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

Abstract

There has been much interest in strategies which modulate tumour necrosis factor-α (TNF-α) levels and/or function in rheumatoid arthritis. The elevation of intracellular levels of cyclic AMP in leukocytes by phosphodiesterase 4 inhibitors is accompanied by significant inhibition of the production of TNF-α. Nevertheless, these drugs may enhance the hyperalgesia induced by a range of inflammatory mediators, including TNF-α. In the present study, we examined the effects of the phosphodiesterase 4 inhibitor rolipram on the local inflammatory infiltrate and hyperalgesia in a rat model of adjuvant-induced arthritis. Rolipram (3 mg/kg) was administered by oral gavage from day 10 to 14 after disease induction. Pretreatment with rolipram abrogated oedema formation and significantly inhibited hyperalgesia. Histopathological analysis revealed a marked inhibition of cellular influx as well as bone and cartilage destruction. Serum and local TNF-α levels were suppressed in treated animals whereas there were little changes in interleukin-1β levels. Although cyclic AMP elevating agents may affect nociceptor threshold to increase the hyperalgesic responses acutely, they also possess significant anti-inflammatory activity, which may hinder local mediator release and/or action. The anti-inflammatory effects of rolipram predominate during this chronic arthritis model in the rat.

Introduction

Rheumatoid arthritis is a common chronic inflammatory disorder involving the synovial membranes of multiple joints in humans (Sewell and Trentham, 1993). Although there are reasonably good drugs used in the symptomatic relief of arthritis (e.g. non-steroidal anti-inflammatory drugs), there are few safe drugs, which modify fundamental pathologic processes responsible for the chronic inflammation (Cash and Klippel, 1994). Recently, there has been much interest in strategies, which inhibit tumour necrosis factor-α (TNF-α) levels and/or function as TNF-α appears to play a major pathophysiological role in rheumatoid arthritis (Feldman et al., 1998). Such interest stems from the clinically beneficial effects of anti-TNF-α treatment of rheumatic patients -Feldman et al., 1998, Moreland et al., 1997.

The elevation of intracellular levels of cyclic AMP in leukocytes is accompanied by significant inhibition of the production of TNF-α Teixeira et al., 1997, Procopio et al., 1999. In this regard, strategies which elevate cyclic AMP may be beneficial in the treatment of rheumatoid arthritis. The levels of cyclic AMP inside cells are controlled by the degree of cyclic AMP production via adenylate cyclase-coupled receptors (e.g. β-adrenoceptors) and the metabolism of cyclic AMP by phosphodiesterases (Teixeira et al., 1997). The main phosphodiesterase activity present in leukocytes is the phosphodiesterases type 4 Teixeira et al., 1997, Torphy, 1998. Blockade of these enzymes is associated with the inhibition of several leukocyte functions, including inhibition of TNF-α production and the release of other inflammatory mediators and reactive oxygen species Teixeira et al., 1997, Torphy, 1998, Au et al., 1998.

A few animal studies have evaluated the effect of phosphodiesterase 4 inhibitors in rodent models of rheumatoid arthritis Sekut et al., 1995, Nyman et al., 1997, Ross et al., 1997. These studies demonstrate that treatment with the prototype phosphodiesterase 4 inhibitor rolipram is effective both prior to (Sekut et al., 1995) and when given after Nyman et al., 1997, Ross et al., 1997 the arthritis-inducing stimulus. However, none of these studies evaluated any possible effect of rolipram on a major characteristic of rheumatoid arthritis, inflammatory hyperalgesia. In this respect, we have recently demonstrated that pretreatment of animals with locally injected rolipram significantly enhanced the hyperalgesia induced by several mediators, including that induced by TNF-α (Cunha et al., 1999). Thus, if phosphodiesterase 4 inhibitors are to be used in the treatment of rheumatoid arthritis, it is essential that their effects on hyperalgesia in animal models of arthritis are evaluated.

In the present study, we have used a model of adjuvant-induced arthritis in rats to evaluate the effect of the phosphodiesterase 4 inhibitor rolipram on the local inflammatory infiltrate and hyperalgesia. The local (in the paw) and circulating levels of TNF-α in control and treated rats were measured to assess the effectiveness of the dose of rolipram used. For comparison, we also assessed the local and systemic levels of interleukin-1α, a cytokine known to play an important role in arthritis (Breedveld, 1999), but usually less affected by phosphodiesterase 4 inhibitor pretreatment (reviewed by Torphy, 1998). Of note, rolipram was given orally after the induction of arthritis.