To examine the effects of the selective 5-HT1A receptor agonist, NLX-112, on urethral function in streptozotocin-induced diabetic rats.

Female Sprague-Dawley rats (n=32) were divided into two groups: rats with type 1 diabetes mellitus (T1DM) and age-matched normal control rats (NC). T1DM was induced by intraperitoneal injection of streptozotocin (65 mg/kg). Isovolumetric cystometry and urethral perfusion pressure (UPP) were evaluated 10 weeks post-injection in rats (n=9 per group). The selective 5-HT1A receptor antagonist, WAY-100635 maleate salt, was administered after NLX-112 hydrochloride dose-response curve was generated (intravenously). The remaining rats were used for immunofluorescence and Western blot assays.

Compared to controls, type 1 diabetic rats (T1D rats) had lower maximal intravesical pressure (IP max) and UPP changes. In NC group, there was no significant change in UPP nadir, UPP change, IP max and HFOs amplitude with the application of NLX-112 hydrochloride. While all of these parameters, except IP max, showed no significant differences after the administration of WAY-100635 maleate salt (0.3 mg/kg). As Fig.1 shown, in T1D rats, NLX-112 hydrochloride (0.003-1.0mg/kg) induced dose-dependent decreases in UPP nadir, IP max, high-frequency oscillations (HFOs) rate; and increases in UPP change and HFOs amplitude. WAY-100635 maleate salt (0.3mg/kg) partially or completely reversed the NLX-112-induced changes. As shown in Fig.2, immunofluorescence revealed that 5-HT1A receptors were found in the L6-S1 spinal cord Onuf’s nucleus, but the expression was significantly higher in the T1D rats (Fig.2A,2C). Additionally, Western blot showed there were significantly more 5-HT1A receptors in the ventral L6-S1 spinal cord of T1D rats.

It’s universally acknowledged that Onuf’s nucleus regulates the activity of external urethral sphincter (EUS). Long-lasting hyperglicemia is associated with a decrease in cerebral concentration of serotonin and other studies have already confirmed the existence of compensatory mechanisms in the serotonergic system of diabetic rats. Therefore, the discrepant expression level of 5-HT1A receptors in Onuf’s nucleus may lead to different effects of NLX-112 on HFOs in NC and T1D groups. Along with the increase of EUS bursting activity, urethral relaxation function was improved. In addition, the decrease of bladder contraction may result from the activation of the central 5-HT1A receptors which inhibited the parasympathetic excitatory input to the bladder.

Taken together, these results suggested that in urethane-anesthetized T1D rats, i.v. administration of NLX-112, a selectivity 5-HT1A receptor agonist could improve the urethral function by enhancing EUS activity in T1D rats. The expression of 5-HT1A receptors was significantly greater on the dorsolateral nucleus of L6-S1 spinal cord in T1D rats, which might be the binding site of the drug. The findings may be a reference for the development of pharmacotherapy for voiding dysfunction in diabetic patients.

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Influence of central serotonergic mechanisms on lower urinary tract function

Continence 2S2 (2022) 100290
DOI: 10.1016/j.cont.2022.100290