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Introduction: Previous studies reported the possibility that the interruption of fibrosis may improve interstitial cystitis (IC). In addition, our previous study with nintedanib, which has an antifibrotic effect and inhibits the receptors of VEGF, FGF, and PDGF, demonstrated the improvement of bladder overactivity and C-fiber hyperexcitability in spinal cord injured mice. Therefore, we investigated whether antifibrotic therapy using nintedanib can improve the IC-like pathologic conditions.
Methods: Female C57BL/6 mice were divided into 3 groups (each N=8): (A) Sham, (B) IC mice treated with vehicle, and (C) IC mice treated with nintedanib. For inducing an IC-like model, intravesical instillation of hyaluronidase mixed with lipopolysaccharide was conducted 3 times once a week. At the last instillation, vehicle or nintedanib (50mg/kg) was administered daily for 3 weeks. Then, pain assessment using Von-Frey filaments and cystometry was conducted. Trichrome staining, RT-PCR in the bladder, and immunohistochemistry of L6-S1 dorsal root ganglia (DRG) and L6 spinal cord were performed to investigate the improvement of bladder fibrosis, inflammation, nociception, and central sensitization.
Results: In pain assessment, 50% thresholds of target force were significantly reduced in group B vs. A, but recovered in group C vs. B. In cystometry, non-voiding contractions and voiding efficiency were worsened in group B, but restored in group C (Fig 1-a). Bladder fibrosis increased in group B were improved in group C in trichrome staining (Fig.1-b). mRNA levels in the bladder related to inflammation (IFN-r, CCR2), nociception (TACR2), P2X purinergic (P2X3, P2X4, P2X7), muscarinic (M2), and ß-adrenergic receptors (ß2, ß3) were increased in group B, but decreased in group C (Fig 1-c). In immunohistochemistry, TRPV1 in L6-S1 DRG and CX3CR1, GFAP, and CCR2 in L6 spinal cord were upregulated in group B, but reduced in group C (Fig 1-d).
Conclusions: Antifibrosis treatment using nintedanib improved bladder pain and bladder overactivity in the IC model. Therapeutic effects seem to be mediated by inhibitions of bladder afferent hyperexcitability as well as central sensitization.
Source of Funding: National Research Foundation of Korea (2020R1C1C1012208)