Department of Urology, Kocaeli University School of Medicine, 41001, Kocaeli, Turkey.
Department of Pharmacology, Kocaeli University School of Medicine, Kocaeli, Turkey.
Int Urogynecol J. 2024 Mar;35(3):677-688. doi: 10.1007/s00192-023-05723-x. Epub 2024 Feb 20.
To evaluate the effect of AF219, a P2X3 receptor antagonist, in animal models of interstitial cystitis/bladder pain syndrome (IC/BPS) induced by cyclophosphamide (CYP) or water avoidance stress (WAS).
Thirty-two adult female Wistar albino rats were used in each IC/BPS model. Assessment of nociception and anxiety and severity of inflammation in the bladder were assessed by behavioral experiments and histopathological examinations respectively. The contraction responses of the bladder were evaluated in vitro and protein levels of P2X3, P2X7, Trk-A, TRPV1, and TRPA1 were analyzed by Western blot.
The IC/BPS groups had shorter response times to noxious stimuli, exhibited more anxiety-like behavior, had higher inflammation-based histological scores, and showed greater increased contraction responses to carbachol, adenosine triphosphate, and electrical field stimulation in in vitro bladder strips than controls for both models (p < 0.05). The improvements in behavioral and bladder contraction responses and inflammation scores in the IC/BPS + AF219 groups were similar to control findings (p > 0.05). Exposure to WAS or CYP increased P2X3 expression in the bladder compared with the controls (p < 0.05). Apart from TRPA1, the levels of P2X7, Trk-A, and TRPV1 were also higher in the IC/BPS groups than in the controls (p < 0.05). No significant differences were observed between IC/BPS + AF219 and controls regarding P2X3, P2X7, Trk-A, and TRPV1 in the WAS model (p > 0.05). Moreover, P2X3 and P2X7 levels were significantly lower in IC/BPS + AF219 than in the AF219-untreated WAS model (p < 0.05).
These findings suggest that P2X3 receptors play a significant role in bladder functional responses, nociception, and also the pathogenesis of IC/BPS. AF219 may be a promising therapeutic strategy for IC/BPS. Comparing AF219 with current IC/BPS treatment agents in future studies may yield valuable insights into its efficacy.
评估 AF219（一种 P2X3 受体拮抗剂）在环磷酰胺（CYP）或水回避应激（WAS）诱导的间质性膀胱炎/膀胱疼痛综合征（IC/BPS）动物模型中的作用。
每个 IC/BPS 模型均使用 32 只成年雌性 Wistar 白化大鼠。通过行为实验评估痛觉和焦虑，通过组织病理学检查评估膀胱炎症的严重程度。通过体外膀胱条评估收缩反应，并通过 Western blot 分析 P2X3、P2X7、Trk-A、TRPV1 和 TRPA1 的蛋白水平。
IC/BPS 组对有害刺激的反应时间更短，表现出更多的焦虑样行为，基于炎症的组织学评分更高，并且与两种模型的对照组相比，对 carbachol、三磷酸腺苷和电刺激的体外膀胱条的收缩反应增加更大（p<0.05）。与对照组相比，IC/BPS+AF219 组的行为和膀胱收缩反应以及炎症评分的改善相似（p>0.05）。与对照组相比，WAS 或 CYP 暴露使膀胱中 P2X3 的表达增加（p<0.05）。除 TRPA1 外，IC/BPS 组的 P2X7、Trk-A 和 TRPV1 水平也高于对照组（p<0.05）。在 WAS 模型中，与对照组相比，IC/BPS+AF219 组的 P2X3、P2X7、Trk-A 和 TRPV1 之间没有观察到显著差异（p>0.05）。此外，与未接受 AF219 治疗的 WAS 模型相比，IC/BPS+AF219 组的 P2X3 和 P2X7 水平显著降低（p<0.05）。
这些发现表明 P2X3 受体在膀胱功能反应、痛觉和 IC/BPS 的发病机制中起重要作用。AF219 可能是一种有前途的 IC/BPS 治疗策略。在未来的研究中，将 AF219 与当前的 IC/BPS 治疗药物进行比较，可能会深入了解其疗效。
