Plant-Derived Spinacetin Mitigates Cyclophosphamide-Induced Hemorrhagic Cystitis in Rats

  • Int J Mol Sci. 2026 Mar 27;27(7):3056. doi: 10.3390/ijms27073056.
Jan Wróbel  1 ,  Łukasz Zapała  2 ,  Grzegorz Niemczyk  2 ,  Anna Bogaczyk  3 ,  Tomasz Kluz  3 ,  Artur Wdowiak  4 ,  Aleksandra Misiek  5 ,  Iwona Bojar  6 ,  Ewa Poleszak  7 ,  Marcin Misiek  8  9 ,  Kinga Gaweł  10 ,  Andrzej Wróbel  11
Affiliations
  • 1. Medical Faculty, Medical University of Lublin, 20-093 Lublin, Poland.
  • 2. Clinic of General, Oncological and Functional Urology, Medical University of Warsaw, Lindleya 4 Lindleya 4 St., 02-005 Warsaw, Poland.
  • 3. Department of Gynecology, Gynecology Oncology and Obstetrics, Faculty of Medicine, University of Rzeszow, Tadeusza Rejtana 16 c St., 35-959 Rzeszow, Poland.
  • 4. Obstetrics and Gynecology, Faculty of Health Sciences, Medical University of Lublin, Staszica 4-6 St., 20-081 Lublin, Poland.
  • 5. Institute of Medical Sciences, Jan Kochanowski University, 25-369 Kielce, Poland.
  • 6. Department of Women's Health, Institute of Rural Health in Lublin, Jaczewskiego 2 St., 20-090 Lublin, Poland.
  • 7. Department of Applied and Social Pharmacy, Laboratory of Preclinical Testing, Medical University of Lublin, Chodźki 1 St., 20-093 Lublin, Poland.
  • 8. Department of Gynecologic Oncology, Holy Cross Cancer Center, 25-377 Kielce, Poland.
  • 9. Faculty of Medicine, Collegium Medicum, Jan Kochanowski University in Kielce, 25-369 Kielce, Poland.
  • 10. Department of Pharmacology, Poznan University of Medical Sciences, Rokietnicka 3 Str., 60-806 Poznan, Poland.
  • 11. Second Department of Gynecology, Medical University of Lublin, Jaczewskiego 8 St., 20-090 Lublin, Poland.
PMID: 41977243 DOI: 10.3390/ijms27073056
Abstract

The purpose of our study was to assess if spinacetin (SPC), a flavonoid found in spinach, can alleviate the cyclophosphamide (CYP)-induced changes in cystometric and inflammatory parameters indicative of the development of hemorrhagic cystitis. The animal experiments were conducted in female Wistar rats. The cohort of 60 Animals was grouped as follows: I-control, II-CYP group, III-SPC group, and IV-CYP + SPC group. The cystometry and biochemical analyses were performed after a fortnight of SPC administration. SPC was found to restore normal cystometric parameters in CYP-induced cystitis and, similarly, it normalized c-Fos expression changes in the central micturition regions. SPC further prevented a massive increase in the bladder wall thickness/permeability due to exposition to CYP administration. CYP instillation resulted in the elevation of biomarkers found in urine (brain-derived neurotrophic factor, BDNF, and nerve growth factor, NGF), and in the bladder detrusor muscle (Rho kinase and vesicular acetylcholine transporter, VAChT), which were successfully restored after administration of SPC. As for the biomarkers in the bladder urothelium, the CYP-induced increases in TNF-α, IL-1β, IL-6, Calcitonin gene-related peptide (CGRP), malondialdehyde, 3-nitrotyrosine, insulin-like growth factor-binding protein 3 (IGFBP-3), occludin, organic cation transporter 3 (OCT-3), orosomucoid-1 (ORM1), pituitary Adenylate Cyclase receptor 1 (PAC1), synaptosomal-associated protein 23 (SNAP23), SNAP25, and synaptic vesicle glycoprotein (SV2A) levels were attenuated by SPC. Finally, CYP administration resulted in a decrease in the heparin-binding EGF-like growth factor (HB-EGF), hemopexin (HPX), T-H protein, and tight junction protein (Z01), and we noted the successful restoration of all these changes in concentrations after application of SPC. In summary, SPC robustly mitigated cyclophosphamide (CYP)-induced cystometric dysfunction and biochemical alterations characteristic of iatrogenic hemorrhagic cystitis. These findings position SPC as a compelling therapeutic candidate and warrant further translational investigation for the management of CYP-induced bladder injury.

Keywords
cyclophosphamide; hemorrhagic cystitis; spinacetin.
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