-treatment with TBBPA and GW1929 inhibited the TBBPA-induced caspase-3 activity, apoptotic body formation, and LDH release as well as TBBPA-induced decrease in PPAR-gamma protein expression. Thus, our data support neuroprotective potential of PPAR-gamma agonists. The PPAR-gamma antagonist GW9662 prevented the TBBPA-induced decrease in PPAR-gamma protein level, but it potentiated TBBPA-induced apoptotic and neurotoxic effects, which suggest that the mechanism of TBBPA action in neuronal cells is not only PPAR-gamma-dependent. Therefore, further studies of the mechanism of TBBPA action in the nervous system are needed.

GW1929 inhibits alpha7 nAChR expression through PPARgamma-independent activation of p38 MAPK and inactivation of PI3-K/mTOR: The role of Egr-1.[Pubmed:24412748]

Cell Signal. 2014 Apr;26(4):730-9.

Studies demonstrated that peroxisome proliferator-activated receptor gamma (PPARgamma) ligands reduce nicotine-induced non small cell lung carcinoma (NSCLC) cell growth through inhibition of nicotinic acetylcholine receptor (nAChR) mediated signaling pathways. However, the mechanisms by which PPARgamma ligands inhibited nAChR expression remain elucidated. Here, we show that GW1929, a synthetic PPARgamma ligand, not only inhibited but also antagonized the stimulatory effect of acetylcholine on NSCLC cell proliferation. Interestingly, GW1929 inhibited alpha7 nAChR expression, which was not blocked by GW9662, an antagonist of PPARgamma, or by PPARgamma siRNA, but was abrogated by the p38 MPAK inhibitor SB239063. GW1929 reduced the promoter activity of alpha7 nAChR and induced early growth response-1 (Egr-1) protein expression, which was overcame by SB239063, but enhanced by inhibitors of PI3-K and mTOR. Silencing of Egr-1 blocked, while overexpression of Egr-1 enhanced, the effect of GW1929 on alpha7 nAChR expression and promoter activity. Finally, GW1929 induced Egr-1 bound to specific DNA areas in the alpha7 nAChR gene promoter. Collectively, these results demonstrate that GW1929 not only inhibits but also antagonizes Ach-induced NSCLC cell growth by inhibition of alpha7 nAChR expression through PPARgamma-independent signals that are associated with activation of p38 MPAK and inactivation of PI3-K/mTOR, followed by inducing Egr-1 protein and Egr-1 binding activity in the alpha7 nAChR gene promoter. By downregulation of the alpha7 nAchR, GW1929 blocks cholinergic signaling and inhibits NSCLC cell growth.

GW1929: a nonthiazolidinedione PPARgamma agonist, ameliorates neurological damage in global cerebral ischemic-reperfusion injury through reduction in inflammation and DNA fragmentation.[Pubmed:20833208]

Behav Brain Res. 2011 Jan 20;216(2):606-12.

Transient global cerebral ischemia results in acute neurodegeneration in selective brain areas. Global cerebral ischemic-reperfusion (IR) injury induced selective hippocampal damage results into various neurobehavioral deficits including spatial memory and learning deficiencies. In this study, we have investigated the protective effects of a nonthiazolidinedione PPARgamma agonist, N-(2-benzoylphenyl)-O-[2-(methyl-2-pyridinylamino)ethyl]-l-tyrosine (GW1929), against global cerebral IR injury induced neurobehavioral deficits and brain damage in gerbils. Bilateral carotid artery occlusion induced global cerebral ischemia in gerbils resulted in neurological deficits, hyperlocomotion, reduced response latency in passive avoidance test and hippocampal damage. Hippocampal neurodegeneration after cerebral IR injury was also associated with significant increase in iNOS and MMP-9 immunoreactivity along with TNFalpha and IL-6 levels. Massive apoptotic DNA fragmentation as evident from increased TUNEL (terminal deoxynucleotidyl transferase mediated dUTP nick end labelling)-positive cells was also observed in the CA1 hippocampal region of IR challenged gerbils. GW1929 treatment significantly ameliorated cerebral IR induced neurological symptoms, hyperlocomotion, cognitive deficits and hippocampal neuronal damage in CA1 hippocampus region in gerbils. Significant reduction in IR injury induced iNOS and MMP-9 immunoreactivity, TNFalpha and IL-6 levels and apoptotic DNA fragmentation was also observed with GW1929 treatment. Pioglitazone, thiazolidinedione PPARgamma agonist also exhibited similar effects on inflammatory parameters after global cerebral IR injury. In summary, this study demonstrates neuroprotective effects of GW1929 in global cerebral IR injury induced neurobehavioral deficits and brain pathology which may be attributed to reduced inflammation and apoptotic DNA fragmentation, suggesting therapeutic potential of PPARgamma agonists in cerebral IR injury.

Ameliorative effects of GW1929, a nonthiazolidinedione PPARgamma agonist, on inflammation and apoptosis in focal cerebral ischemic-reperfusion injury.[Pubmed:21722092]

Curr Neurovasc Res. 2011 Aug 1;8(3):236-45.

PPARgamma agonist; 2-(Benzoylphenyl)-O-[2-(methyl-2-pyridinylamino) ethyl]-L-tyrosine (GW1929) in focal cerebral ischemic-reperfusion (IR) injury in rats. Focal cerebral IR injury resulted significant brain infarction and neurological deficits in rats. A significant increase in various inflammatory mediators like COX-2, iNOS, MMP-9, TNFalpha and IL-6 and massive apoptotic DNA fragmentation was also observed in the IR challenged brains. GW1929 treatment significantly attenuated the neurological damage in focal cerebral IR injury. Neuroprotective effects of GW1929 were found to be associated with significant reduction in the COX-2, iNOS, MMP-9, TNFalpha and IL-6 levels. Together, we have also evaluated the effects of Pioglitazone, a clinically available thiazolidinedione PPARgamma agonist, against focal cerebral IR injury. Like GW1929, Pioglitazone also showed beneficial effects in cerebral IR injury associated neurological damage but at the higher dose as compared to GW1929. Neuroprotective effects of PPARgamma agonists were found to be associated with significant reduction in TUNEL positive cells in IR challenged brain. In summary, these results suggested the neuroprotective potential of PPARgamma agonists in cerebral IR injury and these effects may be attributed to their anti-inflammatory and anti-apoptotic potential.

GW1929 is a potent PPAR-γ agonist, with a pKi of 8.84 for human PPAR-γ, and pEC50s of 8.56 and 8.27 for human PPAR-γ and murine PPAR-γ, respectively.

GW1929,196808-24-9,Natural Products,PPAR, buy GW1929 , GW1929 supplier , purchase GW1929 , GW1929 cost , GW1929 manufacturer , order GW1929 , high purity GW1929