JTS-653 Blocks Afferent Nerve Firing and Attenuates Bladder Overactivity Without Affecting Normal Voiding Function

Abstract

Our findings suggest that TRPV1 is involved in bladder overactivity via afferent nerve activation but it is not associated with normal voiding function. A TRPV1 antagonist would be a useful drug for bladder overactivity with a different pharmacological profile than antimuscarinic agents.

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“…9) was reported to ameliorate PNH pain in rodent models (Kitagawa et al, 2013a). In the rat bladder, JTS-653 suppressed overactivity without affecting normal micturition (Kitagawa et al, 2013b). According to the company website, this compound is now in phase II clinical trials in Japanese patients with painful overactive bladder (www.jt.com/ investors/results/S_information/pharmacauticals/pdf/ P.L.20220207_E.pdf).…”

“…The bladder phenotype of the TRPV1 knockout mouse is, however, less pronounced: these animals showed only mild spotty incontinence (Birder et al, 2002). Furthermore, TRPV1 antagonists did not alter micturition in naïve animals (Charrua et al, 2009a;Kitagawa et al, 2013b). When explaining these seemingly conflicting results, it should be kept in mind that neonatal capsaicin administration ablates not only TRPV1 but also other receptors coexpressed with TRPV1 on bladder afferents that may be involved in micturition.…”

Trpv1

“…Here, TRPV1 antagonists inhibit capsaicin-induced increases in pelvic nerve discharge and intravesical pressure in rats and are able to suppress bladder overactivity induced by resiniferatoxin and acetic acid (Charrua et al 2009;Kitagawa et al 2013b). In addition, TRPV1 antagonists have been demonstrated to be effective in reducing colonic hypersensitivity in rodents (Kiyatkin et al 2013;Wiskur et al 2010).…”

New concepts for the treatment of male lower urinary tract symptoms

“…As an example, in one of the most recent reports the TRPV1 antagonist JTS-653 was shown to reduce afferent nerve firing, and micturition frequency in rats. Intravesical instillation of resiniferatoxin (RTX), an ultrapotent capsaicin analogue, significantly increased the number of electrophysiologically measured bladder afferent nerve impulses per second [41]. This increase of nerve discharge by RTX could be prevented when rats were administered JTS-653 intravenously 5 min prior to electrophysiological recording experiments.…”

“…Thus, the authors concluded that JTS-653 (or in general, TRPV1 antagonism) might be a therapeutic approach to treat OAB [41]. To the best of our knowledge, no TRPV1 antagonist has been tested clinically in regards to OAB and/or LUTS.…”