Neurite outgrowth agent tas3731 prevents urethra denervation and dysfunction following diabetes mellitus in rats

Akasaka D1, Sakakibara F1, Nakano K1, Demizu S1, Hakozaki A1

Research Type

Pure and Applied Science / Translational

Abstract Category

Pharmacology

Abstract 510
The Best of the Rest in Science
Scientific Podium Short Oral Session 33
Saturday 10th September 2022
12:00 - 12:07
Hall G1
Pharmacology Animal Study Neuromodulation Underactive Bladder Voiding Dysfunction
1. Taiho Pharmaceutical Co., Ltd.
Online
Presenter
D

Daichi Akasaka

Links

Abstract

Hypothesis / aims of study
Underactive bladder syndrome (UAB) is a voiding symptom syndrome involving detrusor underactivity (DU), defined as reduced detrusor muscle power and/or duration. Since UAB can cause complications such as urinary tract infections and renal disorders, it is vital to cure voiding dysfunction. DU is reportedly caused by partial loss of nerves innervating the bladder in patients with diabetes mellitus (DM) and bladder outlet obstruction (BOO) (1). TAC-302, which has a neurotropic factor-like effect, is reportedly effective in some animal models (prevention of patchy denervation in the bladder of BOO model and amelioration of neurological function in the urethra of DM model) (2, 3). A randomized, placebo-controlled, double-blind, parallel-group trial of TAC-302 in DU patients with overactive bladder was conducted (NCT03175029). We found TAS3731 to be a derivative of TAC-302, with an equivalent potential in terms of neurite outgrowth but better pharmacokinetics profile compared with TAC-302. In this study, we examined the effect of TAS3731 on neurite outgrowth in neurons and the ameliorative effect of oral administration of TAS3731 on streptozotocin (STZ)-induced diabetic voiding dysfunction in rats.
Study design, materials and methods
To evaluate neurite outgrowth, a neuronal cell line was stimulated using TAS3731 for 6 h. 
DM was induced by an intravenous injection of STZ (50 mg/kg) in Wistar rats (Crlj:WI, female, 10 weeks old). DM rats were orally administered with either vehicle or TAS3731 daily for 4 weeks. Physiological and pathological studies were conducted as follows:
1. To evaluate voiding functions, cystometry was performed at an saline infusion rate of 12 mL/h under urethane anesthesia (0.8 mg/kg, s.c.) at 4 weeks after inducing DM. Residual urine volume was measured by stopping saline infusion and withdrawing intravesical fluid through the catheter by gravity.
2. To evaluate nerve distribution in the urethra, 4% PFA-fixed tissues were cryoprotected with 20% sucrose and frozen in optimal cutting temperature compound. The frozen sections were stained with anti-PGP9.5 antibody, and the PGP9.5-positive area in the sections was assessed quantitatively.
Results
Treatment of neuronal cell line with TAS3731 for 6 h increased neurite length per cell and percentage of neurite-bearing cells in a concentration-dependent manner.
Compared with sham rats, DM rats showed increased blood glucose concentration and residual urine volume and decreased voiding efficiency, indicating that STZ-induced diabetic rats exhibited UAB-like symptoms. TAS3731 treatment did not affect blood glucose concentration and maximal voiding pressure; however, it significantly suppressed the increase in residual urine volume and decrease in voiding efficiency observed in vehicle-treated DM rats in a dose-dependent manner. Additionally, TAS3731 treatment tended to suppress the decrease in the PGP9.5-positive area ratio in the internal urethral sphincter, as observed in vehicle-treated DM rats. Incidentally, TAS3731 treatment did not affect the weight of the study animals, and it is considered that it did not have toxicity issues.
Interpretation of results
Partial denervation of the internal urethral sphincter causes voiding dysfunction in rats with DM. TAS3731 treatment alleviated voiding dysfunction in rats with DM by preventing partial denervation of the urethra.
Concluding message
Treatment with TAS3731, a novel compound with neurite outgrowth promoting activity, alleviates lower urinary tract dysfunction in rats with DM. Therefore, TAS3731 could be a novel therapeutic agent in patients with voiding dysfunctions.
References
  1. Yoshida M, Yamaguchi O (2014) Detrusor underactivity: the current concept of the pathophysiology. Low Urin Tract Symptoms 6:131-137.
  2. Yoshida S, Orimoto N, Tsukihara H, Noma T, Hakozaki A, Sasaki E. TAC-302 promotes neurite outgrowth of isolated peripheral neurons and prevents bladder denervation related bladder dysfunctions following bladder outlet obstruction in rats. Neurourol Urodyn. 2018 Feb;37(2):681-689.
  3. Nakagawa T, Akimoto N, Hakozaki A, Noma T, Nakamura A, Hayashi Y, Sasaki E, Ozaki N, Furue H. Responsiveness of lumbosacral superficial dorsal horn neurons during the voiding reflex and functional loss of spinal urethral-responsive neurons in streptozotocin-induced diabetic rats. Neurourol Urodyn. 2020 Jan;39(1):144-157.
Disclosures
Funding None Clinical Trial No Subjects Animal Species Rat Ethics Committee the Animal Experiments Ethics Committee of Taiho Pharmaceutical Co., Ltd.
Citation

Continence 2S2 (2022) 100461
DOI: 10.1016/j.cont.2022.100461

16/02/2024 02:24:47