Immunosuppressive and anti-inflammatory effects of cyclic AMP phosphodiesterase (PDE) type 4 inhibitors

Souness, John E.; Aldous, David; Sargent, Carol A.

doi:10.1016/s0162-3109(00)00185-5

Cited by 230 publications

(146 citation statements)

References 252 publications

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“…It has also been shown to have immunosuppressive and antiinflammatory effects (35). However, treatment of depression requires long-term administration.…”

Section: Discussionmentioning

confidence: 99%

The phosphodiesterase inhibitor rolipram delivered after a spinal cord lesion promotes axonal regeneration and functional recovery

Nikulina

Tidwell

Dai

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

303

259

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Although there is no spontaneous regeneration of mammalian spinal axons after injury, they can be enticed to grow if cAMP is elevated in the neuronal cell bodies before the spinal axons are cut. Prophylactic injection of cAMP, however, is useless as therapy for spinal injuries. We now show that the phosphodiesterase 4 (PDE4) inhibitor rolipram (which readily crosses the blood-brain barrier) overcomes inhibitors of regeneration in myelin in culture and promotes regeneration in vivo. Two weeks after a hemisection lesion at C3͞4, with embryonic spinal tissue implanted immediately at the lesion site, a 10-day delivery of rolipram results in considerable axon regrowth into the transplant and a significant improvement in motor function. Surprisingly, in rolipram-treated animals, there was also an attenuation of reactive gliosis. Hence, because rolipram promotes axon regeneration, attenuates the formation of the glial scar, and significantly enhances functional recovery, and because it is effective when delivered s.c., as well as post-injury, it is a strong candidate as a useful therapy subsequent to spinal cord injury.

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“…It has also been shown to have immunosuppressive and antiinflammatory effects (35). However, treatment of depression requires long-term administration.…”

Section: Discussionmentioning

confidence: 99%

The phosphodiesterase inhibitor rolipram delivered after a spinal cord lesion promotes axonal regeneration and functional recovery

Nikulina

Tidwell

Dai

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

303

259

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“…PDE4 selectively hydrolyses and inactivates cAMP. Its function in inflammatory cells was intensively studied [2] and research into PDE4 inhibitors has focused primarily on inflammatory disorders such as asthma and chronic obstructive pulmonary disease (COPD) [3]. Recent evidence suggests that PDE4 plays an essential role in glucose and fat metabolism [4][5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

The glucose-lowering effects of the PDE4 inhibitors roflumilast and roflumilast-N-oxide in db/db mice

Vollert

Kaessner²,

Heuser

et al. 2012

Diabetologia

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Aims/hypothesis The cAMP-degrading phosphodiesterase 4 (PDE4) enzyme has recently been implicated in the regulation of glucagon-like peptide-1 (GLP-1), an incretin hormone with glucose-lowering properties. We investigated whether the PDE4 inhibitor roflumilast elevates GLP-1 levels in diabetic db/db mice and whether this elevation is accompanied by glucose-lowering effects. Methods Plasma GLP-1 was determined in db/db mice after single oral administration of roflumilast or its active metabolite roflumilast-N-oxide. Diabetes-relevant variables including HbA 1c , blood glucose, serum insulin, body weight, food and water intake, and pancreas morphology were determined in db/db mice treated daily for 28 days with roflumilast or roflumilast-N-oxide. Pharmacokinetic/pharmacodynamic analysis clarified the contribution of roflumilast vs its metabolite. In addition, the effect of roflumilast-N-oxide on insulin release was investigated in primary mouse islets.Results Single treatment of db/db mice with 10 mg/kg roflumilast or roflumilast-N-oxide enhanced plasma GLP-1 2.5-and fourfold, respectively. Chronic treatment of db/db mice with roflumilast or roflumilast-N-oxide at 3 mg/kg showed prevention of disease progression. Roflumilast-N-oxide abolished the increase in blood glucose, reduced the increment in HbA 1c by 50% and doubled fasted serum insulin compared with vehicle, concomitant with preservation of pancreatic islet morphology. Furthermore, roflumilast-N-oxide amplified forskolininduced insulin release in primary islets. Roflumilast-N-oxide showed stronger glucose-lowering effects than its parent compound, consistent with its greater effect on GLP-1 secretion and explainable by pharmacokinetic/pharmacodynamic modelling. Conclusions/interpretation Our results suggest that roflumilast and roflumilast-N-oxide delay the progression of diabetes in db/db mice through protection of pancreatic islet physiology potentially involving GLP-1 and insulin activities.

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“…Among the eleven families of mammalian PDE described to date, the PDE4 family specifically hydrolyzes cAMP and is predominant in all immunocompetent cells (16). Selective PDE4 inhibitors reduce the production of chemokines, proinflammatory cytokines, and adhesion molecules in leukocytes, endothelial, and airway epithelial cells (17). The PDE4s are encoded by four genes (A, B, C, and D) which generate at least 20 different isoforms.…”

mentioning

confidence: 99%

The PDE4 Inhibitor Rolipram Prevents NF-κB Binding Activity and Proinflammatory Cytokine Release in Human Chorionic Cells

Hervé

Schmitz

Évain-Brion

et al. 2008

The Journal of Immunology

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Spontaneous preterm delivery is linked to intrauterine inflammation. Fetal membranes are involved in the inflammatory process as an important source of mediators, and the chorion leave produces high levels of the proinflammatory cytokine TNF-α when stimulated by LPS. The transcription factor NF-κB is the main regulator of this inflammatory process and controls the production of cytokines by the chorion leave. Phosphodiesterase 4 inhibitors are recognized for their anti-inflammatory and myorelaxant effects. The purpose of this study was to investigate whether PDE4 inhibition affects the LPS signaling in human cultured chorionic cells. We showed that these cells express TLR4, the main LPS receptor, and exhibit a predominant PDE4 activity. Upon LPS challenge, PDE4 activity increases concomitantly to the induction of the specific isoform PDE4B2 and chorionic cells secrete TNF-α. LPS induces the nuclear translocation of the NF-κB p65 subunit and the activation of three different NF-κB complexes in chorionic cells. The presence of the PDE4 inhibitor rolipram reduces the TNF-α production and the activation of the three NF-κB complexes. These data indicate that the PDE4 family interacts with the LPS signaling pathway during the inflammatory response of chorionic cells. PDE4 selective inhibitors may thus represent a new therapeutic approach in the management of inflammation-induced preterm delivery.

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Immunosuppressive and anti-inflammatory effects of cyclic AMP phosphodiesterase (PDE) type 4 inhibitors

Cited by 230 publications

References 252 publications

The phosphodiesterase inhibitor rolipram delivered after a spinal cord lesion promotes axonal regeneration and functional recovery

The phosphodiesterase inhibitor rolipram delivered after a spinal cord lesion promotes axonal regeneration and functional recovery

The glucose-lowering effects of the PDE4 inhibitors roflumilast and roflumilast-N-oxide in db/db mice

The PDE4 Inhibitor Rolipram Prevents NF-κB Binding Activity and Proinflammatory Cytokine Release in Human Chorionic Cells

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