PPAR-α Contributes to the Anti-Inflammatory Activity of 17β-Estradiol

Crisafulli, Concetta; Bruscoli, Stefano; Esposito, Emanuela; Mazzon, Emanuela; Paola, Rosanna Di; Genovese, Tiziana; Bramantı, Placido; Migliorati, Graziella; Cuzzocrea, Salvatore

doi:10.1124/jpet.109.156646

Cited by 25 publications

(23 citation statements)

References 40 publications

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“…The important anti-inflammatory role of PPARα was evident in PPARα lacking mice where the NF-κB activity was less reduced compared to PPARαWT mice. These data confirmed our previous studies that explained the anti-inflammatory effect of PPARα through an inhibition of NF-κB pathway [60,61]. There is evidence that production of pro-inflammatory cytokines, such as TNF-α and IL-1β, is important to induce local and systemic inflammation and that production of this cytokine can be inhibited by treatment with statin [28,62].…”

Section: Discussionsupporting

confidence: 90%

Anti-inflammatory effect of simvastatin in an experimental model of spinal cord trauma: involvement of PPAR-α

Esposito

Rinaldi

Mazzon

et al. 2012

J Neuroinflammation

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BackgroundStatins such as simvastatin are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase used in the prevention of cardiovascular disease. In addition to their cholesterol-lowering activities, statins exert pleiotropic anti-inflammatory effects, which might contribute to their beneficial effects on lipid-unrelated inflammatory diseases. Recently it has been demonstrated that the peroxisome proliferator-activated receptor (PPAR)-α mediates anti-inflammatory effects of simvastatin in vivo models of acute inflammation. Moreover, previous results suggest that PPAR-α plays a role in control of secondary inflammatory process associated with spinal cord injury (SCI).MethodsWith the aim to characterize the role of PPAR-α in simvastatin activity, we tested the efficacy of simvastatin (10 mg/kg dissolved in saline i.p. 1 h and 6 h after the trauma) in an experimental model of SCI induced in mice by extradural compression of the spinal cord (T6-T7 level) using an aneurysm clip with a closing force of 24 g via a four-level T5-T8 laminectomy, and comparing mice lacking PPAR-α (PPAR-α KO) with wild type (WT) mice. In order to elucidate whether the effects of simvastatin are due to activation of the PPAR-α, we also investigated the effect of a PPAR-α antagonist, GW6471 (1 mg/kg administered i.p. 30 min prior treatment with simvastatin) on the protective effects of on simvastatin.ResultsResults indicate that simvastatin activity is weakened in PPAR-α KO mice, as compared to WT controls. In particular, simvastatin was less effective in PPAR-α KO, compared to WT mice, as evaluated by inhibition of the degree of spinal cord inflammation, neutrophil infiltration, nitrotyrosine formation, pro-inflammmatory cytokine expression, nuclear factor (NF)-κB activation, inducible nitric-oxide synthase (iNOS) expression, and apoptosis. In addition we demonstrated that GW6471 significantly antagonized the effect of the statin and thus abolished the protective effect.ConclusionsThis study indicates that PPAR-α can contribute to the anti-inflammatory activity of simvastatin in SCI.

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Section: Discussionsupporting

confidence: 90%

Anti-inflammatory effect of simvastatin in an experimental model of spinal cord trauma: involvement of PPAR-α

Esposito

Rinaldi

Mazzon

et al. 2012

J Neuroinflammation

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“…They may be very likely attributed to the antiinflammatory properties of (n-3) LC-PUFA (52), because of increased production of antiinflammatory eicosanoids derived from EPA and DHA, such as resolvins (53)(54)(55) and limited production of proinflammatory eicosanoids derived from AA, such as prostaglandin E 2 and leukotriene B4 (56-58), or activation of nuclear transcription factors, PPARa and PPARg (59), which regulate the secretion of inflammatory cytokines via NF-kB activation (60). This latter mechanism could be improved specifically in females, because estrogens have been shown to increase the intracellular concentration of effective PPAR ligands, particularly the LC-PUFA and eicosanoids derived from (n-3) LC-PUFA found in the inner membranes of cells (61) and to improve PPAR activation (62).…”

Section: Discussionmentioning

confidence: 97%

(n-3) Long-Chain PUFA Differentially Affect Resistance toPseudomonas aeruginosaInfection of Male and FemalecftrMice

Tiesset

Bernard

Bartke³

et al. 2011

The Journal of Nutrition

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The aim of this study was to determine whether oral supplementation with EPA/DHA (10.5 and 5.1% of fat, respectively) could improve the outcome of pulmonary P. aeruginosa infection in cftr(-/-) mice compared with wild-type (Wt) mice similarly treated. Because gender could influence the susceptibility of cftr-deficient mice, results were analyzed by gender. Wt and (-/-) mice were randomized for 6 wk to consume a control or EPA/DHA diet, infected with endotracheal injection of 5 × 10(7) CFU/mouse of P. aeruginosa, and killed 24 h later. Cftr(-/-) mice were more susceptible to infection than were Wt mice; (-/-) males had more neutrophils (P < 0.01) and a higher keratinocyte-derived chemokine (KC) level (P < 0.05), and (-/-) females had greater lung injury and mortality (P < 0.05). Female (-/-) mice were more susceptible than (-/-) males with a higher mortality and lung injury (P < 0.05). The EPA/DHA diet reduced neutrophil numbers and KC and IL-6 levels (P < 0.05) in (-/-) males and reduced mortality rate (P < 0.001), lung permeability, and IL-6 level (P < 0.05) in (-/-) females compared with (-/-) mice fed the control diet. These results were associated with a reduction in the pulmonary bacterial load (P < 0.05), an increase in the EPA/DHA concentration in cell membranes of (-/-) males and females (P < 0.01), and an increased weight gain only in males compared with (-/-) mice fed the control diet (P < 0.01). In conclusion, EPA/DHA improves the host resistance of (-/-) mice, although the beneficial effect differed in males and females.

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“…24 Four h later, the animals were sacrificed by CO 2 inhalation. The chest was opened and lungs were collected following perfusion with sterile PBS (10 mL), snap-frozen in liquid nitrogen and stored at −80°C until analysis.…”

Section: Methodsmentioning

confidence: 99%

A Potent Systemically Active N-Acylethanolamine Acid Amidase Inhibitor that Suppresses Inflammation and Human Macrophage Activation

et al. 2015

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Fatty acid ethanolamides such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) are lipid-derived mediators that potently inhibit pain and inflammation by ligating type-α peroxisome proliferator-activated receptors (PPAR-α). These bioactive substances are preferentially degraded by the cysteine hydrolase, N-acylethanolamine acid amidase (NAAA), which is highly expressed in macrophages. Here we describe a new class of β-lactam derivatives that are potent, selective and systemically active inhibitors of intracellular NAAA activity. The prototype of this class deactivates NAAA by covalently binding the enzyme's catalytic cysteine, and exerts profound anti-inflammatory effects in both mouse models and human macrophages. This agent may be used to probe the functions of NAAA in health and disease and as a starting point to discover better anti-inflammatory drugs.

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PPAR-α Contributes to the Anti-Inflammatory Activity of 17β-Estradiol

Cited by 25 publications

References 40 publications

Anti-inflammatory effect of simvastatin in an experimental model of spinal cord trauma: involvement of PPAR-α

Anti-inflammatory effect of simvastatin in an experimental model of spinal cord trauma: involvement of PPAR-α

(n-3) Long-Chain PUFA Differentially Affect Resistance toPseudomonas aeruginosaInfection of Male and FemalecftrMice

A Potent Systemically Active N-Acylethanolamine Acid Amidase Inhibitor that Suppresses Inflammation and Human Macrophage Activation

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