Serefko Anna, Wróbel Jan, Szopa Aleksandra, Dobrowolski Piotr, Kluz Tomasz, Wdowiak Artur, Bojar Iwona, Poleszak Ewa, Romejko-Wolniewicz Ewa, Derlatka Paweł, Grabowska-Derlatka Laretta, Kacperczyk-Bartnik Joanna, Gieleta Andrea Weronika, Bartnik Paweł, Jakimiuk Artur, Misiek Marcin, Wróbel Andrzej
Department of Clinical Pharmacy and Pharmaceutical Care, Faculty of Pharmacy, Medical University of Lublin, Lublin, Poland.
Medical Faculty, Medical University of Lublin, Lublin, Poland.
Neurourol Urodyn. 2025 Jan;44(1):229-244. doi: 10.1002/nau.25602. Epub 2024 Oct 14.
In the present study, we wanted to check whether TCS OX2 29 (TCS), a potent selective antagonist of OX2 receptors, would have positive effects in an animal model of detrusor overactivity co-existed with the depression-like state in Wistar male rats.
The forced swim test with the measurement of spontaneous locomotor activity, conscious cystometry, determination of c-Fos expression in central micturition areas, and a set of biochemical analyses (with the use of urine, hippocampus, bladder urothelium, and detrusor muscle of tested animals) were carried out.
The outcomes showed that a 7-day administration of TCS (3 mg/kg/day, subcutaneously) normalizes the cystometric parameters corresponding to overactivity of the detrusor and reverses the pro-depressive response. Furthermore, the antagonism of OX receptors restored the abnormal levels of overactive bladder markers (i.e., ATP, CGRP, OCT3, TRPV1, ROCK1, and VAChT), diminished neuronal overactivity in central micturition areas (i.e., pontine micturition center, ventrolateral periaqueductal gray, and medial preoptic area) as well as restored the altered hippocampal levels of CRF, cytokines (IL-1β, IL-6, IL-10, and TNF-α), and growth factors (BDNF and NGF) that reflected biochemical disturbances detected in depressed people.
It seems that our findings open new perspectives regarding the implication of the orexin system in the functioning of the urinary bladder and in the pathophysiology of depression.
在本研究中，我们想检验OX2受体的强效选择性拮抗剂TCS OX2 29（TCS）对患有逼尿肌过度活动并伴有抑郁样状态的雄性Wistar大鼠动物模型是否有积极作用。
进行了强迫游泳试验并测量自发运动活性、清醒膀胱测压、测定中枢排尿区域的c-Fos表达以及一系列生化分析（使用受试动物的尿液、海马体、膀胱尿路上皮和逼尿肌）。
结果显示，连续7天皮下注射TCS（3毫克/千克/天）可使与逼尿肌过度活动相应的膀胱测压参数恢复正常，并逆转促抑郁反应。此外，OX受体拮抗作用恢复了膀胱过度活动标志物（即ATP、降钙素基因相关肽、有机阳离子转运体3、瞬时受体电位香草酸亚型1、 Rho相关卷曲螺旋形成蛋白激酶1和囊泡乙酰胆碱转运体）的异常水平，减少了中枢排尿区域（即脑桥排尿中枢、腹外侧导水管周围灰质和内侧视前区）的神经元过度活动，并恢复了海马体中促肾上腺皮质激素释放因子、细胞因子（白细胞介素-1β、白细胞介素-6、白细胞介素-10和肿瘤坏死因子-α）以及生长因子（脑源性神经营养因子和神经生长因子）水平的改变，这些改变反映了在抑郁症患者中检测到的生化紊乱。
我们的研究结果似乎为食欲素系统在膀胱功能和抑郁症病理生理学中的作用开辟了新的视角。
