TAS3731, a novel neurite outgrowth inducer, promotes neurite outgrowth via Akt phosphorylation and ameliorates voiding dysfunction in streptozotocin-induced diabetic rats

Background and Objective Underactive bladder lacks effective treatments targeting neural deficits, and promoting neurite outgrowth is a promising strategy to restore lower urinary tract function. This study aimed to assess the effects of TAS3731, a derivative of cyclohexenoic fatty alcohol, on neurite outgrowth activity in a neuronal ND3 cell line and to investigate the efficacy of TAS3731 for voiding dysfunction related to partial urethral denervation in rats with diabetes. Methods ND3 cells were treated with various concentrations of TAS3731 for 6 h to evaluate neurite outgrowth activity. In a streptozotocin-induced diabetic rat model, TAS3731 was administered orally for 4 weeks, starting either on the day of induction or 4 weeks later (after partial denervation). After the treatment, cystometric parameters were assessed and the neuronal area in the urethral smooth muscle was determined. Key Findings and Limitations TAS3731 enhanced neurite outgrowth in a concentration-dependent manner by facilitating Akt phosphorylation in ND3 cells. Neurite outgrowth was significantly inhibited by lipid raft depletion. Additionally, increased post-void residual volume and decreased voiding efficiency were ameliorated by TAS3731 in diabetic rats in a dose-dependent manner; partial denervation of the urethral smooth muscle was also attenuated by TAS3731. However, study limitations include the lack of behavioral assessments, limited nerve analysis, and incomplete identification of molecular targets. Conclusions and Clinical Implications TAS3731 induced neurite outgrowth in vitro and effectively addressed voiding dysfunction associated with partial denervation of the urethra in diabetic rats. Additionally, TAS3731 ameliorated both increased post-void residual volume and decreased voiding efficiency in diabetic rats in a dose-dependent manner and attenuated partial denervation of the urethral smooth muscle. These findings support TAS3731 as a promising therapeutic candidate for the treatment of underactive bladder, with potential efficacy for diabetes-associated urethral dysfunction.