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Pharmacological Inhibition of NAPDH Oxidase NOX2 Improves Bladder Dysfunction in Murine Cyclophosphamide‐Induced Cystitis

Oliveira, Mariana G. ; Monica, Fabiola Z. ; Passos, Gabriela R. ; Oliveira, Akila L. ; Oliveira, Anna Lethicia L. ; Antunes, Edson

The FASEB journal, 2022-05, Vol.36 (S1), p.n/a [Periódico revisado por pares]

The Federation of American Societies for Experimental Biology

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  • Título:
    Pharmacological Inhibition of NAPDH Oxidase NOX2 Improves Bladder Dysfunction in Murine Cyclophosphamide‐Induced Cystitis
  • Autor: Oliveira, Mariana G. ; Monica, Fabiola Z. ; Passos, Gabriela R. ; Oliveira, Akila L. ; Oliveira, Anna Lethicia L. ; Antunes, Edson
  • É parte de: The FASEB journal, 2022-05, Vol.36 (S1), p.n/a
  • Descrição: Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a multifactorial inflammatory disease characterized by suprapubic pain and discomfort associated with excessive voiding frequency, which profoundly impairs patient's quality of life. Among mediators implicated in cystitis, the overproduction of reactive oxygen species (ROS) seems to play a key role. NADPH oxidases isoforms (NOX) generate ROS that are critical in regulating a variety of cellular functions in many physiopathological conditions. The selective inhibitor of NOX2, GSK2795039, exhibit a strong anti‑oxidative activity. This study aimed to investigate the contribution of NOX2 in ROS generation and voiding dysfunction of cyclophosphamide (CYP)‐induced mouse cystitis, a well‐recognized animal model to study IC/BPS. All experimental protocols were approved by the Ethics Committee on Animal Use of the University of Campinas (Protocol No 58291‐1). Female C57BL/6 mice (10 weeks) were divided into 3 different groups, named: 1) Control: saline injection (1 mL/kg, ip) followed by an injection of vehicle (Cremophor® 15% in saline, ip) after 1, 8 and 16 h; 2) CYP: injection of CYP (300 mg/kg, ip) followed by an injection of vehicle after 1, 8 and 16 h; 3) NOX2i: injection of CYP (300 mg/kg, ip) followed by an injection of the selective NOX2 inhibitor GSK2795039 (5 mg/kg, ip) after 1, 8 and 16 h. Voiding spot on filter paper, anesthetized cystometry and bladder hyperalgesia were performed after 4 and 24 h of CYP injection. Bladder histology, ROS generation (DHE) and NOX2, IL1β, IL6 and TNFα expression by RT‐PCR were evaluated 24 h after CYP injection. CYP group showed an increase in voiding frequency of ~30x and a reduction in voiding volume for up to 24 h when compared to Control, which was significantly reversed in NOX2i group (p<0.05 vs CYP). In cystometry, mice exposed to CYP exhibited lower bladder capacity and clearly hyperactive voiding profile when compared to Control group, accompanied by lower bladder capacity and higher threshold pressure and voiding frequency, all reversed by GSK2795039. Suprapubic mechanical stimulation showed a significant reduction of the nociceptive threshold in CYP group, 4 and 24 h after CYP injection (p<0.05 vs Control), while NOX2i group remained similar to Control. In histology, bladders from CYP group exhibited lamina propria edema, tissue disorganization and urothelial denudation. Bladders from NOX2i group showed less edema and intact urothelium. Increased IL1β, IL6 and TNFα mRNA were observed in CYP group (p<0.05 vs Control), while reduced in NOX2i group (p<0.05 vs CYP). ROS generation was increased in bladders of CYP group (p<0.05 vs Control), while NOX2i group was close to Control levels. NOX2 and p47phox subunit mRNA were increased in CYP group (p<0.05 vs Control), but fully reversed by NOX2 inhibition (p<0.05 vs CYP). GSK2795039 reverted mouse bladder dysfunction induced by CYP and constitutes a promising compound for the treatment of IC/BPS, likely by inhibition of overactivated ROS, down‐regulation of proinflammatory factors and amelioration of voiding function.
  • Editor: The Federation of American Societies for Experimental Biology
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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