CN113082032B - Trpv4激动剂的新应用 - Google Patents
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Abstract
本申请属于医药领域，公开了TRPV4激动剂GSK1016790A的新应用，尤其是TRPV4激动剂GSK1016790A在制备治疗阴道干涩药物中的应用。本发明的实验表明TRPV4激动剂GSK1016790A能够提高阴道上皮细胞离子转运活动强度以及能够促进阴道液分泌。
Description
技术领域
本发明属于医药领域，具体涉及TRPV4激动剂GSK1016790A的一种新的应用。
背景技术
阴道干涩是临床常见的女性生殖道疾病，严重影响女性生活质量。有研究指出，30岁以下女性阴道干涩的发生率约为11％～19％，50岁以上女性发生率约为24％～27％，其中，育龄女性常表现为性活动时阴道干涩，即性唤起障碍；而老年女性更为严重，静息状态下阴道已呈现干涩状态。阴道液主要来源于前庭大腺液、子宫颈腺液、子宫液以及阴道上皮粘膜渗出液。既往研究表明，许多活性分子，如神经递质肾上腺素(Adrenaline)与气体信号分子硫化氢(Hydrogen Sulfide)，可通过调节阴道上皮细胞离子转运，引起阴道上皮粘膜渗出液增加，促进阴道湿润。
目前关于阴道干涩的治疗手段较为单一，通常为人工润滑剂及雌激素类药物，具有一定的副作用及健康隐患。例如，雌激素治疗可增加深静脉血栓、脑卒中等风险，甚至增加患子宫内膜癌、乳腺癌的可能性。此外，激素疗法禁忌证包括雌激素依赖性肿瘤、乳腺癌、子宫内膜癌、黑色素瘤、原因不明的阴道出血、严重肝肾疾病、近6个月内患血栓栓塞性疾病、系统性红斑狼疮、耳硬化症、血卟啉症、脑膜瘤等。因此，仍需寻找一种新的替代疗法。
GSK1016790A属于TRPV4激动剂，其化学结构如下所示，分子式为C28H32C12N406S2；分子量为655.61；CAS号为942206-85-1，为白色粉末，其化学式为：
发明内容
有鉴于此，本发明提供了TRPV4激动剂的新应用，即TRPV4激动剂GSKI016790A在制备治疗阴道干涩的药物中的应用。
在一个实施方案中，本发明以TRPV4激动剂GSKI016790A作为研究对象，采用短路电流实验考察TRPV4激动剂GSKI016790A对阴道组织上皮细胞离子转运活动强度的影响。结果显示GSKI016790A可以引起大鼠阴道组织产生上升相短路电流反应，表明GSKI016790A能够显著提高上皮细胞离子转运活动强度。因此，本发明提供了TRPV4激动剂GSKI016790A在制备提高阴道上皮细胞离子转运活动强度药物中的应用。
本发明还考察了TRPV4激动剂GSK1016790A对阴道液分泌的影响，结果显示在阴道内施加TRPV4激动剂GSK1016790A，可引起大鼠阴道液分泌明显升高，表明GSK1016790A可促进阴道液体分泌。因此，本发明提供了TRPV4激动剂GSKI016790A在制备促进阴道液分泌药物中的应用。
通过实施例中的实验证明TRPV4激动剂GSKI016790A可引起大鼠阴道液分泌明显升高，表明GSK1016790A可促进阴道液体分泌，同时也证明GSK1016790A可治疗阴道干涩。因此，本发明提供了TRPV4激动剂GSKI016790A在制备治疗阴道干涩药物中的应用。
进一步地，所述TRPV4激动剂GSK1016790A的给药浓度为10μM。
进一步地，所述药物包括有效剂量的GSK1016790A。
进一步地，所述药物还包括药学上可接受的辅料。
本发明的有益效果为：本发明为TRPV4激动剂GSKI016790A应用于缓解女性阴道干涩的治疗提供理论依据，拓展了阴道干涩的治疗策略。如可使用TRPV4激动剂治疗老年阴道干涩，或使用涂抹了TRPV4激动剂的安全套缓解阴道干涩，增加湿润度等应用。与其他增加阴道湿润的药物相比，本发明技术无激素应用的副作用，安全可靠，且给药操作较为方便。
附图说明
图1为短路电流实验中TRPV4激动剂GSKI016790A提升大鼠阴道组织上皮细胞离子转运活动强度示意图。
图2为在大鼠阴道内施加TRPV4激动剂GSK1016790A提高分泌液的示意图。
具体实施方式
为了更加简洁明了的展示本发明的技术方案、目的和优点，下面结合具体实施例详细说明本发明的技术方案。如无特殊说明，本发明实施例中所涉及的试剂均为市售产品，均可以通过商业渠道购买获得。
实施例1考察TRPV4激动剂GSKI016790A对阴道分泌的影响
实验动物：SPF级SD大鼠，雌性，6-8周，200～250g购自广东省实验动物中心。
实验试剂：NaCl、KCl、MgSO4·7H2O、KH2PO4、NaHCO3、CaCl2、葡萄糖购自广东化学试剂厂，GSK1016790A、HC067047(TRPV4抑制剂)购自Sigma公司。
短路电流实验：大鼠吸入CO2后将其处死，急性分离阴道组织，稍作修剪后，将组织固定在孔径为0.45cm2的灌流小室中，并装载在短路电流装置(VCCMC6 Revision B型多功能电压-电流钳放大器，美国Physiologic Instruments公司)上。在灌流小室两侧分别加入6ml K-H溶液(配方为117mM NaCl、4.7mM KCl、1.2mM MgSO4·7H2O、1.2mM KH2PO4、24.8mMNaHCO3、2.56mM CaCl2、11.1mM葡萄糖)，将电压钳制为0mV，待电流基线水平稳定后，在灌流小室细胞腔膜面侧加入GSK1016790A(1μM)，记录短路电流值。
动物体内实验测定大鼠阴道液分泌情况：对大鼠腹腔注射戊巴比妥钠(50mg/kg体重)进行麻醉，将麻醉后的大鼠平躺放在干净的操作台上，腹面朝上，并给与热源光照，以保持大鼠的体温。将滤纸小心插入大鼠阴道，吸收原有的分泌液。随后，分别对不同组别大鼠阴道内给予生理盐水、GSK1016790A(1μM)或GSK1016790A(1μM)与HC067047(10μM)处理、给药完毕后立即开始计时，5min后将已知重量的滤纸小心插入大鼠阴道，继续停留5min，取出后对滤纸进行称重，其重量差即代表大鼠的阴道液分泌量。
数据处理：实验数据由平均值±标准误(mean±SEM)的方式呈现。对于三组或以上数据，采用单因素方差分析(Analysis of Variance，ANOVA)并使用Bonferroni法进行事后检验。设置P<0.05为显著性差异。
实验结果显示，图1显示了短路电流实验中，腔面给予TRPV4激动剂GSK1016790A刺激，可引起大鼠阴道组织产生上升相短路电流反应，该反应代表了上皮细胞离子转运活动增强。图2显示了体内实验中在阴道内施加TRPV4激动剂GSK1016790A，可引起大鼠阴道液分泌明显升高，表明GSK1016790A可促进阴道液体分泌；通过在添加GSK1016790A的基础上再添加TRPV4抑制剂HC067047，则出现阴道液分泌下降的现象，说明TRPV4抑制剂HC067047可阻断GSK1016790A能使阴道液分泌升高的现象，从而更加证明了TRPV4激动剂GSK1016790A具有促进阴道液分泌的效果。
最后所应当说明的是，以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制，尽管参照较佳实施例对本发明作了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的实质和范围。
Claims (3)
1.TRPV4激动剂-GSK1016790A作为唯一活性成分在制备治疗阴道干涩药物中的应用，其特征在于，GSK1016790A通过提高阴道上皮细胞离子转运活动强度以及促进阴道液分泌实现治疗阴道干涩的目的。
2.根据权利要求1所述的应用，其特征在于，所述TRPV4激动剂 GSK1016790A的给药浓度为10μM。
3.根据权利要求1所述应用，其特征在于，所述药物还包括药学上可接受的辅料。
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| Determinants of TRPV4 Activity following Selective Activation by Small Molecule Agonist GSK1016790A;Jin, M 等;《PLoS ONE》;20110214;第 6 卷(第 2 期);摘要、fig1-5 * |
| The TRPV4 Channel in Ciliated Epithelia;Yaniré N Andrade 等;《TRP Ion Channel Function in Sensory Transduction and Cellular Signaling Cascades》;20071231;TRP CHANNELS IN EPITHELIA小节部分 * |
| 瞬时感受器电位香草酸受体4型通道蛋白在气道压力诱导大鼠气道黏液高分泌中的作用;吴砚樵,周向东 等;《第三军医大学学报》;20110715;第 33 卷(第 13 期);摘要、结果部分图1-图2、讨论部分第2-3段落 * |
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