Zl-n-91, a selective phosphodiesterase 4 inhibitor, suppresses inflammatory response in a COPD-like rat model

Wang, Yajuan; Jiang, Yali; Tang, Huifang; Zhao, Chun-zhen; Chen, Jiqiang

doi:10.1016/j.intimp.2009.11.008

Cited by 20 publications

(17 citation statements)

References 29 publications

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“…One report has suggested that Zl-n-91 has direct inhibition of IL-17 production from memory Th17 cells [5]. Our previous report also suggested Zl-n-91 could decrease inflammation and improve lung function in COPD-like rat model prepared by challenging with LPS and cigarette smoking in male Sprague-Dawley rats, the mechanism maybe involve in inhibiting PDE4 activity and MMP-9 level in lungs [14]. Those study suggested Zl-n-91 have powerful potential as an alternative therapy for pulmonary diseases and regulation of immunity.…”

Section: Discussionmentioning

confidence: 87%

Action of a Novel PDE4 inhibitor ZL-n-91 on lipopolysaccharide-induced acute lung injury

Tang

et al. 2010

International Immunopharmacology

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Section: Discussionmentioning

confidence: 87%

Action of a Novel PDE4 inhibitor ZL-n-91 on lipopolysaccharide-induced acute lung injury

Tang

et al. 2010

International Immunopharmacology

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“…The effective dose of roflumilast in the present study was comparable with those described in previous reports. [16][17][18][19] In this model, increase in gelatinolytic activity in BALF was also observed in the LPS control group as a main band at 92 kDa (proMMP-9) on gelatin zymogram gels (Fig. 2B).…”

Section: Inhibition Of Pde Isozymes By Gpd-1116 and Gpd-1133 In Vitromentioning

confidence: 86%

“…13) Briefly, 200 µL of CSE, which was made by bubbling the smoke of one cigarette (Hi Lite, Japan Tabaco) in 1 mL of saline, was intratracheally instilled into guinea pigs once daily on days 1-4, 6-9, 11-14, and [16][17][18][19], and 200 µL of LPS solution (500 µg/mL) was intratracheally instilled into the guinea pigs once daily on days 5, 10, and 15. On day 20, the guinea pigs were anesthetized with sodium pentobarbital (35 mg/kg, i.p.…”

Section: Cigarette Smoke Extract (Cse)+lps-induced Copd Model In Guinmentioning

confidence: 99%

Pharmacological Profile of GPD-1116, an Inhibitor of Phosphodiesterase 4

Nose

Kondo

Shimizu

et al. 2016

Biological & Pharmaceutical Bulletin

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We have previously reported that GPD-1116, an inhibitor of phosphodiesterase (PDE) 4, exhibits antiinflammatory effects in a model of cigarette smoke-induced emphysema in senescence-accelerated P1 mice. In the present study, we further characterized the pharmacological profile of GPD-1116 in several experiments in vitro and in vivo. GPD-1116 and its metabolite GPD-1133 predominantly inhibited not only human PDE4, but also human PDE1 in vitro. Moreover, GPD-1116 was effective in several disease models in animals, including acute lung injury, chronic obstructive pulmonary disease (COPD), asthma and pulmonary hypertension; the effective doses of GPD-1116 were estimated to be 0.3-2 mg/kg in these models. With regard to undesirable effects known as class effects of PDE4 inhibitors, GPD-1116 showed suppression of gastric emptying in rats and induction of emesis in dogs, but showed no such suppression of rectal temperature in rats, and these side effects of GPD-1116 seemed to be less potent than those of roflumilast. These results suggested that GPD-1116 could be a promising therapeutic agent for the treatment of inflammatory pulmonary diseases. Furthermore, the inhibitory effects of GPD-1116 for PDE1 might be associated with its excellent pharmacological profile. However, the mechanisms through which PDE1 inhibition contributes to these effects should be determined in future studies. Key words phosphodiesterase; naphthyridine; pulmonary inflammationEnzymes of the cyclic nucleotide phosphodiesterase (PDE) family hydrolyze both cAMP and cGMP. PDE isozymes have been grouped into 11 classes according to their substrate specificity and biochemical features.1) Because inhibition of PDE activity increases intracellular concentrations of cyclic nucleotides by suppressing these degradation to 5′-nucleotides and alters intracellular signal transduction, the PDE family has been recognized as promising targets for therapeutic drugs. For example, inhibitors of PDE3 and PDE5 have actually been used in medicinal therapy for acute heart failure, erectile dysfunction and pulmonary hypertension.1-4) Furthermore, inhibition of PDE4 results in excellent anti-inflammatory effects under experimental conditions, 1,2,5) and an inhibitor of PDE4, roflumilast, has recently emerged as a therapeutic drug for the treatment of chronic obstructive pulmonary disease (COPD). 6)We have previously reported that GPD-1116, a novel PDE4 inhibitor created by ASKA Pharmaceutical, can attenuate the development of cigarette smoke-induced emphysema in senescence-accelerated P1 mice 7) ; however, other pharmacological characteristics of GPD-1116, such as the selectivity toward PDE isozymes and the effects of GPD-1116 in animal models of other pulmonary diseases, have not yet been clarified. In the present study, we clarified more extensive pharmacological profiling of GPD-1116 in several experiments in vitro and in vivo. MATERIALS AND METHODSAnimals Male CD Sprague-Dawley (SD) rats, male Hartley guinea pigs and female Beagle dogs were obtained from Charles Rive...

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“…The PDE4 inhibitor roflumilast N‐oxide partly reverses CS‐induced epithelial dysfunction (Milara et al ., 2014, 2012; Schmid et al ., 2015; Tyrrell et al ., 2015), and the PDE4 inhibitors, GPD‐1116 and piclamilast can prevent the development of CS‐induced emphysema and pulmonary hypertension in mice (Mori et al ., 2008; Seimetz et al ., 2015, p. 4). Zl‐n‐91, a selective PDE4 inhibitor can also suppress CS‐induced lung inflammatory in rats (Wang et al ., 2010; Bucher et al ., 2016). The aim of the present study was to investigate whether CS may directly induce changes in PDE expression or activity, thus contributing to lung pathophysiology.…”

Section: Discussionmentioning

confidence: 99%

Cigarette smoke up‐regulates PDE3 and PDE4 to decrease cAMP in airway cells

Zuo

Han

Poppinga

et al. 2018

British J Pharmacology

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Background and PurposecAMP is a central second messenger that broadly regulates cell function and can underpin pathophysiology. In chronic obstructive pulmonary disease, a lung disease primarily provoked by cigarette smoke (CS), the activation of cAMP‐dependent pathways, via inhibition of hydrolyzing PDEs, is a major therapeutic strategy. Mechanisms that disrupt cAMP signalling in airway cells, in particular regulation of endogenous PDEs, are poorly understood.Experimental ApproachWe used a novel Förster resonance energy transfer (FRET) based cAMP biosensor in mice in vivo, ex vivo precision cut lung slices (PCLS) and in human cell models, in vitro, to track the effects of CS exposure.Key ResultsUnder fenoterol stimulation, FRET responses to cilostamide were significantly increased in in vivo, ex vivo PCLS exposed to CS and in human airway smooth muscle cells exposed to CS extract. FRET signals to rolipram were only increased in the in vivo CS model. Under basal conditions, FRET responses to cilostamide and rolipram were significantly increased in in vivo, ex vivo PCLS exposed to CS. Elevated FRET signals to rolipram correlated with a protein up‐regulation of PDE4 subtypes. In ex vivo PCLS exposed to CS extract, rolipram reversed down‐regulation of ciliary beating frequency, whereas only cilostamide significantly increased airway relaxation of methacholine pre‐contracted airways.Conclusion and ImplicationsExposure to CS, in vitro or in vivo, up‐regulated expression and activity of both PDE3 and PDE4, which affected real‐time cAMP dynamics. These mechanisms determine the availability of cAMP and can contribute to CS‐induced pulmonary pathophysiology.

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Zl-n-91, a selective phosphodiesterase 4 inhibitor, suppresses inflammatory response in a COPD-like rat model

Cited by 20 publications

References 29 publications

Action of a Novel PDE4 inhibitor ZL-n-91 on lipopolysaccharide-induced acute lung injury

Action of a Novel PDE4 inhibitor ZL-n-91 on lipopolysaccharide-induced acute lung injury

Pharmacological Profile of GPD-1116, an Inhibitor of Phosphodiesterase 4

Cigarette smoke up‐regulates PDE3 and PDE4 to decrease cAMP in airway cells

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