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Article of the Month: Have TRP channels fulfilled their promise in LUTS?

Every Month the Editor-in-Chief selects the Article of the Month from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Month heading on the homepage will consist of additional material or media. This week we feature a video from Dr. Wouter Everaerts, discussing his paper. 

If you only have time to read one article this week, it should be this one.

Transient receptor potential channel modulators as pharmacological treatments for lower urinary tract symptoms (LUTS): myth or reality?

Yves Deruyver*‡¶, Thomas Voets†¶, Dirk De Ridder*‡¶ and Wouter Everaerts*§¶

 

*Laboratory of Experimental Urology, Department of Development and Regeneration,† Laboratory for Ion Channel Research, Department of Molecular Cell Biology, KU Leuven, University Hospitals Leuven, TRP Research Platform Leuven (TRPLe), Leuven, Belgium, and §Royal Melbourne Hospital, Melbourne, Australia

 

Transient receptor potential (TRP) channels belong to the most intensely pursued drug targets of the last decade. These ion channels are considered promising targets for the treatment of pain, hypersensitivity disorders and lower urinary tract symptoms (LUTS). The aim of the present review is to discuss to what extent TRP channels have adhered to their promise as new pharmacological targets in the lower urinary tract (LUT) and to outline the challenges that lie ahead.

  • TRP vanilloid 1 (TRPV1) agonists have proven their efficacy in the treatment of neurogenic detrusor overactivity (DO), albeit at the expense of prolonged adverse effects as pelvic ‘burning’ pain, sensory urgency and haematuria.
  • TRPV1 antagonists have been very successful in preclinical studies to treat pain and DO. However, clinical trials with the first generation TRPV1 antagonists were terminated early due to hyperthermia, a serious, on-target, side-effect.
  • TRP vanilloid 4 (TRPV4), TRP ankyrin 1 (TRPA1) and TRP melastatin 8 (TRPM8) have important sensory functions in the LUT. Antagonists of these channels have shown their potential in pre-clinical studies of LUT dysfunction and are awaiting clinical validation.

Editorial: TRP channel – a reality that still requires many years of scientific efforts

Seventeen years have elapsed since the capsaicin receptor was first cloned by Caterina et al. [1] and the excellent review with an unusual provocative title by Deruyver et al. [2] was written. The capsaicin channel, re-named transient receptor potential (TRP) vanilloid receptor subtype 1 (TRPV1), is now commonly referred to as the founding member of the TRP family, as it currently includes 28 related channels, a number difficult to foresee in those early years [3].

TRP channels have been extensively studied in the lower urinary tract (LUT) with the aim of clarifying their role in micturition control and in the generation of LUTS. It is well accepted that TRP receptors have neuronal and non-neuronal expression [3, 4]. TRPV1 is fundamental to bladder hyperactivity and pain associated with LUT inflammation [3], while TRPV4 may participate in the generation of the normal sensation to void [5]. Another group of TRP receptors may even participate in bladder oncogenesis, which seems to be a role of TRPV2 [3]. The main substance of all this information is not a myth; rather it represents a large body of very solid scientific data.

There are certainly still many obscure areas. The distribution of TRP receptors in the bladder is certainly one of them. However, I disagree that a substantial part of available technical and financial resources have been allocated to study this matter. One should not forget that other matters, like the role of many TRP channels for bladder function, remain elusive. Broadly speaking, in my opinion, future key studies should tackle three very relevant but still unclear points. The importance of most TRP channels for bladder function is difficult to predict at the moment [3]. Just as an example, TRPA1 and TRPM8, which are sensitive to cold temperatures, are expressed in the bladder. However, the bladder, as all internal organs, is conserved at very constant physiological temperatures, making it difficult to understand the relevance of cold receptors to its function. Then, we need to find what the endogenous agonists for TRP receptors are in the LUT. Anandamide has been largely explored as an endogenous agonist for TRPV1 in the bladder [6], a fruitful observation as drugs able to manipulate endogenous levels of anandamide are currently being explored in clinical trials. The same holds true for the other members of the TRP family. TRPA1 may respond to infections due to its capacity to react to hydrogen sulphide [3]. But for the large majority of the TRP family endogenous agonists remain unknown. Finally, TRP antagonists that are simultaneously effective and safe must be generated. Most available TRPV1 antagonists, produced to date, although able to control bladder dysfunction in models of cystitis and spinal cord injury [3], cause hyperthermia and have been associated with an enlargement of ischaemic areas of the heart after coronary artery obstruction [3]. TRPV4 antagonists look very promising for controlling frequency but a compound safe for human use is still eagerly awaited [2]. Eventually the combination of antagonists for more than one of these receptors may prove effective at very low doses, so low that they do not generate serious adverse effects [7].

In conclusion, TRP receptors are a reality that still needs an enormous amount of work and dedication before becoming therapeutically useful. And that may take more time than we anticipate at the moment.

 

Francisco Cruz
Department of Urology, Al. Hernani Monteiro, Porto, Portugal

 

References

 

1 Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JDJulius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997; 389: 81624

 

 

3 Avelino A, Charrua A, Frias B et al. Transient receptor potential channels in bladder function. Acta Physiol (Oxf) 2013; 207: 110122

 

4 Birder LA, Kanai AJ, de Groat WC et al. Vanilloid receptor expression suggests a sensory role for urinary bladder epithelial cells. Proc Natl Acad Sci U S A 2001; 98: 13396401

 

5 Gevaert T, Vriens J, Segal A et al. Deletion of the transient receptor potential cation channel TRPV4 impairs murine bladder voiding. J Clin Invest 2007; 117: 345362

 

 

Video: TRP channel modulators as pharmacological treatments for LUTS – myth or reality?

Transient receptor potential channel modulators as pharmacological treatments for lower urinary tract symptoms (LUTS): myth or reality?

Yves Deruyver*‡¶, Thomas Voets†¶, Dirk De Ridder*‡¶and Wouter Everaerts*§¶

 

*Laboratory of Experimental Urology, Department of Development and Regeneration,† Laboratory for Ion Channel Research, Department of Molecular Cell Biology, KU Leuven, University Hospitals Leuven, TRP Research Platform Leuven (TRPLe), Leuven, Belgium, and §Royal Melbourne Hospital, Melbourne, Australia

 

Transient receptor potential (TRP) channels belong to the most intensely pursued drug targets of the last decade. These ion channels are considered promising targets for the treatment of pain, hypersensitivity disorders and lower urinary tract symptoms (LUTS). The aim of the present review is to discuss to what extent TRP channels have adhered to their promise as new pharmacological targets in the lower urinary tract (LUT) and to outline the challenges that lie ahead.

  • TRP vanilloid 1 (TRPV1) agonists have proven their efficacy in the treatment of neurogenic detrusor overactivity (DO), albeit at the expense of prolonged adverse effects as pelvic ‘burning’ pain, sensory urgency and haematuria.
  • TRPV1 antagonists have been very successful in preclinical studies to treat pain and DO. However, clinical trials with the first generation TRPV1 antagonists were terminated early due to hyperthermia, a serious, on-target, side-effect.
  • TRP vanilloid 4 (TRPV4), TRP ankyrin 1 (TRPA1) and TRP melastatin 8 (TRPM8) have important sensory functions in the LUT. Antagonists of these channels have shown their potential in pre-clinical studies of LUT dysfunction and are awaiting clinical validation.
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