Anti-inflammatory and analgesic effects of the phosphodiesterase 4 inhibitor rolipram in a rat model of arthritis

Francischi, Janetti Nogueira de; Yokoro, C.M.; Poole, Stephen; Tafuri, Wagner Luiz; Cunha, Fernando; Teixeira, Mauro Martins

doi:10.1016/s0014-2999(00)00330-7

Cited by 76 publications

(55 citation statements)

References 17 publications

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“…This represents the major signaling pathway in different biologic responses. Several studies have highlighted the therapeutic potential of cAMP agonists for the treatment of arthritis (41,42). Our data confirm the functional coupling of VIP receptors to AC in OA FLS and RA FLS.…”

Section: Discussionsupporting

confidence: 85%

Differential expression of vasoactive intestinal peptide and its functional receptors in human osteoarthritic and rheumatoid synovial fibroblasts

Juarranz

Gutiérrez‐Cañas

Santiago

et al. 2008

Arthritis & Rheumatism

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Objective. Vasoactive intestinal peptide (VIP) hasshown potent antiinflammatory effects in murine arthritis and ex vivo in human rheumatoid arthritis (RA) synovial cells. To investigate the potential endogenous participation of this system in the pathogenesis of RA, we analyzed the expression and regulation of VIP and its functional receptors in human fibroblast-like synoviocytes (FLS) from patients with osteoarthritis (OA) and patients with RA.Methods. The expression of VIP was studied by reverse transcription-polymerase chain reaction (RT-PCR), enzyme immunoassay, and immunofluorescence in cultured FLS, and by immunohistochemical analysis in synovial tissue. The expression and function of the potential VIP receptors in FLS were studied by RT-PCR, determination of intracellular cAMP production, cell membrane adenylate cyclase (AC) activity, and interleukin-6, CCL2, and CXCL8 production in response to VIP or specific agonists and antagonists.Results. VIP expression was detected in human FLS at the messenger RNA and protein levels, and it was significantly decreased in RA FLS compared with OA FLS. VIP receptor type 1 (VPAC 1 ) was the dominant AC-coupled receptor in OA FLS, in contrast with RA FLS, in which VPAC 2 was dominant. Tumor necrosis factor ␣-treated OA FLS reproduced the VIP and VPAC receptor expression pattern of RA FLS. The antagonistic effects of VIP on FLS proinflammatory factor production were reproduced by VPAC 1 -and VPAC 2 -specific agonists in OA FLS and RA FLS, respectively.Conclusion. VIP expression is down-regulated in RA and in tumor necrosis factor ␣-treated FLS, suggesting that down-regulation of this endogenous antiinflammatory factor may contribute to the pathogenesis of RA. In RA FLS, VPAC 2 mediates the antiinflammatory effects of VIP, suggesting that VPAC 2 agonists may be an alternative to VIP as antiinflammatory agents.The vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating peptide (PACAP) system consists of 2 peptides and 3 receptors: VIP receptor type 1 (VPAC 1 ), VPAC 2 , and PACAP type 1 (PAC 1 ) receptor. These receptors belong to family 2 of the G proteincoupled receptors, which in recent years have shown remarkable antiinflammatory and immunomodulatory properties (1-3). VPAC 1 is constitutively expressed in macrophages and lymphocytes and binds VIP and PACAP with equal affinity (1,3). VPAC 2 has also been described in lymphocytes and macrophages as an inducible receptor after T cell receptor triggering or lipopolysaccharide (LPS) stimulation (1,3). The bestcharacterized effects of VIP/PACAP on immune cells are mediated by the adenylate cyclase (AC) pathway coupled to these receptors. Finally, the PAC 1 receptor is the PACAP-specific receptor, although at high concentrations VIP is a heterologous ligand (4). Endogenous VIP and PACAP can be produced by both neural and immune cells, but their regulation and participation in the pathogenesis of human inflammation are not known.

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Section: Discussionsupporting

confidence: 85%

Differential expression of vasoactive intestinal peptide and its functional receptors in human osteoarthritic and rheumatoid synovial fibroblasts

Juarranz

Gutiérrez‐Cañas

Santiago

et al. 2008

Arthritis & Rheumatism

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“…Rolipram has also been shown to be antiinflammatory, but it is unlikely that this property is influencing recovery under the conditions used here for two reasons. First, the dose of rolipram most effective as an antiinflammatory agent is 3-to 6-fold higher than the optimal dose we report here for functional recovery after spinal cord injury (22)(23)(24). Second, methylprednisolone, a known antiinflammatory already used as a therapy in humans, prevents some secondary cell loss in animal models of spinal cord injury but does not produce any significant improvement in functional recovery (25)(26)(27) Regardless, of the mechanism of action, rolipram is effective and should be considered as a therapy for spinal cord injury.…”

Section: Discussionmentioning

confidence: 76%

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.

310

270

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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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“…The anti-inflammatory versus pain-producing effects of cAMP and PDEi are contradictory. Although rolipram is a cognition-enhancing antidepressant agent, it has strong antiinflammatory properties, but it will prolong inflammatory pain if given locally (21,(26)(27)(28)(29). It was suggested earlier that rolipram may have analgesic-like effects (26).…”

Section: Discussionmentioning

confidence: 99%

Analgesia mediated by soluble epoxide hydrolase inhibitors is dependent on cAMP

Inceoglu

Wagner

Schebb

et al. 2011

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

124

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Pain is a major health concern even though numerous analgesic agents are available. Side effects and lack of wide-spectrum efficacy of current drugs justify efforts to better understand pain mechanisms. Stabilization of natural epoxy-fatty acids (EFAs) through inhibition of the soluble epoxide hydrolase (sEH) reduces pain. However, in the absence of an underlying painful state, inhibition of sEH is ineffective. Surprisingly, a pain-mediating second messenger, cAMP, interacts with natural EFAs and regulates the analgesic activity of sEH inhibitors. Concurrent inhibition of sEH and phosphodiesterase (PDE) dramatically reduced acute pain in rodents. Our findings demonstrate a mechanism of action of cAMP and EFAs in the pathophysiology of pain. Furthermore, we demonstrate that inhibition of various PDE isozymes, including PDE4, lead to significant increases in EFA levels through a mechanism independent of sEH, suggesting that the efficacy of commercial PDE inhibitors could result in part from increasing EFAs. The cross-talk between the two major pathways-one mediated by cAMP and the other by EFAs-paves the way to new approaches to understand and control pain.nociception | antinociceptive | epoxyeicosatrienoic acid

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Anti-inflammatory and analgesic effects of the phosphodiesterase 4 inhibitor rolipram in a rat model of arthritis

Cited by 76 publications

References 17 publications

Differential expression of vasoactive intestinal peptide and its functional receptors in human osteoarthritic and rheumatoid synovial fibroblasts

Differential expression of vasoactive intestinal peptide and its functional receptors in human osteoarthritic and rheumatoid synovial fibroblasts

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

Analgesia mediated by soluble epoxide hydrolase inhibitors is dependent on cAMP

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