Neuroprotective mechanisms of peroxisome proliferator-activated receptor agonists in Alzheimer��s disease

Alzheimer's disease (AD) is the most common causes of dementia accounting for 50-60% of all cases. The pathological hallmarks of AD are the formation of extracellular plaques consisting of amyloid-β protein, intracellular neurofibrillary tangles of hyperphosphorylated tau proteins and presence of chronic neuroinflammation causing progressive decline in memory and cognitive functions. The current therapeutic strategies to improve memory deficits aim at preventing the formation and accumulation of amyloid-β and tau phosphorylation. Beyond the plaque and tangle-related targets, other aspects of pathophysiology including molecular transport mechanism, oxidative damage, inflammation and glucose and lipid metabolism may also provide opportunities to slow down the progression of memory loss. A novel therapeutic approach to the treatment of AD is through the exploration of nuclear receptor agonists, peroxisome proliferator-activated receptors (PPARs), which have been clinically used as antidiabetic and dyslipidemic agents. The findings that PPAR agonists may possess antiamyloidogenic, anti-inflammatory, insulin-sensitizing, and cholesterol-lowering potential suggest that they could be interesting candidates for AD drugs. Through this review, we will discuss the probable pathophysiological mechanisms that may elicit the defending role of these receptors in brains of AD patients.     

Mode of peroxisome proliferator-activated receptor γ activation by luteolin

The peroxisome proliferator-activated receptor γ (PPARγ) is a target for treatment of type II diabetes and other conditions. PPARγ full agonists, such as thiazolidinediones (TZDs), are effective insulin sensitizers and anti-inflammatory agents, but their use is limited by adverse side effects. Luteolin is a flavonoid with anti-inflammatory actions that binds PPARγ but, unlike TZDs, does not promote adipocyte differentiation. However, previous reports suggested variously that luteolin is a PPARγ agonist or an antagonist. We show that luteolin exhibits weak partial agonist/antagonist activity in transfections, inhibits several PPARγ target genes in 3T3-L1 cells (LPL, ORL1, and CEBPα) and PPARγ-dependent adipogenesis, but activates GLUT4 to a similar degree as rosiglitazone, implying gene-specific partial agonism. The crystal structure of the PPARγ ligand-binding domain (LBD) reveals that luteolin occupies a buried ligand-binding pocket (LBP) but binds an inactive PPARγ LBD conformer and occupies a space near the β-sheet region far from the activation helix (H12), consistent with partial agonist/antagonist actions. A single myristic acid molecule simultaneously binds the LBP, suggesting that luteolin may cooperate with other ligands to bind PPARγ, and molecular dynamics simulations show that luteolin and myristic acid cooperate to stabilize the Ω-loop among H2', H3, and the β-sheet region. It is noteworthy that luteolin strongly suppresses hypertonicity-induced release of the pro-inflammatory interleukin-8 from human corneal epithelial cells and reverses reductions in transepithelial electrical resistance. This effect is PPARγ-dependent. We propose that activities of luteolin are related to its singular binding mode, that anti-inflammatory activity does not require H12 stabilization, and that our structure can be useful in developing safe selective PPARγ modulators.     

Bezafibrate induces myotoxicity in human rhabdomyosarcoma cells via peroxisome proliferator-activated receptor α signaling

Fibrates, the ligands of peroxisome proliferator-activated receptor α (PPARα), are used as a class of lipid-lowering drugs in clinical practice for the treatment of dyslipidemia. Fibrates are well tolerated in most cases concomitantly with occasional adverse reactions including muscular toxicity, which is enhanced by the combination with statins. This study was designed to investigate the effects of bezafibrate as a PPARα agonist on human embryo rhabdomyosarcoma (RD) cells and possible mechanisms responsible for bezafibrate-mediated myopathy. The results revealed that bezafibrate caused a dose-dependent decrease in cell viability, which was fortified in association with atorvastatin at a pharmacological dose. Bezafibrate at toxic doses of 300 and 1000 μM upregulated PPARα at the mRNA level, counteracted by a PPARα antagonist (MK886). Bezafibrate at a toxic dose induced typical apoptotic characteristics related to the inhibition of phosphorylation of Akt which was blocked by PPARα antagonist. Toxic doses of bezafibrate initiated a significant increase in pyruvate dehydrogenase kinase 4 mRNA and protein levels, compromised by MK886. These results suggest the critical roles of PPARα signaling in bezafibrate-induced myotoxicity and the involvement of apoptosis through Akt pathway.     

Molecular recognition of long chain fatty acids by peroxisome proliferator-activated receptor α

In the present study, flexible ligand docking and multiple scoring were used to study the binding of long-chain fatty acid (LCFAs) to the peroxisome proliferator-activated receptor α (PPARα). The calculations indicated that LCFAs bind PPARα in nanomolar affinities, which is in agreement with the intracellular concentrations of LCFAs. Calculated binding affinities were linearly related with the chain length up to 20 carbon atoms. The best correlation between the rank order of experimentally detected binding affinities and the predicted scores was found with the internal coordinate mechanics (ICM) binding energy method. This study contributes molecular insight into the binding process, which is of pivotal importance for designing new ligands interfering with lipid and glucose homeostasis.     

Irbesartan prevents metabolic syndrome in rats via activation of peroxisome proliferator-activated receptor γ

Irbesartan, an angiotensin-receptor blocker, is a known agonist of peroxisome proliferator-activated receptor (PPAR) γ. In this study, thirteen-week-old spontaneously hypertensive (SHR)/NDmcr-cp rats, representing a genetic model of metabolic syndrome, were treated daily with placebo, irbesartan (30 mg/kg), valsartan (10 mg/kg), or pioglitazone (10 mg/kg) for 4 weeks. Significant reductions in systolic blood pressure were seen in the irbesartan- and valsartan-treated groups, but not in the pioglitazone-treated group. Compared with the placebo group, plasma insulin, homeostasis model assessment of insulin resistance index, and plasma triglyceride levels were significantly lower while plasma adiponectin levels were significantly higher in the pioglitazone- and irbesartan-treated groups, but not in the valsartan-treated group. Significant increases in the gene expression of adiponectin and GLUT4 within adipose tissue were also observed in the pioglitazone- and irbesartan-treated groups, but not in the valsartan-treated group. These findings suggest that through PPARγ stimulation along with angiotensin II inhibition, irbesartan may be an optimal treatment option in the prevention of metabolic syndrome as well as hypertension.     

Smenospongidine suppresses the proliferation of multiple myeloma cells by promoting CCAAT/enhancer-binding protein homologous protein-mediated β-catenin degradation

Abnormal up-regulation of β-catenin expression is associated with the development and progression of multiple myeloma and is thus a potential therapeutic target. Here, we screened cell-based natural compounds and identified smenospongidine, a metabolite isolated from a marine sponge, as an antagonist of the Wnt/β-catenin signaling pathway. Smenospongidine promoted the degradation of intracellular β-catenin that accumulated via Wnt3a or 6-bromoindirubin-3′-oxime, an inhibitor of glycogen synthase kinase-3β. Consistently, smenospongidine down-regulated β-catenin expression and repressed the levels of β-catenin/T cell factor-dependent genes such as axin2, c-myc, and cyclin D1 in RPMI-8226 multiple myeloma cells. Smenospongidine suppressed proliferation and significantly induced apoptosis in RPMI-8266 cells. In addition, smenospongidine-induced β-catenin degradation was mediated by up-regulating CCAAT/enhancer-binding protein homologous protein (CHOP). These findings indicate that smenospongidine exerts its anti-proliferative activity by blocking the Wnt/β-catenin signaling pathway and may be a potential chemotherapeutic agent against multiple myeloma.     

Effects of peroxisome proliferator-activated receptor γ agonists on Na+ transport and activity of the kinase SGK1 in epithelial cells from lung and kidney

Background and purpose:

Peroxisome proliferator-activated receptor γ (PPARγ) agonists, such as rosiglitazone and pioglitazone, sensitize cells to insulin, and are therefore used to treat type 2 diabetes. However, in some patients, these drugs induce oedema, and the present study tests the hypothesis that this side effect reflects serum and glucocorticoid-inducible kinase 1 (SGK1)-dependent enhancement of epithelia Na⁺ absorption.

Experimental approach:

Na⁺ absorbing epithelial cells (H441 cells, mpkCCD cells) on permeable membranes were mounted in Ussing chambers, and the effects of rosiglitazone (2 µM) and pioglitazone (10 µM) on transepithelial Na⁺ absorption were quantified electrometrically. Changes in SGK1 activity were assessed by monitoring phosphorylation of residues within an endogenous protein.

Key results:

Both cell types absorbed Na⁺ via an electrogenic process that was enhanced by insulin. In mpkCCD cells, this stimulation of Na⁺ transport was associated with increased activity of SGK1, whereas insulin regulated Na⁺ transport in H441 cells through a mechanism that did not involve activation of this kinase. Rosiglitazone and pioglitazone had no discernible effect on transepithelial Na⁺ absorption in unstimulated or insulin-stimulated cells and failed to alter cellular SGK1 activity.

Conclusions and implications:

Our results do not support the view that PPARγ agonists stimulate epithelial Na⁺ absorption or alter the control of cellular SGK1 activity. It is therefore likely that other mechanisms are involved in PPARγ-mediated fluid retention, and a better understanding of these mechanisms may help with the identification of patients likely to develop oedema or heart failure when treated with these drugs.     

Regulation of adipogenesis through retinoid X receptor and/or peroxisome proliferator-activated receptor by designed lignans based on natural products in 3T3–L1 cells

Journal of Natural Medicines - We previously synthesized two retinoid X receptor (RXR) agonists, 4′-hydroxy-3′-propyl-[1,1′-biphenyl]-3-propanoic acid ethyl ester (4′OHE)...     

Rosiglitazone, a peroxisome proliferator-activated receptor γ stimulant, abrogates diabetes-evoked hypertension by rectifying abnormalities in vascular reactivity

In addition to insulin sensitization, rosiglitazone exhibits favourable circulatory effects. In the present study, we tested the hypothesis that rosiglitazone protects against hypertension and vascular derangements caused by diabetes. Diabetes was induced by a single bolus injection of streptozotocin (50 mg/kg, i.p.). After 2 weeks, rats were started on a treatment regimen of 5 mg/kg rosiglitazone daily for a period of 6 weeks. The control group consisted of rats treated with vehicle (distilled water) for the same period of time. After 6 weeks treatment, blood pressure (BP) was recorded and serum levels of glucose, advanced glycation end-products (AGE), triglycerides, total cholesterol and low-density lipoprotein-cholesterol (LDL-C) were determined. In in vitro experiments, concentration-response curves were constructed to phenylephrine (PE), KCl and acetylcholine (ACh) in thoracic aorta rings. In addition, ACh-induced nitric oxide (NO) generation and KCl-induced intracellular Ca accumulation were determined in the aorta. Compared with values in control rats, both diastolic and systolic BP were increased in diabetic rats. Rosiglitazone treatment of diabetic rats abolished the increase in diastolic BP and significantly reduced the increased systolic BP without affecting the development of hyperglycaemia. The possibility that changes in vascular reactivity and/or lipid profile contributed to the effects of rosiglitazone on BP in diabetic rats was investigated. In aortic rings from diabetic rats, contractile responses to KCl were increased, whereas the relaxant responses to ACh were decreased. In rings from diabetic rosiglitazone-treated rats, the exaggerated response to KCl and the impaired response to ACh were abolished. Furthermore, rosiglitazone abrogated impaired ACh-stimulated NO generation in aortas isolated from diabetic rats. Diabetes in rats was accompanied by elevated levels of triglycerides, total cholesterol, LDL-C and AGE. Rosiglitazone treatment abrogated the increased levels of triglycerides, total cholesterol and LDL-C, but only partially reduced AGE levels. Collectively, these observations indicate that rosiglitazone abrogates diabetes-evoked hypertension by ameliorating detrimental changes in vascular reactivity and lipid profiles.     

Honokiol inhibits gastric tumourigenesis by activation of 15-lipoxygenase-1 and consequent inhibition of peroxisome proliferator-activated receptor-�� and COX-2-dependent signals

Background and purpose:

Peroxisome proliferator-activated receptor-γ (PPAR-γ), COX-2 and 15-lipoxygenase (LOX)-1 have been shown to be involved in tumour growth. However, the roles of PPAR-γ, COX-2 or 15-LOX-1 in gastric tumourigenesis remain unclear. Here, we investigate the role of 15-LOX-1 induction by honokiol, a small-molecular weight natural product, in PPAR-γ and COX-2 signalling during gastric tumourigenesis.

Experimental approach:

Human gastric cancer cell lines (AGS, MKN45, N87 and SCM-1) were cultured with or without honokiol. Gene and protein expressions were analysed by RT–PCR and Western blotting respectively. Small interfering RNAs (siRNAs) for COX-2, PPAR-γ and 15-LOX-1 were used to interfere with the expressions of these genes. A xenograft gastric tumour model in mouse was used for in vivo study.

Key results:

PPAR-γ and COX-2 proteins were highly expressed in gastric cancer cells. Inhibitors, or siRNA for COX-2 or PPAR-γ, significantly decreased cell viability. Honokiol markedly inhibited PPAR-γ and COX-2 expressions in gastric cancer cells and tumours of xenograft mice, and induced apoptosis and cell death. Honokiol markedly activated cellular 15-LOX-1 expression and 13-S-hydroxyoctadecadienoic acid (a primary product of 15-LOX-1 metabolism of linoleic acid) production. 15-LOX-1 siRNA could reverse the honokiol-induced down-regulation of PPAR-γ and COX-2, and cell apoptosis. 15-LOX-1 was markedly induced in tumours of xenograft mice treated with honokiol.

Conclusions and implications:

These findings suggest that induction of 15-LOX-1-mediated down-regulation of a PPAR-γ and COX-2 pathway by honokiol may be a promising therapeutic strategy for gastric cancer.