Beneficial effects of suplatast tosilate (IPD‐1151T) in a rat cystitis model induced by intravesical hydrochloric acid

Kirimoto, Tsukasa; Nakano, Koushi; Irimura, Kenji; Hayashi, Yukio; Matsuura, Naosuke; Kiniwa, Mamoru; Oka, Toshinori; Yoshimura, Naoki

doi:10.1111/j.1464-410x.2007.07044.x

Cited by 16 publications

(16 citation statements)

References 23 publications

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“…In addition, although rats with repetitive administration of cyclophosphamide have frequently been used as another chronic cystitis model (28,61), this animal model requires one-time application of HCl and exhibits histological changes including mastcytosis in the bladder. Although the robust inflammatory changes seen in rats with HCl-induced cystitis are not usually found in the human bladder of PBS/IC, the increased number of mast cells and their degranulation resulting in release of chemical mediators, such as histamine or nerve growth factor, are reportedly linked to neural changes in humans with PBS/IC (26,51).…”

Section: Discussionmentioning

confidence: 99%

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Bladder hyperactivity and increased excitability of bladder afferent neurons associated with reduced expression of Kv1.4 α-subunit in rats with cystitis

Hayashi

Takimoto²,

Chancellor³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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Hayashi Y, Takimoto K, Chancellor MB, Erickson KA, Erickson VL, Kirimoto T, Nakano K, de Groat WC, Yoshimura N. Bladder hyperactivity and increased excitability of bladder afferent neurons associated with reduced expression of Kv1.4 ␣-subunit in rats with cystitis. Am J Physiol Regul Integr Comp Physiol 296: R1661-R1670, 2009. First published March 11, 2009 doi:10.1152/ajpregu.91054.2008.-Hyperexcitability of C-fiber bladder afferent pathways has been proposed to contribute to urinary frequency and bladder pain in chronic bladder inflammation including interstitial cystitis. However, the detailed mechanisms inducing afferent hyperexcitability after bladder inflammation are not fully understood. Thus, we investigated changes in the properties of bladder afferent neurons in rats with bladder inflammation induced by intravesical application of hydrochloric acid. Eight days after the treatment, bladder function and bladder sensation were analyzed using cystometry and an electrodiagnostic device of sensory function (Neurometer), respectively. Whole cell patch-clamp recordings and immunohistochemical staining were also performed in dissociated bladder afferent neurons identified by a retrograde tracing dye, Fast Blue, injected into the bladder wall. Cystitis rats showed urinary frequency that was inhibited by pretreatment with capsaicin and bladder hyperalgesia mediated by C-fibers. Capsaicin-sensitive bladder afferent neurons from sham rats exhibited high thresholds for spike activation and a phasic firing pattern, whereas those from cystitis rats showed lower thresholds for spike activation and a tonic firing pattern. Transient A-type K ϩ current density in capsaicinsensitive bladder afferent neurons was significantly smaller in cystitis rats than in sham rats, although sustained delayed-rectifier K ϩ current density was not altered after cystitis. The expression of voltage-gated K ϩ Kv1.4 ␣-subunits, which can form A-type K ϩ channels, was reduced in bladder afferent neurons from cystitis rats. These data suggest that bladder inflammation increases bladder afferent neuron excitability by decreasing expression of Kv1.4 ␣-subunits. Similar changes in capsaicin-sensitive C-fiber afferent terminals may contribute to bladder hyperactivity and hyperalgesia due to acid-induced bladder inflammation. urinary bladder; hyperalgesia; inflammation; C-fiber afferent; potassium channel IT HAS BEEN DEMONSTRATED THAT afferent pathways innervating the urinary bladder consist of myelinated A␦-fibers and unmyelinated C-fibers and that hyperexcitability of C-fibers in bladder afferent pathways contributes to bladder overactivity and/or bladder pain under pathological conditions such as painful bladder syndrome/interstitial cystitis (PBS/IC) (60, 61).Voltage-gated K ϩ (Kv) currents are major determinants of neuronal excitability. Kv currents in sensory neurons are divided into two major categories; i.e., sustained delayed rectifier-type K ϩ (K DR ) and transient A-type K ϩ (K A ) currents (19,21,30,57). K A currents in sensory neurons ...

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Section: Discussionmentioning

confidence: 99%

“…Bladder inflammation was induced according to a previously used method (26). Briefly, a polyethylene catheter (PE-50) was inserted transurethrally into the bladder under pentobarbital (50 mg/kg ip) anesthesia.…”

Section: Methodsmentioning

confidence: 99%

Bladder hyperactivity and increased excitability of bladder afferent neurons associated with reduced expression of Kv1.4 α-subunit in rats with cystitis

Hayashi

Takimoto²,

Chancellor³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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“…1a,b). 8 It has also been reported that the HCl‐induced chronic cystitis rats showed bladder hyperalgesia mediated by C‐fiber afferent neurons. 9 Figure 1c shows the data on the eosinophils and mast cell counts in the bladder of the chronic cystitis and sham rats.…”

Section: Basic Experimental Effect Of Ipd‐1151t On Hydrochloric Acmentioning

confidence: 95%

Interstitial Cystitis and the Therapeutic Effect of Suplatast Tosilate

Hayashi

Ueda

Kirimoto

et al. 2009

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Painful bladder syndrome (PBS)/interstitial cystitis (IC) can be a chronic and debilitating disease characterized by urinary urgency, frequency, and bladder pain, which are often very difficult to treat, regardless of currently‐proposed treatments. Suplatast tosilate (IPD‐1151T) is an immunoregulator that suppresses Th2 cytokine production, immunoglobulin E (IgE) synthesis, chemical mediator release from mast cells, and eosinophilic recruitment. In a preliminary, open‐label clinical study of IPD‐1151T in 14 women with IC, treatment with IPD‐1151T significantly increased bladder capacity and decreased urinary urgency, urinary frequency, and lower abdominal pain, as measured by the IC symptom index, in patients with non‐ulcerative IC. A concomitant reduction in immunological parameters (eosinophils, IgE, and urine T cells) was observed. Also, in basic experimental studies using hydrochloric acid‐induced chronic cystitis rats, the oral administration of IPD‐1151T (0.1–100 mg/kg/day) for 7 days after the induction of cystitis dose dependently increased the intercontraction intervals and micturition volume. In addition, the infiltration of mast cells and eosinophils into the bladder was suppressed by IPD‐1151T. These findings suggest that IPD‐1151T could be a new medicine for treating debilitating symptoms, such as bladder pain and urinary frequency in PBS/IC.

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“…A more direct evidence linking chronic inflammation with functional changes in C-fiber afferents has been derived from a rat model of chronic cystitis induced by systemic application of cyclophosphamide, which undergoes hepatic metabolism to acrolein, an irritant excreted in the urine71 or intravesical application of hydrochloric acid (HCI) 72. In the cyclophosphamide model, it has been documented that the majority of bladder afferent neurons from both control and chronic cystitis rats are capsaicin sensitive and exhibit tetrodotoxin-resistant action potentials, whereas those from treated rats exhibit significantly lower thresholds for spike activation and show high-frequency firing characteristics 73.…”

Section: C-fiber Activation In Ic/pbs Pathology and Pain Managementmentioning

confidence: 99%

Herpes simplex virus vector-mediated gene delivery for the treatment of lower urinary tract pain

et al. 2009

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Interstitial cystitis (IC)/painful bladder syndrome (PBS) is a painful debilitating chronic visceral pain disorder of unknown etiology that affects an estimated 1 million people in the United States alone. It is characterized by inflammation of the bladder that results in chronic pelvic pain associated with bladder symptoms of urinary frequency and urgency. Regardless of the etiology, IC/PBS involves either increased and/or abnormal activity in afferent nociceptive sensory neurons. Pain-related symptoms in patients with IC/PBS are often very difficult to treat. Both medical and surgical therapies have had limited clinical utility in this debilitating disease and numerous drug treatments, such as heparin, dimethylsulfoxide and amitriptyline, have proven to be palliative at best, and in some IC/PBS patients provide no relief whatsoever. Although opiate narcotics have been employed to help alleviate IC/PBS pain, this strategy is fraught with problems as systemic narcotic administration causes multiple unwanted side effects including mental status change and constipation. Moreover, chronic systemic narcotic use leads to dependency and need for dose escalation due to tolerance; therefore, new therapies are desperately needed to treat refractory IC/PBS. This has led our group to develop a gene therapy strategy that could potentially alleviate chronic pelvic pain using the herpes simplex virusdirected delivery of analgesic proteins to the bladder.

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Beneficial effects of suplatast tosilate (IPD‐1151T) in a rat cystitis model induced by intravesical hydrochloric acid

Cited by 16 publications

References 23 publications

Bladder hyperactivity and increased excitability of bladder afferent neurons associated with reduced expression of Kv1.4 α-subunit in rats with cystitis

Bladder hyperactivity and increased excitability of bladder afferent neurons associated with reduced expression of Kv1.4 α-subunit in rats with cystitis

Interstitial Cystitis and the Therapeutic Effect of Suplatast Tosilate

Herpes simplex virus vector-mediated gene delivery for the treatment of lower urinary tract pain

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