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Therapeutic Effects of a Novel Agonist of Peroxisome Proliferator-Activated Receptor Alpha for the Treatment of Diabetic Retinopathy.

ABSTRACT: Clinical studies have shown that peroxisome proliferator-activated receptor alpha (PPAR?) agonist fenofibrate has therapeutic effects on diabetic retinopathy (DR). The purpose of this study was to identify a novel PPAR? agonist and to evaluate its beneficial effects on DR.The transcriptional activity of PPAR? was measured by a luciferase-based promoter assay. TUNEL was used to evaluate apoptosis in retinal precursor cells (R28). Diabetes was induced in rats by injection of streptozotocin. Retinal inflammation was examined using leukostasis assay, and retinal vascular leakage was measured using permeability assay. Retinal function was measured using electroretinogram (ERG) recording, and retinal apoptosis was quantified using the cell death ELISA. The anti-angiogenic effect was evaluated in the oxygen-induced retinopathy (OIR) model.A compound, 7-chloro-8-methyl-2-phenylquinoline-4-carboxylic acid (Y-0452), with a chemical structure distinct from existing PPAR? agonists, activated PPAR? transcriptional activity and upregulated PPAR? expression. Y-0452 significantly inhibited human retinal capillary endothelial cell migration and tube formation. The compound also protected R28 cells against apoptosis and inhibited NF-?B signaling in R28 cells exposed to palmitate. In diabetic rats, Y-0452 ameliorated leukostasis and vascular leakage in the retina. In addition, Y-0452 preserved the retinal function and reduced retinal cell death in diabetic rats. Y-0452 also alleviated retinal neovascularization in the OIR model.Y-0452 is a novel PPAR? agonist and has therapeutic potential for DR.

SUBMITTER: Deng G

PROVIDER: S-EPMC5633008 | biostudies-other | 2017 Oct

REPOSITORIES: biostudies-other

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Therapeutic Effects of a Novel Agonist of Peroxisome Proliferator-Activated Receptor Alpha for the Treatment of Diabetic Retinopathy.

Deng Guotao G Moran Elizabeth P EP Cheng Rui R Matlock Greg G Zhou Kelu K Moran David D Chen Danyang D Yu Qiang Q Ma Jian-Xing JX

Investigative ophthalmology & visual science 20171001 12

<h4>Purpose</h4>Clinical studies have shown that peroxisome proliferator-activated receptor alpha (PPARα) agonist fenofibrate has therapeutic effects on diabetic retinopathy (DR). The purpose of this study was to identify a novel PPARα agonist and to evaluate its beneficial effects on DR.<h4>Methods</h4>The transcriptional activity of PPARα was measured by a luciferase-based promoter assay. TUNEL was used to evaluate apoptosis in retinal precursor cells (R28). Diabetes was induced in rats by inj ...[more]

PMID: 28979999

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Project description:Background and Aims: Therapeutic drugs that are used to treat cholestatic liver disease are limited; however, the results of clinical trials on primary biliary cholangitis treatment targeting peroxisome proliferator-activated receptors (PPARs) are encouraging. In this study, we aimed to identify the effects of MBT1805, a novel balanced PPARα/γ/δ agonist, on cholestasis induced by α-naphthylisothiocyanate (ANIT) and elucidate the underlying mechanisms through untargeted and bile acid-targeted metabolomic analysis. Methods: Levels of serum biochemical indicators (transaminase, aspartate transaminase, alkaline phosphatase, and total bilirubin) and liver histopathology were analyzed to evaluate the therapeutic effects of MBT1805 on ANIT-induced cholestasis in C57BL/6 mice. Untargeted and bile acid-targeted metabolomic analysis of liver tissues was performed using ultrahigh-performance liquid chromatography-triple quadrupole mass spectrometry (UPLC-MC/MC). qRT-PCR and Western blot analysis were carried out to measure the expression of key enzymes and transporters regulating bile acid synthesis, biotransformation, and transport. Results: MBT1805 significantly improved abnormal levels of liver biochemical indicators and gallbladder enlargement induced by ANIT. Histopathological analysis showed that MBT1805 effectively relieved ANIT-induced necrosis, vacuolation, and inflammatory infiltration. Untargeted metabolomic analysis identified 27 metabolites that were involved in the primary biliary acid biosynthesis pathway. In addition, bile acid-targeted metabolomics showed that MBT1805 could alleviate the abnormal bile acid content and composition induced by ANIT. Furthermore, qRT-PCR and Western blot results confirmed that MBT1805 could effectively regulate bile acid synthesis, biotransformation, and transport which helps relieve cholestasis. Conclusions: MBT1805 is a potential candidate drug for cholestasis, with a balanced PPARα/γ/δ activation effect.

Project description:Our aim was to investigate if the peroxisome proliferator-activated receptor (PPAR)-gamma agonist pioglitazone modulates inflammation through PPARalpha mechanisms.The thiazolidinediones (TZDs) pioglitazone and rosiglitazone are insulin-sensitizing PPARgamma agonists used to treat type 2 diabetes (T2DM). Despite evidence for TZDs limiting inflammation and atherosclerosis, questions exist regarding differential responses to TZDs. In a double-blinded, placebo-controlled 16-week trial among recently diagnosed T2DM subjects (n = 34), pioglitazone-treated subjects manifested lower triglycerides and lacked the increase in soluble vascular cell adhesion molecules (sVCAM)-1 evident in the placebo group. Previously we reported PPARalpha but not PPARgamma agonists could repress VCAM-1 expression. Since both triglyceride-lowering and VCAM-1 repression characterize PPARalpha activation, we studied pioglitazone's effects via PPARalpha.Pioglitazone effects on known PPARalpha responses--ligand binding domain activation and PPARalpha target gene expression--were tested in vitro and in vivo, including in wild-type and PPARalpha-deficient cells and mice, and compared with the effects of other PPARgamma (rosiglitazone) and PPARalpha (WY14643) agonists.Pioglitazone repressed endothelial TNFalpha-induced VCAM-1 messenger ribonucleic acid expression and promoter activity, and induced hepatic IkappaBalpha in a manner dependent on both pioglitazone exposure and PPARalpha expression. Pioglitazone also activated the PPARalpha ligand binding domain and induced PPARalpha target gene expression, with in vitro effects that were most pronounced in endothelial cells. In vivo, pioglitazone administration modulated sVCAM-1 levels and IkappaBalpha expression in wild-type but not PPARalpha-deficient mice.Pioglitazone regulates inflammatory target genes in hepatic (IkappaBalpha) and endothelial (VCAM-1) settings in a PPARalpha-dependent manner. These data offer novel mechanisms that may underlie distinct TZD responses.

Dataset Information

Therapeutic Effects of a Novel Agonist of Peroxisome Proliferator-Activated Receptor Alpha for the Treatment of Diabetic Retinopathy.

Publications

Therapeutic Effects of a Novel Agonist of Peroxisome Proliferator-Activated Receptor Alpha for the Treatment of Diabetic Retinopathy.

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