Differential type 4 cAMP-specific phosphodiesterase (PDE4) expression and functional sensitivity to PDE4 inhibitors among rats, monkeys and humans

Hong, Bo; Zhang, Ji; Wu, Ping; Varty, Lori A.; Jia, Yanlin; Mayhood, Todd; Hey, John A.; Wang, Peng

doi:10.1016/j.bcp.2004.08.014

Cited by 31 publications

(23 citation statements)

References 32 publications

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“…There is also little knowledge whether and how species differences seen in in vitro models translate into differences in vivo. For PDE4 inhibitors, the highest functional sensitivity towards the inhibition of TNF-α release from leukocytes was demonstrated in rats followed by monkeys and humans [48]. The authors concluded that these differences might be responsible for the higher susceptibility of rats to toxicity induced by PDE4 inhibitors since they demonstrated significantly higher mRNA levels in toxicologically relevant tissues from rats in comparison with human tissue.…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 76%

Impact of p38 MAP Kinase Inhibitors on LPS-Induced Release of TNF-α in Whole Blood and Primary Cells from Different Species

Fehr

Unger²,

Schaeffeler

et al. 2015

Cell Physiol Biochem

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Background/Aims: Inhibition of p38 mitogen-activated protein kinase (p38 MAPK) is promising for the treatment of inflammatory disorders, however, the efficacy of p38 MAPK inhibitors in clinical trials is limited so far. Since functional sensitivity of p38 MAPK is commonly predicted by preclinical species, we systematically investigated interspecies differences including human tissue. Methods: Ex vivo test models were established using whole blood and primary cells from different species such as mice, rats, pigs and humans to compare LPS-induced TNF-α inhibition of four different p38 MAPK reference inhibitors SB 203580, BIRB-796, Pamapimod, and a Losmapimod analogue as well as a proprietary imidazole-based p38 MAPK Inhibitor. Results: All analysed p38 MAPK inhibitors resulted in significant inhibition of LPS-induced TNF-α release but with high interspecies differences for dose sensitivity. IC₅₀ values from human whole blood and PBMC showed significant higher sensitivity towards p38 MAPK inhibition compared with data from pig and rat. Conclusion: Inhibition of TNF-α release by p38 MAPK inhibitors can be reliably identified in well-established laboratory species such as rat or mouse. However, our data indicate that animal models appear to be limited for valid prediction of the inhibitory potential for TNF-α release in humans. Thus, human tissues should be considered early in the drug development process of p38 MAPK inhibitors.

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Section: Cellular Physiology and Biochemistrymentioning

confidence: 76%

Impact of p38 MAP Kinase Inhibitors on LPS-Induced Release of TNF-α in Whole Blood and Primary Cells from Different Species

Fehr

Unger²,

Schaeffeler

et al. 2015

Cell Physiol Biochem

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“…It is well known, that there are species differences in the expression of PDEs in various organs (Bian et al 2004, Johnson et al 2012). This poses a problem when translating results obtained in one species to another.…”

Section: Phosphodiesterases In the Rat Ovarymentioning

confidence: 99%

Phosphodiesterases in the rat ovary: effect of cAMP in primordial follicles

2015

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Phosphodiesterases (PDEs) are important regulators of the intracellular cAMP concentration, which is a central second messenger that affects a multitude of intracellular functions. In the ovaries, cAMP exerts diverse functions, including regulation of ovulation and it has been suggested that augmented cAMP levels stimulate primordial follicle growth. The present study examined the gene expression, enzyme activity and immunolocalization of the different cAMP hydrolysing PDEs families in the rat ovary. Further, the effect of PDE4 inhibition on primordial follicle activation in cultured neonatal rat ovaries was also evaluated. We found varied expression of all eight families in the ovary with Pde7b and Pde8a having the highest expression each accounting for more than 20% of the total PDE mRNA. PDE4 accounted for 15-26% of the total PDE activity. Immunoreactive PDE11A was found in the oocytes and PDE2A in the corpora lutea. Incubating neonatal rat ovaries with PDE4 inhibitors did not increase primordial follicle activation or change the expression of the developing follicle markers Gdf9, Amh, Inha, the proliferation marker Mki67 or the primordial follicle marker Tmeff2. In addition, the cAMP analogue 8-bromo-cAMP did not increase AKT1 or FOXO3A phosphorylation associated with follicle activation or increase the expression of Kitlg known to be associated with follicle differentiation but did increase the Tmeff2, Mki67 and Inha expression in a dose-dependent manner. In conclusion, this study shows that both Pde7b and Pde8a are highly expressed in the rodent ovary and that PDE4 inhibition does not cause an increase in primordial follicle activation. Reproduction (2015) 150 11-20

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“…In clinical and preclinical trials, the main human PDE4 inhibitor side effect, thought to be due to PDE4D activity (Robichaud, Savoie et al 2002;Robichaud, Stamatiou et al 2002;Conti, Richter et al 2003), is emesis at clinical doses while rats are more susceptible to toxic effects like arteriopathy. One explanation for this effect is the reduced PDE4 enzyme activity in humans relative to monkeys and rats (Bian, Zhang et al 2004). …”

Section: Camp Therapymentioning

confidence: 99%

The cyclic AMP phenotype of fragile X and autism

Kelley

Bhattacharyya

Lahvis

et al. 2008

Neuroscience & Biobehavioral Reviews

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Cyclic AMP (cAMP) is a second messenger involved in many processes including mnemonic processing and anxiety. Memory deficits and anxiety are noted in the phenotype of fragile X (FX), the most common heritable cause of mental retardation and autism. Here we review reported observations of altered cAMP cascade function in FX and autism. Cyclic AMP is a potentially useful biochemical marker to distinguish autism comorbid with FX from autism per se and the cAMP cascade may be a viable therapeutic target for both FX and autism.

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Differential type 4 cAMP-specific phosphodiesterase (PDE4) expression and functional sensitivity to PDE4 inhibitors among rats, monkeys and humans

Cited by 31 publications

References 32 publications

Impact of p38 MAP Kinase Inhibitors on LPS-Induced Release of TNF-α in Whole Blood and Primary Cells from Different Species

Impact of p38 MAP Kinase Inhibitors on LPS-Induced Release of TNF-α in Whole Blood and Primary Cells from Different Species

Phosphodiesterases in the rat ovary: effect of cAMP in primordial follicles

The cyclic AMP phenotype of fragile X and autism

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