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• Input integration around the dendritic branches in hippocampal dentate granule cells

  2014.03

  DOI PubMed

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• Effects of low-intensity extracorporeal shock wave on bladder and urethral dysfunction in spinal cord injured rats

  Kawase K, Kamijo TC, Kusakabe N, Nakane K, Koie T, Miyazato M

  International Urology and Nephrology     2024.06 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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  Purpose: To investigate the effects of low-intensity extracorporeal shock wave therapy (LiESWT) on bladder and urethral dysfunction with detrusor overactivity and detrusor sphincter dyssynergia (DSD) resulting from spinal cord injury (SCI). Methods: At 3 weeks after Th9 spinal cord transection, LiESWT was performed on the bladder and urethra of adult female Sprague Dawley rats with 300 shots of 2 Hz and an energy flux density of 0.12 mJ/mm2, repeated four times every 3 days, totaling 1200 shots. Six weeks postoperatively, a single cystometrogram (CMG) and an external urethral sphincter electromyogram (EUS-EMG) were simultaneously recorded in awake animals, followed by histological evaluation. Results: Voiding efficiency significantly improved in the LiESWT group (71.2%) compared to that in the control group (51.8%). The reduced EUS activity ratio during voiding (duration of reduced EUS activity during voiding/EUS contraction duration with voiding + duration of reduced EUS activity during voiding) was significantly higher in the LiESWT group (66.9%) compared to the control group (46.3%). Immunohistochemical examination revealed that fibrosis in the urethral muscle layer was reduced, and S-100 stained-positive area, a Schwann cell marker, was significantly increased in the urethra of the LiESWT group. Conclusion: LiESWT targeting the urethra after SCI can restore the EUS-EMG tonic activity during voiding, thereby partially ameliorating DSD. Therefore, LiESWT is a promising approach for treating bladder and urethral dysfunction following SCI.

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• Effects of oral administration of nonselective Trk inhibitor on bladder overactivity in rodent models of prostatic inflammation

  Igarashi T, Mizoguchi S, Matsuoka K, Kamijo T, Kawano S, Furuta A, Suzuki Y, Kimura T, Pascal LE, Wang Z, Yoshimura N

  The Prostate ( Wiley )  84 ( 11 ) 1016 - 1024   2024.05 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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  Background: Our research focused on the assessment of the impact of systemic inhibition of Trk receptors, which bind to nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), on bladder hypersensitivity in two distinct rodent models of prostatic inflammation (PI). Methods: Male Sprague-Dawley rats were divided into three groups (n = 6 each): the control group (no PI, vehicle administration), the untreated group (PI, vehicle administration), and the treated group (PI, nonselective Trk inhibitor, GNF 5837, administration). PI in rats was induced by a intraprostatic injection of 5% formalin. Posttreatment, we carried out conscious cystometry and a range of histological and molecular analyses. Moreover, the study additionally evaluated the effects of a nonselective Trk inhibitor on bladder overactivity in a mouse model of PI, which was induced by prostate epithelium-specific conditional deletion of E-cadherin. Results: The rat model of PI showed upregulations of NGF and BDNF in both bladder and prostate tissues in association with bladder overactivity and inflammation in the ventral lobes of the prostate. GNF 5837 treatment effectively mitigated these PI-induced changes, along with reductions in TrkA, TrkB, TrkC, and TRPV1 mRNA expressions in L6-S1 dorsal root ganglia. Also, in the mouse PI model, GNF 5837 treatment similarly improved bladder overactivity. Conclusions: The findings of our study suggest that Trk receptor inhibition, which reduced bladder hypersensitivity and inflammatory responses in the prostate, along with a decrease in overexpression of Trk and TRPV1 receptors in sensory pathways, could be an effective treatment strategy for male lower urinary tract symptoms associated with PI and bladder overactivity..

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• Improvement of lower urinary tract dysfunction by a monoacylglycerol lipase inhibitor in mice with spinal cord injury.

  Cho KJ, Hashimoto M, Karnup S, Matsuoka K, Kamijo T, Kim JC, Koh JS, Yoshimura N

  Neurourology and urodynamics ( Wiley )  43 ( 5 ) 1207 - 1216   2024.03 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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  Aims: Activation of the endocannabinoid system by monoacylglycerol lipase (MAGL) blockade may affect the lower urinary tract function. We investigated the effect of an MAGL inhibitor, MJN110, on neurogenic lower urinary tract dysfunction (LUTD) in the mouse model of spinal cord injury (SCI). Methods: Female C57BL/6 mice that underwent spinal cord transection at T8-10 level were divided into three groups consisting of (1) vehicle-treated SCI mice, (2) 5 mg/kg, or (3) 10 mg/kg of MJN110-treated SCI mice. MJN110 and vehicle were administered intraperitoneally for 7 days from 4 weeks after spinal cord transection. We then conducted awake cystometrograms and compared urodynamic parameters between three groups. The expression of cannabinoid (CB) receptors, TRP receptors, and inflammatory cytokines in L6-S1 dorsal root ganglia (DRG) or the bladder mucosa were evaluated and compared among three groups. Changes in the level of serum 2-arachidonoylglycerol (2-AG) and bladder MAGL were also evaluated. Results: In the cystometrogram, detrusor overactivity (DO) parameters, such as the number of nonvoiding contraction (NVC), a ratio of time to the 1st NVC to intercontraction interval (ICI), and NVC integrals were improved by MJN110 treatment, and some effects were dose dependent. Although MJN110 did not improve voiding efficiency, it decreased bladder capacity, ICI, and residual urine volume compared to vehicle injection. MJN110 treatment groups had lower CB2, TRPV1, TRPA1, and inflammatory cytokines mRNA levels in DRG and bladder mucosa. Serum 2-AG was increased, and bladder MAGL was decreased after MAGL inhibitor treatment. Conclusions: MAGL inhibition improved LUTD including attenuation of DO after SCI. Thus, MAGL can be a therapeutic target for neurogenic LUTD after SCI.

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• Pathophysiology of Overactive Bladder and Pharmacologic Treatments Including β3-Adrenoceptor Agonists -Basic Research Perspectives-

  Kwon J, Kim DY, Cho KJ, Hashimoto M, Matsuoka K, Kamijo T, Wang Z, Karnup S, Robertson AM, Tyagi P, Yoshimura N

  International Neurourology Journal ( Korean Continence Society )  28 ( Suppl 1 ) 12   2024.02 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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  Overactive bladder (OAB) is a symptom-based syndrome defined by urinary urgency, frequency, and nocturia with or without urge incontinence. The causative pathology is diverse; including bladder outlet obstruction (BOO), bladder ischemia, aging, metabolic syndrome, psychological stress, affective disorder, urinary microbiome, localized and systemic inflammatory responses, etc. Several hypotheses have been suggested as mechanisms of OAB generation; among them, neurogenic, myogenic, and urothelial mechanisms are well-known hypotheses. Also, a series of local signals called autonomous myogenic contraction, micromotion, or afferent noises, which can occur during bladder filling, may be induced by the leak of acetylcholine (ACh) or urothelial release of adenosine triphosphate (ATP). They can be transmitted to the central nervous system through afferent fibers to trigger coordinated urgency-related detrusor contractions. Antimuscarinics, commonly known to induce smooth muscle relaxation by competitive blockage of muscarinic receptors in the parasympathetic postganglionic nerve, have a minimal effect on detrusor contraction within therapeutic doses. In fact, they have a predominant role in preventing signals in the afferent nerve transmission process. β3-adrenergic receptor (AR) agonists inhibit afferent signals by predominant inhibition of mechanosensitive Aδ-fibers in the normal bladder. However, in pathologic conditions such as spinal cord injury, it seems to inhibit capsaicin-sensitive C-fibers. Particularly, mirabegron, a β3-agonist, prevents ACh release in the BOO-induced detrusor overactivity model by parasympathetic prejunctional mechanisms. A recent study also revealed that vibegron may have 2 mechanisms of action: inhibition of ACh from cholinergic efferent nerves in the detrusor and afferent inhibition via urothelial β3-AR.

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• Effects of low-intensity extracorporeal shock wave therapy on lipopolysaccharide cystitis in a rat model of interstitial cystitis/bladder pain syndrome

  Kusakabe N, Kamijo TC, Wada N, Chaba H, Shinohara N, Miyazato M

  International Urology and Nephrology ( Springer Link )  56   77 - 86   2023.09 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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  Purpose To investigate the effect of low-intensity extracorporeal shock wave therapy (LiESWT) on lipopolysaccharide (LPS)-induced cystitis in an animal model of interstitial cystitis/bladder pain syndrome (IC/BPS). Methods Sprague–Dawley rats were divided into three groups: control, cystitis (LPS group, intravesical injection of LPS (1 mg) twice), and cystitis with LiESWT (LiESWT group). On the third and fourth days, LiESWT was administered (0.12 mJ/mm2, 300 shots each time) on the lower abdomen toward the bladder. On the seventh day, the rats underwent pain assessment and a metabolic cage study. Subsequently, a continuous cystometrogram (CMG) was performed under urethane anaesthesia. Immunohistochemical studies were also performed, including S-100 staining, an immunohistochemical marker of Schwann cells in the bladder. Results In the LPS group, the pain threshold in the lower abdomen was significantly lower than that in the control group. In the metabolic cage study, the mean voided volume in the LPS group significantly increased. The CMG also revealed a significant decrease in bladder contraction amplitude, compatible with detrusor underactivity in the LPS group. Immunohistochemical studies showed inflammatory changes in the submucosa, increased fibrosis, and decreased S-100 stain-positive areas in the muscle layer of the LPS group. In the LiESWT group, tactile allodynia and bladder function were ameliorated, and S-100 stain-positive areas were increased. Conclusion By restoring nerve damage, LiESWT improved lower abdominal pain sensitivity and bladder function in an LPS-induced cystitis rat model. This study suggests that LiESWT may be a new therapeutic modality for IC/BPS.

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Grant-in-Aid for Scientific Research 【 display / non-display 】

Grant-in-Aid for Scientific Research 【 display / non-display 】

• Grant-in-Aid for Research Activity start-up

  Project Year: 2020.09  -  2022.03 

  Direct: 2,200,000 (YEN)  Overheads: 2,860,000 (YEN)  Total: 660,000 (YEN)