Improvement of urethral dysfunction by 5‐HT 1A receptor agonist NLX‐112 in diabetic rats
Improvement of urethral dysfunction by 5‐HT 1A receptor agonist NLX‐112 in diabetic rats
复制标题
5-HT 1A 受体激动剂 NLX-112 对糖尿病大鼠尿道功能障碍的改善作用
DOI：
10.1002/nau.24993
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Baojun Gu
中科院分区：
文献类型：
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作者：
Mingzhuo Li;Xun Chen;Nailong Cao;Rong lv;Baojun Gu
目的 研究选择性 5-HT1A 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。将雌性 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大鼠 (NC)。 T1DM通过腹腔注射链脲佐菌素(65mg/kg)诱导。注射后 10 周对大鼠（每组 9 只）进行等容膀胱测压和尿道灌注压 (UPP) 评估。在生成NLX-112盐酸盐剂量反应曲线后（静脉注射）施用选择性5-HT1A受体拮抗剂WAY-100635马来酸盐。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 (0.003-1.0 mg/kg) 诱导 UPP 最低点、IP 最大、高频振荡 (HFO) 率呈剂量依赖性下降； UPP 变化和 HFO 幅度增加。 WAY-100635 马来酸盐 (0.3 mg/kg) 部分或完全逆转了 NLX-112 诱导的变化。免疫荧光显示5-HT1A受体存在于L6-S1脊髓背外侧核中，但在T1D大鼠中表达显着较高。此外，Western blot结果显示，T1D大鼠的腹侧L6-S1脊髓中5-HT1A受体明显增多。NLX-112可改善T1D大鼠的尿道功能障碍。 T1D 大鼠 L6-S1 脊髓背外侧核中 5-HT1A 受体上调。这些发现表明 NLX-112 可能构成治疗糖尿病尿道功能障碍的新治疗策略。
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 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.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.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.