Improvement of urethral dysfunction by 5-HT1A receptor agonist NLX-112 in diabetic rats

Objective To examine the effects of the selective 5-HT1A receptor agonist, NLX-112, on urethral function in streptozotocin-induced diabetic rats. Materials and Methods 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 postinjection 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. Results Compared to controls, type 1 diabetic rats (T1D rats) had lower maximal intravesical pressure (IP max) and UPP changes. In T1D rats, NLX-112 hydrochloride (0.003-1.0 mg/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 (0.3 mg/kg) partially or completely reversed the NLX-112-induced changes. Immunofluorescence revealed that 5-HT1A receptors were found in the L6-S1 spinal cord dorsolateral nucleus, but the expression was significantly higher in the T1D rats. Additionally, Western blot showed there were significantly more 5-HT1A receptors in the ventral L6-S1 spinal cord of T1D rats. Conclusions Urethral dysfunction in T1D rats was improved by NLX-112. 5-HT1A receptors were upregulated in the dorsolateral nucleus of L6-S1 spinal cord in T1D rats. These findings suggest that NLX-112 may constitute a novel therapeutic strategy to treat diabetic urethral dysfunction.