Bladder, Год журнала: 2024, Номер 11(2), С. e21200011 - e21200011

Опубликована: Окт. 28, 2024

Background: Repeated intravesical activation of protease-activated receptor-4 (PAR4) serves as a model persistent bladder hyperalgesia (BHA) in mice, which lasts several days after the final stimulus. Spinal macrophage migration inhibitory factor (MIF) and high mobility group box 1 (HMGB1) are critical mediators persistence BHA. Objective: We aimed to identify effective systemic treatments for BHA using antagonists or transgenic deletions. Methods: Persistent was induced through transurethral instillations PAR4-activating peptide (PAR4-AP; 100 μM, h; scrambled peptide, control) under anesthesia, administered on Days 0, 2, 4. Lower abdominal hypersensitivity measured 0–4 7–9. Systemic injections from 2–8 included ISO-1 (a MIF antagonist), ethyl pyruvate (an inhibitor HMGB1 release), phosphate-buffered saline, 10% DMSO (vehicle C57BL/6 mice. To examine role receptors, Toll-like (TLR4)-null mice treatment with FPS-ZM1 (receptor advanced glycation end product [RAGE] antagonist) were used. In addition, TIR-domain-containing adaptor-inducing interferon-β (TRIF)-null tested assess involvement TLR4 signaling pathways. Micturition volume frequency assessed Day 9, histopathologically examined inflammation edema. Results: antagonism significantly reversed BHA, whereas led partial reduction deficiency administration mitigated while TRIF-deficient experienced faster onset Only inhibition resulted increased micturition volume. The histopathological examination revealed no changes Conclusion: HMGB1, acting RAGE, mediated TRIF might modulate its onset. Further exploration downstream may uncover novel therapeutic targets treating pain.

Язык: Английский