PPAR dual agonists: Are they opening Pandora's Box?

Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India.
Pharmacological Research (Impact Factor: 4.41). 09/2007; 56(2):91-8. DOI: 10.1016/j.phrs.2007.03.002
Source: PubMed


Cardiovascular disorders are the major cause of mortality in patients of diabetes mellitus. Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors of nuclear hormone receptor superfamily comprising of three subtypes such as PPARalpha, PPARgamma and PPARdelta/beta. Activation of PPARalpha reduces triglycerides and involves in regulation of energy homeostasis. Activation of PPARgamma causes insulin sensitization and enhances glucose metabolism, whereas activation of PPARdelta enhances fatty acid metabolism. Current therapeutic strategies available for the treatment of diabetes do not inhibit the associated secondary cardiovascular complications. Hence, the development of multimodal drugs which can reduce hyperglycemia and concomitantly inhibit the progression of secondary cardiovascular complications may offer valuable therapeutic option. Several basic and clinical studies have exemplified the beneficial effects of PPARalpha and PPARgamma ligands in preventing the cardiovascular risks. The PPARalpha/gamma dual agonists are developed to increase insulin sensitivity and simultaneously prevent diabetic cardiovascular complications. Such compounds are under clinical trials and proposed for treatment of Type II diabetes with secondary cardiovascular complications. However, PPARalpha/gamma dual agonists such as muraglitazar, tesaglitazar and ragaglitazar have been noted to produce several cardiovascular risks and carcinogenicity, which raised number of questions about the clinical applications of dual agonists in diabetes and its associated complications. The ongoing basic studies have elucidated the cardio protective role of PPARdelta. Therefore, further studies are on the track to develop PPARalpha/delta and PPAR gamma/delta dual agonists and PPARalpha/gamma/delta pan agonists for the treatment of diabetic cardiovascular complications. The present review critically analyzes the protective and detrimental effect of PPAR agonists in diabetic cardiovascular complications. Moreover, the newly developed PPARalpha/delta and PPAR gamma/delta dual agonists and PPARalpha/gamma/delta pan agonists have also been discussed which may open a new vista in the management of diabetic cardiovascular complications in near future.

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    • "Recently, it has been suggested that the pharmacological activation of PPARδ can be considered a potential target because of its anti-inflammatory/antioxidant/antiexcitotoxic/proenergetic profile in some neurological and inflammatory-related diseases [23]. PPARδ has drawn much attention as a drug discovery target for regulating glucose and lipid metabolism [24] because PPARs are widely distributed throughout the body and are mainly known for their effects on metabolism. Three isoforms of PPAR have been identified: PPARα, PPARδ (also called PPARβ), and PPARγ [25]. "
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    ABSTRACT: Changes in the peroxisome proliferator-activated receptors- δ (PPAR δ ) expression in rats after spinal cord injury (SCI) have been previously reported. Diabetic animals show a higher mortality after SCI. However, the relationship between the progress of diabetes and PPAR δ in SCI remains unknown. In the present study, we used compressive SCI in streptozotocin-(STZ-) induced diabetic rats. GW0742, a PPAR δ agonist, was used to evaluate its merit in STZ rats after SCI. Changes in PPAR δ expression were detected by Western blot. Survival rates were also estimated. A lower expression of PPAR δ in spinal cords of STZ-diabetic rats was observed. In addition, the survival times in two-week induction diabetes were longer than those in eight-week induction group, which is consistent with the expression of PPAR δ in the spinal cord. Moreover, GW0742 significantly increased the survival time of STZ rats. Furthermore, their motor function and pain response were attenuated by GSK0660, a selective PPAR δ antagonist, but were enhanced by GW0742. In conclusion, the data suggest that higher mortality rate in STZ-diabetic rats with SCI is associated with the decrease of PPAR δ expression. Thus, change of PPAR δ expression with the progress of diabetes seems responsible for the higher mortality rate after SCI.
    PPAR Research 04/2014; 2014(1–4):456386. DOI:10.1155/2014/456386 · 1.64 Impact Factor
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    • "PPARγ participates in the proliferation and differentiation of adipocytes. It is mainly expressed in the fat tissue, colon, endothelial cells, and in the smooth muscle cells of blood vessels [48–50]. PPARD is widely expressed, but its physiological roles are not as well understood as the ones of the other subtypes. "
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    ABSTRACT: Valproic acid (VPA) is a widely used anticonvulsant and mood-stabilizing drug whose use is often associated with drug-induced weight gain. Treatment with VPA has been shown to upregulate Wfs1 expression in vitro. Aim of the present study was to compare the effect of chronic VPA treatment in wild type (WT) and Wfs1 knockout (KO) mice on hepatic gene expression profile. Wild type, Wfs1 heterozygous, and homozygous mice were treated with VPA for three months (300 mg/kg i.p. daily) and gene expression profiles in liver were evaluated using Affymetrix Mouse GeneChip 1.0 ST array. We identified 42 genes affected by Wfs1 genotype, 10 genes regulated by VPA treatment, and 9 genes whose regulation by VPA was dependent on genotype. Among the genes that were regulated differentially by VPA depending on genotype was peroxisome proliferator-activated receptor delta (Ppard), whose expression was upregulated in response to VPA treatment in WT, but not in Wfs1 KO mice. Thus, regulation of Ppard by VPA is dependent on Wfs1 genotype.
    PPAR Research 04/2014; 2014(6):349525. DOI:10.1155/2014/349525 · 1.64 Impact Factor
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    • "PPARc is expressed predominantly in adipose tissue, where it is a key regulator of adiposity differentiation, triglyceride storage, and energy homeostasis (Lehrke and Lazar 2005; Balakumar et al. 2007) In the kidney, PPARc is expressed in different cells, including the inner medullary collecting ducts, proximal tubules, thick ascending limb of Henle's loop (THAL), glomeruli and renal microvascular endothelial cells in rats (Yang et al. 1999; Satoh et al. 2004; Nicholas et al. 2001), rabbits, and humans (Guan et al. 1997, 2001) Because multiple renal cell types have endogenous PPARc expression and activity, the kidney has been suggested as a direct target of PPARc agonists, and PPARc activation in the kidney may be critical for maintaining normal renal function. Since the introduction of thiazolidinediones (TZDs), insulin sensitizers in diabetic clinical treatment, the role of PPARc in the kidney and the potential for PPARc agonists as therapy for diabetic nephropathy have been extensively investigated. "
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    ABSTRACT: Nuclear receptors are ligand-activated transcriptional regulators of several key aspects of renal physiology and pathophysiology. As such, nuclear receptors control a large variety of metabolic processes, including kidney lipid metabolism, drug clearance, inflammation, fibrosis, cell differentiation, and oxidative stress. Derangement of nuclear receptor regulation, that is, mainly due to obesity may induce metabolic syndrome, may contribute to the pathogenesis and progression of chronic renal disease and may result in end-stage renal disease. This places nuclear receptors at the forefront of novel therapeutic approaches for a broad range of kidney disorders and diseases, including glomerulosclerosis, tubulointerstitial disease, renal lipotoxicity, kidney fibrosis, and hypertension. This review focuses on the importance of the transcription factors peroxisome proliferator-activated receptor alpha, peroxisome proliferator-activated receptor beta, peroxisome proliferator-activated receptor gamma, liver X receptors, farnesoid X receptor, and the pregnane X receptor/steroid and xenobiotic receptor (PXR) on the physiology and pathophysiology of renal diseases associated with obesity and metabolic syndrome.
    Genes & Nutrition 04/2012; 7(4):483-98. DOI:10.1007/s12263-012-0295-5 · 2.79 Impact Factor
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