Phosphodiesterase inhibitors in inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) is fundamentally a relapsing and remitting disease appearing in forms of ulcerative colitis (UC) or Crohn's disease (CD) with a non-well-known etiology. With the hope to prevent adverse drug events and to increase the efficacy of therapies for IBD, in the recent years, other than new monoclonal antibodies such as infliximab, the novel phosphodiesterase inhibitors (PDEIs) have been introduced. Among PDE4Is, rolipram, OPC-6535, mesopram, roflumilast and tetomilast have shown beneficial effects in experimental colitis. Unfortunately until now, human studies have not been successful in showing significant superiority of PDE4Is in the treatment of IBD. Parallel with discovery of PDE4Is and their anti-inflammatory properties, inhibiting other PDE isoenzymes in immune and proinflammatory cells is on the way. PDE7Is have shown synergistic effect with PDE4Is and they may act similar to PDE3Is in experimental settings. Sildenafil as the PDE5I has shown good effects in experimental colitis by balancing oxidant–antioxidant status. Although the present data about PDE superfamily and their specific roles in gastrointestinal tract is limited but inhibitors of PDE4, PDE5 and PDE7 seem good candidates as the next generation of effective drugs. The synergistic anti-inflammatory effect of PDE4Is and PDE7Is is also important.

Keywords:

• inflammatory bowel disease
• phosphodiesterase inhibitors

Inflammatory bowel disease (IBD) is fundamentally a relapsing and remitting disease appearing in forms of ulcerative colitis (UC) or Crohn's disease (CD). Intestinal mucosal inflammation, followed by bloody-mucous diarrhea and abdominal pain are main demonstrations. The etiology of IBD is not absolutely determined yet but it seems to be multifactorial where role of genetics cannot be ignored. In the recent years, major reviews have been conducted and have clarified the involvement of some pathological cytokines [1], immune dysfunction [2], potassium channel openers [3], adenosine triphosphate (ATP) donors [4] and various phosphodiesterase inhibitors (PDEIs) [5,6]. Potential of current medicines in causing adverse effects and the high morbidity of IBD have urged investigators to expand their studies to find out better understandings of the disease pathophysiology.

Therefore, investigators try to target specific cells, cytokines and receptors but side effects and inability to cure the disease still concern. With the hope to prevent adverse events and to increase the efficacy, new studies target the affected tissues. Keeping these in mind, other than new monoclonal antibodies such as infliximab, the novel PDEIs have been newly introduced.

PDEIs elevate the level of second messengers including cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in different organs. They activate protein kinases followed by phosphorylation of a wide variety of cellular substances and finally cellular functions. The concentration of cAMP and cGMP depends on the balance between synthesis and degradation. PDE consists of several families with different subtypes and activities. Each member of PDE superfamily is involved in different functions in different organs and consequently in several pathophysiologic conditions such as inflammatory diseases, cancer and neurodegeneration. Thus, it is not surprising to track a wide range of effects of PDEIs in different pathophysiological conditions. Targeting PDE as non-specific inhibition was considered in the first generation of PDEIs and specific inhibitors are now called second-generation ones. For example, theophylline as a first-generation PDEI poses anti-inflammatory effects especially in the respiratory system but current evidences are not convincing [7]. It is notable that various first- and second-generation PDEIs have been isolated from herbal medicines [8].

As recently reviewed by Salari-Sharif and Abdollahi [6], among PDEIs, PDE 4 family is the dominant isoenzyme in inflammatory cells and consists of four genes (A – D). The principal variant of PDE4 in the most inflammatory and immunomudulatory cells are PDE4A, PDE4B and PDE4D. The anti-inflammatory and immunoregulatory effects of PDE4Is are currently targeted by most of the investigators. The anti-inflammatory effect of PDE4Is is the result of suppression of cAMP in inflammatory mediators and cytokines including tumor necrosis factor-α (TNF-α), interferon-γ (INF-γ), transforming growth factor-β (TGF-β) and prostaglandin E2 (PGE2). The similarity between different inflammatory pathogenesis in chronic inflammatory diseases has raised the concern about effectiveness of PDE4Is in IBD. Animal studies have shown favorable effects of rolipram, OPC-6535, mesopram, roflumilast and tetomilast in experimental colitis. Unfortunately until now, human studies have failed to show success in the superiority of PDE4Is in the treatment of IBD. In the Phase II randomized placebo-controlled double-blind study on 186 patients with mild to moderate UC, the primary end point (disease activity index) did not show significant improvement in the tetomilast group in comparison with placebo while the secondary end point achieved by post hoc analysis indicated that patients with high disease activity scores respond better to tetomilast [9]. The Phase III study could not show significant difference between tetomilast and placebo at primary and secondary end points; however, there was a trend toward decreasing severity of bleeding in tetomilast group [10].

Parallel with discovery of PDE4Is and their anti-inflammatory properties, inhibiting other PDE isoenzymes in immune and proinflammatory cells is on the way. PDE7Is are regulated by two genes (A and B). Formerly, it was found that up-regulation of PDE7A may be involved in the pathogenesis of chronic inflammatory conditions including asthma and chronic obstructive pulmonary disease (COPD). Investigation in regulation of PDE7A has identified its role in peripheral CD4⁺ and CD8⁺ T lymphocytes in lung, immune system, skeletal muscle, heart and the kidney. Inhibition of PDE7 has no proved anti-inflammatory effect in normal condition but it promotes antibody response to injection of vaccine. Furthermore, it has been proposed that PDE7Is have synergistic effect with PDE4Is and they may act the same as PDE3Is in experimental settings [11]. Apart from PDE4, involvement of PDE7 in induction and function of mouse cytotoxic T lymphocytes via intracellular cAMP has been suggested [12]. This finding may be of great help toward finding new therapeutic drugs for autoimmune diseases.

The other family of PDE is PDE5 family in which its inhibition has different pharmacological effects. Sildenafil, the selective PDE5I, increases cGMP and relaxes smooth muscle cells while recent studies have indicated its anti-inflammatory action by nitric oxide (NO)-dependent mechanisms which prevent leukocyte adhesion [13]. An in vivo study reported beneficial effect of sildenafil in experimental colitis by balancing oxidant–antioxidant status and inhibiting reactive oxygen metabolites (ROM) production and release of cytokines [13,14]. Notably, PDEIs may mediate immunosuppressive action of adenosine by increasing cAMP [14].

The studies that investigated the possible effects of PDEIs on inflammation and/or colitis are summarized in Table 1.

Table 1. Summary of studies investigated by various types of PDEIs in human IBD or animal colitis.

Study (year)	Protocol	Outcome	Conclusion
Barnette et al. (1993) [6]	Rolipram (canine)	Rolipram antagonized colonic contractility	Rolipram may have favorable effects in IBD
Maeda et al. (1997) [6]	OPC-6535, salazosulfapyridine (rat)	OPC-6535 and salazosulfapyridine reduced frequency of diarrhea; only OPC-6535 reduced neutrophils	Only OPC-6535 reduces intestinal inflammation
Miyakado et al. (1997) [6]	OPC-6535, salazosulfapyridine (rat)	Both drugs decreased incidence of diarrhea	Both drugs reduce the size of intestinal inflammation
Izzo et al. (1998) [6]	Rolipram (guinea pig)	Rolipram inhibited nerve-mediated contractions of ileum (10 – 91%)	PDE4 inhibition depress neural transmission of enteric nervous system
Puig et al. (1998) [6]	Rolipram, arofylline (rat)	Both drugs decreased bleeding, LTB4; arofylline reduced MPO	PDE4Is show similar curative effect with prednisolone in IBD
Hartmann et al. (2000) [6]	Rolipram (mouse)	Rolipram reduced clinical activity of colitis and suppressed colonic TNF-α	Rolipram prevents and treats experimental colitis
Diaz-Granados et al. (2000) [6]	Rolipram (mouse)	Rolipram reduced severity of colonic histopathology	Specific PDE4I reduces tissue damage in colitis and enhances recovery of colonic function
Loher et al. (2003) [6]	Mesopram (mouse)	Mesopram reduced clinical and histologic scores of colitis and reduced colonic INF-γ	Mesopram is effective in prevention and treatment of murine colitis
Videla et al. (2006) [6]	Rolipram (rat)	Rolipram reduced colonic TNF-α, lesion scores and collagen content	Rolipram ameliorates chronic colitis especially in preventing collagen deposition
Barone et al. (2008) [6]	Rolipram/roflumilast (rat)	Both drugs inhibited fecal output dose-dependently	PDE4Is are effective in reducing rodent stress-induced defecation
Ichikawa et al. (2008) [6]	Tetomilast (mouse, human monocytes)	Tetomilast suppressed TNF-α and IL-12 production induced by LPS in monocytes, and TNF-α, IFN-γ, IL-10 from CD4 cells, reduced clinical and histological scores of colitis	Tetomilast is a novel drug for IBD
Giembycz et al. (2006) [11]	PDE7	PDE7 exists in CD4^+ and CD8^+ cells in lung, immune system, skeletal muscle, heart, kidney; no effect of PDEIs in normal condition	PDE7Is have synergistic effect with PDE4Is
Kadoshima-Yamaoka et al. (2009) [12]	PDEI ASB16165	Major involvement of PDEI ASB16165 in the induction and function of cytotoxic T lymphocytes in mouse	Probably PDEI ASB16165 affects intracellular cAMP levels. It may be useful in treatment of autoimmune diseases
Iseri et al. (2009) [13]	Sildenafil	Sildenafil reverses TNF-α and IL-1β in the colitis back to the control values	In the rat model of colitis sildenafil prevents lipid peroxidation, cytokine production and neutrophil accumulation
Khoshakhlagh et al. (2007) [5]	Sildenafil	Sildenafil and prednisolone recovered MPO and TBARS and lowered the score of the disease	Sildenafil is a potent antioxidant agent useful in IBD which acts through cGMP

cAMP: Cyclic adenosine monophosphate; cGMP: Cyclic guanosine monophosphate; IBD: Inflammatory bowel disease; IL-10: Interleukin-10; IL-12: Interleukin-12; IL-1β: Interleukin-1β; INF-γ: Interferon-γ; LPS: Lipopolysaccharide; LTB4: Leukotrien B4; MPO: Myeloperoxidase; PDE4: Phosphodiesterase 4; PDE4Is: Phosphodiesterase 4 inhibitors; PDE7: Phosphodiesterase 7; PDE7Is: Phosphodiesterase 7 inhibitors; PDEI: Phosphodiesterase 7 inhibitors; TBARS: Thiobarbituric acid reactive substances; TNF-α: Tumor necrosis factor-α.

Expert opinion

Taken together it seems that PDEIs have helped to better understand the role of inflammation and autoimmune drive in the pathogenesis of IBD. Presently, data about PDE superfamily is limited and further investigations into their specific roles in gastrointestinal tract would be of great importance. Other than PDE4, PDE5 and PDE7, the present knowledge about the rest of PDE superfamily is limited; however, investigations into the benefits of these three subfamilies are promising. Thus, more attention to PDE4 and PDE5 and their specific inhibitors that affect intestine are of further significance. Likewise, more studies on the synergistic anti-inflammatory effect of PDE4Is and PDE7Is or other combinations of PDEIs are highly recommended.

Declaration of interest

This paper is the outcome of an in-house non-financially supported study on an invitation of Prof. Mohammad Abdollahi by the senior editor of Expert Opinion on Investigational New Drugs. Authors have no conflict of interest.