Department of Urology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Neurourol Urodyn. 2022 Sep;41(7):1528-1538. doi: 10.1002/nau.24993. Epub 2022 Jul 23.
To examine the effects of the selective 5-HT 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 postinjection in rats (n = 9 per group). The selective 5-HT 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 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-HT 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-HT receptors in the ventral L6-S1 spinal cord of T1D rats.
Urethral dysfunction in T1D rats was improved by NLX-112. 5-HT 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.
研究选择性 5-HT 受体激动剂 NLX-112 对链脲佐菌素诱导的糖尿病大鼠尿道功能的影响。
雌性 Sprague-Dawley 大鼠（n=32）分为两组：1 型糖尿病（T1DM）大鼠和年龄匹配的正常对照组（NC）大鼠。T1DM 大鼠通过腹腔注射链脲佐菌素（65mg/kg）诱导。在注射后 10 周，通过等容膀胱测压法和尿道灌注压（UPP）评估每组 9 只大鼠的尿道功能。在生成 NLX-112 盐酸盐剂量-反应曲线后，给予选择性 5-HT 受体拮抗剂 WAY-100635 马来酸盐（静脉注射）。其余大鼠用于免疫荧光和 Western blot 检测。
与对照组相比，1 型糖尿病大鼠（T1D 大鼠）的最大膀胱内压（IP max）和 UPP 变化较低。在 T1D 大鼠中，NLX-112 盐酸盐（0.003-1.0mg/kg）呈剂量依赖性降低 UPP 最低点、IP max、高频震荡（HFOs）率；增加 UPP 变化和 HFOs 幅度。WAY-100635 马来酸盐（0.3mg/kg）部分或完全逆转了 NLX-112 引起的变化。免疫荧光显示 5-HT 受体存在于 L6-S1 脊髓背外侧核，但在 T1D 大鼠中表达明显升高。此外，Western blot 显示 T1D 大鼠 L6-S1 脊髓腹侧 5-HT 受体明显增多。
NLX-112 改善了 T1D 大鼠的尿道功能障碍。T1D 大鼠 L6-S1 脊髓背外侧核中 5-HT 受体上调。这些发现表明，NLX-112 可能成为治疗糖尿病性尿道功能障碍的一种新的治疗策略。
