Article Text

Download PDFPDF
An apPEAling new therapeutic for ulcerative colitis?
  1. Declan P McKernan,
  2. David P Finn
  1. Pharmacology and Therapeutics, School of Medicine, Galway Neuroscience Centre and Centre for Pain Research, NCBES, National University of Ireland Galway, Galway, Ireland
  1. Correspondence to Dr Declan P McKernan Pharmacology and Therapeutics, School of Medicine, National University of Ireland, Galway, University Road, Galway, Ireland; declan.mckernan{at}nuigalway.ie

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

IBD includes Crohn's Disease and ulcerative colitis (UC), which are multifaceted chronic inflammatory conditions. Their aetiology is thought to involve the interaction of genetic, immunological and environmental factors. Current therapeutics have not succeeded in eliminating the burden of these diseases. Some are associated with side effects, which themselves can cause discomfort for the patient, leading to a decrease in compliance and a return to the status quo prior to medication. In addition, the cost of current therapeutics is very high.1 All of these considerations require the development of less toxic, better tolerated, more efficacious and cheaper drugs.

Enteric glial cells (EGCs) are major constituents of the enteric nervous system, outnumbering neurones by 4–1.2 They are thought to help control motility, secretion, nutrient uptake and blood flow via their interactions with enteric nerves. Evidence of their importance in the transduction of inflammatory signals is now emerging. They are capable of producing many inflammatory cytokines as well as neurokinin A and substance P, which can act on immune cells in their vicinity.2 Glial proliferation is seen in animal models of inflammation, as well as a concomitant reduction in the number of enteric neurones, a finding replicated in IBD patients.3

EGCs produce S100B, a member of a group of small calcium/zinc binding proteins known to regulate cytoskeletal function and calcium homeostasis.4 S100B also stimulates the expression of inducible nitric oxide synthase and subsequently nitric oxide (NO), in UC patients.5 Recent findings indicate that NO release in EGCs can be stimulated via both S100B and toll-like receptor (TLR4) on those cells, leading to the release of proinflammatory cytokines.6

The paper by Esposito et al 7 presents a large body of novel data on the anti-inflammatory effects of palmitoylethanolamide (PEA) in a mouse model of UC, as well as in human patient biopsy tissue and primary cultures of EGCs from mice and humans. It also adds to the growing body of data highlighting the important role EGCs play in the amplification of the inflammatory response in the colon. PEA is an endogenous N-acylethanolamide, previously shown to modulate pain and inflammation.8 Anti-inflammatory effects of PEA depend upon its ability to activate peroxisome proliferator-activated receptors (PPARs), members of the nuclear hormone receptor superfamily of ligand-activated transcription factors.9 The multiple approaches employed in the paper by Esposito et al and the large number of inflammatory markers/mediators measured make a convincing case for PEA-induced anti-inflammatory effects, mediated via PPAR-α. The results demonstrate convincingly that PEA reduces immune cell infiltration and activity in the colon of dextran sodium sulfate (DSS)-treated mice and human UC biopsies. The expression of TLR4, S100B proteins and signalling molecules was reduced in the DSS mouse model and in UC biopsies following PEA treatment. The use of single doses/concentrations of the antagonists means that it is not possible to definitively rule out a role for PPAR-γ in mediating the effects of PEA (ie, perhaps higher doses/concentrations of the PPAR-γ antagonist GW9662 would have blocked the effects of PEA?). However, the demonstration that the anti-inflammatory effects of PEA are abolished following silencing of PPAR-α expression in EGCs or in PPAR-α knockout mice does support the contention that the contribution of PPAR-γ to the effects of PEA observed in these studies appears to be minimal and that the effects of PEA are largely dependent on PPAR-α.

In this study, mice with DSS-induced colitis have quite low inflammation scores of approximately 1.8 (on a scale from 0 to 12) and PEA significantly reduces the score from approximately 1.8 to 0.8. The low inflammation scores in untreated mice may mean that the efficacy of PEA is somewhat underestimated in the present study. The reason for the low scores may relate to the fact that mice were killed 7 days after DSS, while, according to literature, disease activity in the DSS model peaks on days 8–9.10 Nevertheless, the very robust increase in inflammatory markers in DSS-treated mice suggests that the treatment was effective in inducing a significant acute colitis, which in turn, was attenuated significantly by PEA treatment.

The results of this study raise the exciting possibility that PEA might be used therapeutically for the effective treatment of UC. However, before such promise is realised, it would be important to further characterise the pharmacokinetics and efficacy of PEA in relevant animal models and in human clinical trials. The intraperitoneal route of administration was used in the present study. However, it would be interesting to investigate the efficacy of PEA following oral administration in the DSS model and in other models of ulcerative colitis. Assessment of the efficacy of PEA coadministered with an inhibitor of fatty acid amide hydrolase (FAAH) would also be of interest and potential therapeutic relevance. Although further studies on the potential adverse effects of PEA are warranted, a recent case series showed that pain patients treated with a high dose of PEA reported no significant adverse or toxic reactions and a review of the clinical trials published to-date also suggests that PEA has a good safety profile.11

The paper by Esposito et al therefore represents an important contribution to our understanding of PEA and its mechanism of action, particularly with respect to its anti-inflammatory effects in the gastrointestinal tract. The data suggest that PEA may represent a viable therapeutic option for the effective treatment of UC and provide a solid foundation on which to design clinical trials to address this question.

References

Footnotes

  • Contributors Both authors contributed equally to this article.

  • Competing interests None.

  • Provenance and peer review Commissioned; internally peer reviewed.

Linked Articles