PPARgamma Agonist Research Articles

Evidence for a Luteotropic Role of Peroxisome Proliferator-Activated Receptor Gamma: Expression and In Vitro Effects on Enzymatic and Hormonal Activities in Corpora Lutea of Pseudopregnant Rabbits1

The expression of peroxisome proliferator-activated receptor gamma (PPARgamma) and its role in corpora lutea (CL) function were studied in pseudopregnant rabbits. Corpora lutea were collected at an early stage (Day 4), midstage (Day 9), and late stage (Day 13) of pseudopregnancy. Immunohistochemistry found evidence for the presence of PPARgamma in the perinuclear cytoplasm and nucleus of all the luteal cells; immunoreactivity decreased from the early to the late stage, with immunonegativity of the nuclei of late stage CL. PPARgamma mRNA transcript was expressed in all the luteal stages with the lowest level in the late stage. In CL cultured in vitro, the PPARgamma agonist (15-deoxy delta12,14 prostaglandin J2 [15d-PGJ2], 200 nM) increased and the antagonist (T0070907, 50 nM) decreased progesterone secretion at early and midluteal stages, whereas 15d-PGJ2 reduced and T0070907 increased PGF2alpha at the same stages. Prostaglandin-endoperoxide synthase 2 (PTGS2) activity was reduced by 15d-PGJ2 and increased by T0070907 in CL of early and midluteal stages. Conversely, 15d-PGJ2 increased and T0070907 reduced 3beta-hydroxysteroid dehydrogenase (3beta-HSD) activity in early and midluteal stage CL. PGE2 in vitro secretion as well as PTGS1 and 20alpha-HSD enzymatic activities were not affected by 15d-PGJ2 and T0070907 in any CL types. These results indicate that PPARgamma plays a luteotropic role in pseudopregnant rabbits, through PTGS2 down-regulation and 3beta-HSD up-regulation, with a consequent PGF2alpha decrease and progesterone increase.

Apoptosis rate and transcriptional response of pancreatic islets exposed to the PPAR gamma agonist Pioglitazone

To explore the molecular pathways underlying thiazolidinediones effects on pancreatic islets in conditions mimicking normo- and hyperglycemia, apoptosis rate and transcriptional response to Pioglitazone at both physiological and supraphysiological glucose concentrations were evaluated. Adult rat islets were cultured at physiological (5.6 mM) and supraphysiological (23 mM) glucose concentrations in presence of 10 μM Pioglitazone or vehicle. RNA expression profiling was evaluated with the PancChip 13k cDNA microarray after 24-h, and expression results for some selected genes were validated by qRT-PCR. The effects of Pioglitazone were investigated regarding apoptosis rate after 24-, 48- and 72-h. At 5.6 mM glucose, 101 genes were modulated by Pioglitazone, while 1,235 genes were affected at 23 mM glucose. Gene networks related to lipid metabolism were identified as altered by Pioglitazone at both glucose concentrations. At 23 mM glucose, cell cycle and cell death pathways were significantly regulated as well. At 5.6 mM glucose, Pioglitazone elicited a transient reduction in islets apoptosis rate while at 23 mM, Bcl2 expression was reduced and apoptosis rate was increased by Pioglitazone. Our data demonstrate that the effect of Pioglitazone on gene expression profile and apoptosis rate depends on the glucose concentration. The modulation of genes related to cell death and the increased apoptosis rate observed at supraphysiological glucose concentration raise concerns about Pioglitazone’s direct effects in conditions of hyperglycemia and reinforce the necessity of additional studies designed to evaluate TZDs effects on the preservation of β-cell function in situations where glucotoxicity might be more relevant than lipotoxicity.

Docking, Synthesis and Anti-Diabetic Activity of Novel Sulfonylhydrazone Derivatives Designed as PPAR-Gamma Agonists

Diabetes is a metabolic disorder characterized by hyperglycemia. When not properly controlled, complications include neuropathy, coronary artery disease, and renal failure. Several drugs are approved for diabetes treatment; however their use is associated with side effects and lack of efficacy in attenuating the development of long-term complications. This work describes the virtual screening and synthesis of a novel series of sulfonylhydrazone derivatives designed as peroxisome proliferator-activated receptor gamma (PPARγ) agonists and investigation of the analogs for hypoglycemic activity in a murine model of diabetes. Docking studies identified LASSBio-331 (5) as having theoretical affinity for PPARγ similar to the prototype (S)-rosiglitazone. Several structural modifications were proposed for the structure of LASSBio-331, resulting in the synthesis of five novel compounds, which showed experimental affinity for PPARγ. Among these new compounds, LASSBio-1471 (15) had the best theoretical binding energy for PPARγ and was selected for testing in STZ-induced diabetes. Four weeks after single intravenous injection of STZ (60 mg/kg), Wistar rats were treated with vehicle (DMSO) or LASSBio-1471 (20 mg/kg, i.p.) for 7 days. The blood glucose levels of rats treated with LASSBio-1471 were reduced from 548.4 ± 26.0 mg/dL before treatment to 259.6 ± 73.1 mg/dL (P < 0.05). Paw withdrawal threshold was significantly reduced in diabetic rats and was restored from 21.9 ± 1.7 g to 36.7 ± 1.2 g after 7 days of treatment with LASSBio-1471 (P < 0.05). Thus, the novel sulfonylhydrazone derivative is a PPARγ ligand that is effective for treatment of diabetic neuropathy in STZ-injected rats. Keywords: Diabetic neuropathy, virtual screening, sulfonylhydrazone, hypoglycemic activity, PPARγ, metabolic disorder, Diabetes mellitus (DM), coronary heart disease, hyperglycemia, antidiabetic agents, postural hypotension.

Targeting peroxisome proliferator-activated receptors (ppar) for the treatment l-dopa-induced dyskinesias

L administration of L-DOPA to Parkinson’s disease (PD) patients is accompanied by fluctuations in its duration of action and chorea-like motor complications known as L-DOPA-induced dyskinesias (LID). As L-DOPA is the most effective treatment for PD, there is a strong need to identify new pharmacological targets to control LID while maintaining L-DOPA beneficial effects.LID can be modeled in rats with unilateral 6-OHDA lesions via chronic administration of L-DOPA, which induces increasingly severe axial, limb and oro-facial abnormal involuntary movements (AIMs). Previous studies in our laboratory showed that systemic administration of the PPAR gamma agonist rosiglitazone (5 & 10 mg/kg, i.p.) ameliorated axial, oral and limb AIMs without reducing L-DOPA’s anti-parkinsonian activity. Rosiglitazone also attenuated the L-DOPA-induced elevation of dyskinesia (Zif-268 and prodynorphin) and inflammation (COX-2) markers within the denervated striatum. Interestingly, chronic L-DOPA significantly increased the PPAR beta/delta isoform in dyskinetic rats and this elevation was reversed by rosiglitazone treatment. These data suggest that targeting PPAR gamma/delta receptors can ameliorate dyskinetic symptoms, possibly by reducing the underlying neuroinflammatory response observed in PD. Supported by RO1 -NS050401-06 (A.G).

Rational Design of a Therapeutic Program for Multiple Myeloma Using a Strategy of Drug Repurposing and Combination Therapy

AbstractAbstract 5022 Background:The extremely long development time and low success rate for new drug development programs has translated into limited clinical options in the treatment of cancer. The challenge is further compounded by drug resistance seen in clinical settings for approved standard of care therapeutic options like chemotherapy and targeted drugs like Bortezomib in Multiple Myeloma (MM). This has accelerated the need for initiatives and strategies which promote innovation but drastically reduce drug development failures through prediction of clinical outcomes. We present here a methodology and rationally designed therapeutic program for MM. This program has novel first-in-class mechanism of action and has been developed using a strategy of re-purposing and combinations based on National Center for Advanced Translational Sciences (NCATS) library of industry-provided drugs. Methods:The therapy design and development was completed using validated proprietary technology from Cellworks which enables simulation of cancer disease physiology computationally for predicting clinical outcomes. The comprehensive integrated representation of signaling and metabolic networks across all disease phenotypes and functional proteomics abstraction facilitated a large number of predictive studies in weeks with quantitative transparency into the network. The predictive cancer technology was customized to four MM profiles: OPM2, RPM1, SKMM2 and U266. Ten of the molecularly targeted drugs from the NCATS library were digitally screened alone and in combinations of two across the four MM profiles at four concentrations (C, C/2, C/4, and C/8). Based on screening of over six thousand predictive studies, three designed therapeutics hits were intelligently shortlisted based on synergistic impact on viability and proliferation. Results:The focused therapeutic candidate hit was selected based on synergy using viability endpoints and apoptosis markers such as caspase 3, PARP1 at sub-therapeutic doses. The proposed therapeutic regimen is a sub-therapeutic combination of AT101 and AVE0847. AT101 is a BCL2 inhibitor and AVE0847 is a PPAR alpha and gamma agonist agent. The concentration of each drug used in the designed therapy was close to IC30. The predictive results showed a synergistic increase in apoptotic markers caspase 3 and PARP1 cleaved form. This hit candidate is being pre-clinically validated experimentally across four MM profiles and results will be presented.Table 1:Showing the impact on viability phenotype and apoptotic biomarker caspase 3 with the IC30 combination of the two drugs.PhenotypesU266OPM2SKMMRPMIViability−58.96−62.71−55.39−69.64Caspase 3+90.26+132.67+69.31+202.91 Conclusion:The design of first in class mechanism of action based therapeutic strategies of drug rescue/repurposing has been used to identify AT101 and AVE0847 as a promising drug combination for use in MM which predicatively results in a synergistic increase in apoptosis. These results are currently being validated in vitro. The inherent multi target mechanism of action predicted by this combination could potentially eliminate the drug resistance challenges of single target therapeutics. Disclosures:No relevant conflicts of interest to declare.

Docking, Synthesis and Anti-Diabetic Activity of Novel Sulfonylhydrazone Derivatives Designed as PPAR-Gamma Agonists

Diabetes is a metabolic disorder characterized by hyperglycemia. When not properly controlled, complications include neuropathy, coronary artery disease, and renal failure. Several drugs are approved for diabetes treatment; however their use is associated with side effects and lack of efficacy in attenuating the development of long-term complications. This work describes the virtual screening and synthesis of a novel series of sulfonylhydrazone derivatives designed as peroxisome proliferator-activated receptor gamma (PPARγ) agonists and investigation of the analogs for hypoglycemic activity in a murine model of diabetes. Docking studies identified LASSBio-331 (5) as having theoretical affinity for PPARγ similar to the prototype (S)-rosiglitazone. Several structural modifications were proposed for the structure of LASSBio-331, resulting in the synthesis of five novel compounds, which showed experimental affinity for PPARγ. Among these new compounds, LASSBio-1471 (15) had the best theoretical binding energy for PPARγ and was selected for testing in STZ-induced diabetes. Four weeks after single intravenous injection of STZ (60 mg/kg), Wistar rats were treated with vehicle (DMSO) or LASSBio-1471 (20 mg/kg, i.p.) for 7 days. The blood glucose levels of rats treated with LASSBio-1471 were reduced from 548.4 ± 26.0 mg/dL before treatment to 259.6 ± 73.1 mg/dL (P < 0.05). Paw withdrawal threshold was significantly reduced in diabetic rats and was restored from 21.9 ± 1.7 g to 36.7 ± 1.2 g after 7 days of treatment with LASSBio-1471 (P < 0.05). Thus, the novel sulfonylhydrazone derivative is a PPARγ ligand that is effective for treatment of diabetic neuropathy in STZ-injected rats.

Differential Effects of Short-Term Treatment with Two AT1 Receptor Blockers on Diameter of Pial Arterioles in SHR

Chronic treatment with angiotensin receptor blockers is largely accepted for protecting cerebral circulation during hypertension, but beneficial effects of short-term treatments are questionable, as highlighted by the recent SCAST trial. We compared the impact of 10 days treatment with candesartan (as SCAST) versus telmisartan (previously described to reverse arteriolar remodeling, chronic treatment) on pial arterioles of spontaneously hypertensive rats (SHR). We explored whether PPAR-gamma agonist activity or AT1 receptor blockade are involved in their differential effects. In the first study, 4-month-old male SHR were treated with telmisartan (TELMI, 2 mg/kg per day) or candesartan cilexetil (CANDE, 10 mg/kg per day) and compared to vehicle treated SHR and normotensive WKY. In a second study, SHR were treated with CANDE, pioglitazone (a PPAR-gamma agonist, PIO 2.5 mg/kg per day) or CANDE+PIO, compared to TELMI. Internal diameter of pial arterioles (ID, cranial window) was measured at baseline, during hemorrhage-induced hypotension, or following suffusion of Ang II (10−6 mol/L) or EDTA inactivation of smooth muscle cells (passive ID). PPAR-gamma and eNOS (target gene of PPAR-gamma) mRNA were evaluated in brain microvessels. For similar antihypertensive effects, TELMI (+44% versus SHR), but not CANDE, increased baseline ID. During hemorrhage, ID in TELMI group was similar to WKY, while ID in SHR and CANDE remained lower. In the second study, TELMI (+36%, versus SHR) and CANDE+PIO (+43%) increased baseline ID, but not CANDE or PIO alone. TELMI (−66%) and CANDE+PIO (−69%), but neither CANDE nor PIO alone, decreased Ang II-induced vasoconstriction. CANDE+PIO, but not CANDE, increased passive ID. In both studies, PPAR-gamma and eNOS expressions were higher in TELMI than CANDE. Short-term treatment with TELMI, but not with CANDE, reverses narrowing of pial arteriolar ID in SHR. This may involve PPAR-gamma related mechanisms, since CANDE+PIO treatment induced similar effects, and a better blockade of AT1 receptors.

590P - Phase 1B Study of a Novel Oral Ppar-Gamma Agonist, Efatutazone in Combination with Folfiri in Japanese Patients with Metastatic Colorectal Cancer who Failed the First-Line Therapy

ABSTRACT Background Efatutazone is a highly-selective peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonist of thiazolidinedione (TZD) class, which shows higher potency than rosiglitazone. The recommended dose (RD) is 0.50 mg twice-daily (BID) in accordance with pharmacokinetics (PK), pharmacodynamics (PD, adiponectin) and safety analyses in US and Japanese phase 1 studies. This study assessed the safety, tolerability, antitumor activity, PK, PD, and determined the RD of efatutazone in combination with FOLFIRI in Japanese patients. Materials and methods This was an open-label, dose-escalation study using a 3 + 3 design. Each patient participated in only 1 dose group and received oral efatutazone 0.25 or 0.50 mg BID with every 2-week administration of FOLFIRI (Irinotecan 180 mg/m2 IV infusion over 90 minutes,l-LV 200 mg/m2 IV infusion over 120 minutes, and 5-FU IV continuous infusion 2400 mg/m2 over 46 hours). After determining the RD of efatutazone, 9 additional patients were enrolled for the further assessment of efatutazone. PK samples for efatutazone, Irinotecan and SN-38 were collected to assess the drug–drug interaction. PD samples were also collected. All patients provided written informed consent. Results A total of 15 patients were enrolled (7 male and 8 female; median age of 63 years old, range: 41–73 years). Dose-limiting toxicities were not observed, and the maximum tolerated dose (MTD) was not reached. Most patients experienced edema (80.0%) and weight increase (100.0%) which were manageable with diuretics. The most common haematological toxicities were neutropenia and anaemia, managed with supportive therapy and/or modification of FOLFIRI. Seven out of 15 patients showed stable disease (SD). Efatutazone increased plasma adiponectin levels. Plasma concentration of efatutazone increased according to dose. Efatutazone doesn't affect plasma concentration of Irinotecan and SN-38. Conclusions Efatutazone in combination with FOLFIRI is a novel anticancer therapy, which is tolerated in Japanese patients with metastatic colorectal cancer. Although the MTD was not reached, 0.50 mg BID, corresponding to the RD in western patients, was selected as the RD for Japanese patients based on safety analyses. Full safety data and clinical activity data will be presented. Disclosure T. Yoshino: I have honoraria with Chugai, Takeda, Bristol-Myers Squibb, Yakult and Merck Serono. I have research funding from Bayer,Taiho, Daiichi-sankyo and Quintiles. I have received consulting fee from Takeda. Y. Komatsu: Y.Komatsu has honoraria with DAIICHI SANKYO COMPANY, LIMITED, YAKULT HONSHA CO., LTD, Pfizer. Y.Komatsu has research funding from DAIICHI SANKYO COMPANY, LIMITED, YAKULT HONSHA CO., LTD, Pfizer. R. Oyama: R.Oyama is an employee of Daiichisankyo CO.,LTD. Y. Yachi: Y.Yachi is an employee of Daiichisankyo CO.,LTD. H. Onuma: H.Onuma is an employee of Daiichisankyo CO., LTD. A. Ohtsu: A.Ohtsu has an advisory role and/or honoraria with Takeda Pharmaceutical Co., Ltd, DAIICHI SANKYO, Novartis, CHUGAI PHARMACEUTICAL CO., LTD, TAIHO Pharmaceutical Co., Ltd, Glaxosmithkline, Pfizer, YAKULT HONSHA, Merck Serono, Bristol-Myers Squibb. All other authors have declared no conflicts of interest.

56. Age dependant effects of the PPAR-gamma agonist rosiglitazone on the brain and periphery during systemic LPS-induced inflammation in rats

Aging is associated with altered immune responses to stimuli such as lipopolysaccharide (LPS) and a mitochondrial decline is proposed to be a main underlying factor in age-related diseases. Recently, rosiglitazone (RZG), a peroxisome proliferator-activated receptor (PPAR) gamma agonist was shown to exert anti-inflammatory properties and to induce a key regulator of mitochondrial biogenesis, namely, PPARgamma co-activator-1-alpha (PGC-1alpha). Here, we aimed to further elucidate age-dependent changes in signaling pathways and sickness response during LPS-induced inflammation and to test potential beneficial effects of rosiglitazone. Pretreatment of old (24 months) and young (2 months) rats with RZG or solvent was followed by intraperitoneal injection of LPS (100 μg/kg) or saline. 24 h after stimulation blood, brain and liver were withdrawn for further analysis. We found age-dependent differences in fever and severity of other sickness symptoms after LPS-stimulation. Pretreatment with rosiglitazone, however, did not alter this response in young or old rats. Nevertheless, analysis of the liver by RT-PCR revealed increased mRNA-levels of markers of mitochondrial biogenesis in saline-injected and RZG-pretreated animals. Interestingly, several plasma cytokines including interleukin (IL)-6, IL-10, and IL-1ra and brain/liver inflammatory mediators such as nuclear factor IL-6 showed age-dependent changes independent of RZG-injections. Overall, beneficial effects of RZG could not be revealed in the current experimental paradigm. Nonetheless, our results reveal further insights into changes of brain and peripheral inflammatory mediators during aging and LPS-induced inflammation.

Rosiglitazone Improves Survival and Hastens Recovery from Pancreatic Inflammation in Obese Mice

Obesity increases severity of acute pancreatitis (AP) by unclear mechanisms. We investigated the effect of the PPAR-gamma agonist rosiglitazone (RGZ, 0.01% in the diet) on severity of AP induced by administration of IL-12+ IL-18 in male C57BL6 mice fed a low fat (LFD) or high fat diet (HFD), under the hypothesis that RGZ would reduce disease severity in HFD-fed obese animals. In both LFD and HFD mice without AP, RGZ significantly increased body weight and % fat mass, with significant upregulation of adiponectin and suppression of erythropoiesis. In HFD mice with AP, RGZ significantly increased survival and hastened recovery from pancreatic inflammation, as evaluated by significantly improved pancreatic histology, reduced saponification of visceral adipose tissue and less severe suppression of erythropoiesis at Day 7 post-AP. This was associated with significantly lower circulating and pancreas-associated levels of IL-6, Galectin-3, osteopontin and TIMP-1 in HFD + RGZ mice, particularly at Day 7 post-AP. In LFD mice with AP, RGZ significantly worsened the degree of intrapancreatic acinar and fat necrosis as well as visceral fat saponification, without affecting other parameters of disease severity or inflammation. Induction of AP lead to major suppression of adiponectin levels at Day 7 in both HFD and HFD + RGZ mice. In conclusion, RGZ prevents development of severe AP in obese mice even though it significantly increases adiposity, indicating that obesity can be dissociated from AP severity by improving the metabolic and inflammatory milieu. However, RGZ worsens selective parameters of AP severity in LFD mice.

Design Novel Dual Agonists for Treating Type-2 Diabetes by Targeting Peroxisome Proliferator-Activated Receptors with Core Hopping Approach

Owing to their unique functions in regulating glucose, lipid and cholesterol metabolism, PPARs (peroxisome proliferator-activated receptors) have drawn special attention for developing drugs to treat type-2 diabetes. By combining the lipid benefit of PPAR-alpha agonists (such as fibrates) with the glycemic advantages of the PPAR-gamma agonists (such as thiazolidinediones), the dual PPAR agonists approach can both improve the metabolic effects and minimize the side effects caused by either agent alone, and hence has become a promising strategy for designing effective drugs against type-2 diabetes. In this study, by means of the powerful “core hopping” and “glide docking” techniques, a novel class of PPAR dual agonists was discovered based on the compound GW409544, a well-known dual agonist for both PPAR-alpha and PPAR-gamma modified from the farglitazar structure. It was observed by molecular dynamics simulations that these novel agonists not only possessed the same function as GW409544 did in activating PPAR-alpha and PPAR-gamma, but also had more favorable conformation for binding to the two receptors. It was further validated by the outcomes of their ADME (absorption, distribution, metabolism, and excretion) predictions that the new agonists hold high potential to become drug candidates. Or at the very least, the findings reported here may stimulate new strategy or provide useful insights for discovering more effective dual agonists for treating type-2 diabetes. Since the “core hopping” technique allows for rapidly screening novel cores to help overcome unwanted properties by generating new lead compounds with improved core properties, it has not escaped our notice that the current strategy along with the corresponding computational procedures can also be utilized to find novel and more effective drugs for treating other illnesses.

Combined activation of PPAR-gamma and PPAR-alpha reduces the negative effects of PPAR-gamma agonism on bone and may attenuate PPAR-gamma-mediated loss of bone strength

Combined activation of PPAR-gamma and PPAR-alpha reduces the negative effects of PPAR-gamma agonism on bone and may attenuate PPAR-gamma-mediated loss of bone strength

Is the age-related macular degeneration (AMD) vascular disease, part of vasculopathy, respectively? Novel considerations on AMD arising from the newest pathophysiological, clinical and clinical- pharmacological observations (Preliminary Communication)

Is the age-related macular degeneration (AMD) vascular disease, part of vasculopathy, respectively? Novel considerations on AMD arising from the newest pathophysiological, clinical and clinical- pharmacological observations (Preliminary Communication)

Combined activation of PPAR-gamma and PPAR-alpha reduces the negative effects of PPAR-gamma agonism on bone and may attenuate PPAR-gamma-mediated loss of bone strength

Combined activation of PPAR-gamma and PPAR-alpha reduces the negative effects of PPAR-gamma agonism on bone and may attenuate PPAR-gamma-mediated loss of bone strength

Telmisartan-induced eNOS gene expression is partially independent of its PPAR-gamma agonist property

Telmisartan, an angiotensin II receptor blocker (ARB), also acts as an activator of peroxisome proliferator-activated receptor-gamma (PPAR-gamma; PPAR-γ). Several studies have explored the PPAR-γ-endothelial nitric oxide synthase (eNOS) pathway associated with improvement of endothelial function by telmisartan. The ability of telmisartan to induce gene expression and protein level of eNOS and PPARγ in adipocytes was investigated. Expression of aP2, PPARγ, eNOS and iNOS genes were measured using the quantitative real-time polymerase chain reaction. The changes, at the protein level, were explored by Western blot, which evaluated the native and phosphorylated eNOS forms, eNOS-Ser(1177) and eNOS-Thr(495). Adipocytes, exposed to telmisartan, exhibited an increase in PPARγ gene expression but a decrease in protein level. Nonetheless, after the exposure to telmisartan, eNOS-Ser(1177) phosphorylation, associated with eNOS activity increment, reached its highest value while eNOS-Thr(495) phosphorylation, involved in the inhibition of eNOS activity, showed its lowest value. The results suggest that telmisartan preserves eNOS activity via a mechanism that is partially independent of the PPARγ-eNOS pathway in adipocytes.

Differential susceptibility to the PPAR-γ agonist pioglitazone in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine rodent models of Parkinson's disease

A growing body of evidence suggests that peroxisome proliferator-activated receptor (PPAR) agonists are valuable candidates as disease modifiers in Parkinson's disease (PD) and may thus enable neuroprotection and preserve motor function. The present study sought to evaluate the effect of the PPAR-gamma agonist pioglitazone in two different animal models of PD. The study was based on nigral dopaminergic neuron labelling and the assessment of motor behaviour in (i) the frequently investigated MPTP mouse model and (ii) the less well-known bilateral 6-OHDA rat model.In MPTP-injected mice, pioglitazone reversed body weight loss and the reduction in rearing frequency and induced significant neuroprotection of the nigrostriatal dopaminergic pathway (by 24%, compared with vehicle). In contrast, pioglitazone did not have any effect on the 73.5% loss of dopaminergic neurons or motor impairments (a reduced rearing frequency and a loss of strength in the forepaws) in bilateral 6-OHDA rats.The PPAR-gamma agonist pioglitazone had a significant neuroprotective effect in MPTP mice but not in bilateral 6-OHDA rats. The various effects of PPAR agonists in both models can be accounted by the different action mechanism of the 2 toxins or by the fact that 3μg 6-OHDA injection was too harmful to be alleviated by the compound. This work supports PPAR-agonists to be relevant in the therapeutic strategy research in Parkinson's disease and highlights the importance in evaluating neuroprotective agent in different models.

Update on Cardiovascular Safety of PPARgamma Agonists and Relevance to Medicinal Chemistry and Clinical Pharmacology

Peroxisome proliferator-activator receptors (PPARs) are now known as members of the nuclear hormonereceptor superfamily of ligand-activated transcription factors that regulate gene expression in response to nutritional and physiological stimuli. PPARγ plays a crucial role in glucose homeostasis and it is involved in the regulation of lipid metabolism and adipocyte differentiation and function. From all the PAARγ ligands, the thiazolidindiones (TZDs) are of most clinical importance. Rosiglitazone and pioglitazone have been largely used so far in the clinical practice. They provide similar effects on glycemic control, as well as a range of similar adverse effects, such as weight gain, fluid retention, and increased risk of hearth failure, which seem to be PPARγ mediated. Interestingly, they differ on their effect on lipid and cardiovascular safety profile, indicating a PPARγ-independent mechanism. Indeed, rosiglitazone was recently withdrawn in Europe and its use has been restricted in USA as a consequence of increased risk of cardiovascular events in type 2 diabetic patients. This review is focused on the cardiovascular effects of rosiglitazone and pioglitazone as representative members of PPARγ ligands, because they were widely evaluated in many clinical trials and experimental studies and data obtained from these studies are relevant from medicinal chemistry and clinical pharmacology point of view. Finally, an overview on the development of selective PPARγ modulators and/or dual PPARα/γ agonists will be given. These new approaches might provide anti-hyperglycemic efficacy without the associated undesirable side-effects. However, further experimental and clinical studies evaluating the theoretical benefit and safety of this therapeutic strategy are needed.

Hepatocellular carcinoma in non-alcoholic fatty liver disease: An emerging menace

Hepatocellular carcinoma (HCC) is a common cancer worldwide that primarily develops in cirrhosis resulting from chronic infection by hepatitis B virus and hepatitis C virus, alcoholic injury, and to a lesser extent from genetically determined disorders such as hemochromatosis. HCC has recently been linked to non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of obesity and related metabolic disorders such as diabetes. This association is alarming due to the globally high prevalence of these conditions and may contribute to the rising incidence of HCC witnessed in many industrialized countries. There is also evidence that NAFLD acts synergistically with other risk factors of HCC such as chronic hepatitis C and alcoholic liver injury. Moreover, HCC may complicate non-cirrhotic NAFLD with mild or absent fibrosis, greatly expanding the population potentially at higher risk. Major systemic and liver-specific molecular mechanisms involved include insulin resistance and hyperinsulinemia, increased TNF signaling pathways, and alterations in cellular lipid metabolism. These provide new targets for prevention, early recognition, and effective treatment of HCC associated with NAFLD. Indeed, both metformin and PPAR gamma agonists have been associated with lower risk and improved prognosis of HCC. This review summarizes current evidence as it pertains to the epidemiology, pathogenesis, and prevention of NAFLD-associated HCC.

Balaglitazone: A Second Generation Peroxisome Proliferator-Activated Receptor (PPAR) Gamma (&amp;#947;) Agonist

Balaglitazone (DRF-2593) is a novel partial agonist of PPAR-gamma (γ), which is developed by Dr. Reddy's laboratories India. Balaglitazone is a second generation peroxisome proliferator-activated receptor (PPAR) gamma agonist with only partial agonistic properties. Balaglitazone is currently being evaluated in phase III clinical trial in United States and Europe. Selective PPAR-γ modulators bind in distinct manners to the ligand-binding pocket of PPAR-γ, leading to alternative receptor conformations, differential cofactor recruitment/displacement, differential gene expression, and ultimately differential biological responses. Based on this concept, new and improved novel antidiabetic agents are in current development. Clinical studies conducted with 409 subjects of randomized, double blind, parallel-group placebo and active comparator-controlled subject groups to determine the efficacy and safety of Balaglitazone. The study showed that the trial met its primary endpoint. Balaglitazone treated groups shown significantly reduce of HbA1c (%), FSG (mmol/L), postprandial glucose as comparison to pioglitazone. Phase III clinical studies data clearly shows that Balaglitazone provides robust glycemic control as an add-on to insulin therapy. Balaglitazone 10 mg and 20 mg show the similar magnitudes of the effects which comparable to the effects seen in the pioglitazone 45 mg group. The incidence of fluid retention and fat accumulation fewer than those observed with pioglitazone 45 mg. Hence, Balaglitazone is prominent candidate of new glitazone which requires fewer doses as comparison pioglitazone and shows better safety profile less incidence of special adverse effect like heart failure, peripheral oedema, and myocardial infarction. Unlike other marketed PPAR gamma agonists, Balaglitazone shows less fluid retention, less heart enlargement and no reduction of bone formation than full PPAR gamma agonists in preclinical studies. In present review, we have tried to cover classification PPARs various ligands, chemistry, physical properties, commercial synthesis, current patent status, polymorphic information, receptor interaction, pharmacophore rational, mechanism, adverse effect and clinical status of Balaglitazone, giving emphasis on medicinal chemistry aspect.

The PPAR Gamma Agonist Troglitazone Regulates Erk 1/2 Phosphorylation via a PPARγ-Independent, MEK-Dependent Pathway in Human Prostate Cancer Cells

Thiazolidinediones (TZDs) dramatically reduce the growth of human prostate cancer cells in vitro and in vivo. To determine whether the antitumor effects of TZDs were due in part to changes in the MEK/Erk signaling pathway, we examined the regulation of Erk phosphorylation by the TZD troglitazone within the PC-3 and C4-2 human prostate cancer cell lines. Western blot analysis revealed troglitazone-induced phosphorylation of Erk in both PC-3 and C4-2 cells. Troglitazone-induced increases in Erk phosphorylation were suppressed by the MEK inhibitor U0126 but not by the PPARγ antagonist GW9662. Pretreatment with U0126 did not alter the ability of troglitazone to regulate expression of two proteins that control cell cycle, p21, and c-Myc. Troglitazone was also still effective at reducing PC-3 proliferation in the presence of U0126. Therefore, our data suggest that troglitazone-induced Erk phosphorylation does not significantly contribute to the antiproliferative effect of troglitazone.