Spasmolytic and Uroprotective Effects of Apigenin by Downregulation of TGF-β and iNOS Pathways and Upregulation of Antioxidant Mechanisms: In Vitro and In Silico Analysis

Abstract

Apigenin is a phytochemical obtained from Chamomilla recutita. Its role in interstitial cystitis is not yet known. The present study is aimed at understanding the uroprotective and spasmolytic effects of apigenin in cyclophosphamide-induced interstitial cystitis. The uroprotective role of apigenin was analyzed by qRT-PCR, macroscopic analysis, Evans blue dye leakage, histological evaluation, and molecular docking. The spasmolytic response was measured by adding cumulative concentrations of apigenin to isolated bladder tissue pre-contracted with KCl (80 mM) and carbachol (10−9–10−4) on non-incubated and pre-incubated tissues with atropine, 4DAMP, methoctramine, glibenclamide, barium chloride, nifedipine, indomethacin, and propranolol. Apigenin inhibited pro-inflammatory cytokines (IL-6, TNF-α and TGF 1-β) and oxidant enzymes (iNOS) while increasing antioxidant enzymes (SOD, CAT, and GSH) in CYP-treated groups compared to the control. Apigenin restored normal tissue of the bladder by decreasing pain, edema, and hemorrhage. Molecular docking further confirmed the antioxidant and anti-inflammatory properties of apigenin. Apigenin produced relaxation against carbachol-mediated contractions, probably via blockade of M3 receptors, KATP channels, L-type calcium channels, and prostaglandin inhibition. While the blockade of M2 receptors, KIR channels, and β-adrenergic receptors did not contribute to an apigenin-induced spasmolytic effect, apigenin presented as a possible spasmolytic and uroprotective agent with anti-inflammatory, antioxidant effects by attenuating TGF-β/iNOS-related tissue damage and bladder muscle overactivity. Thus, it is a potential agent likely to be used in treatment of interstitial cystitis.

Antispasmodic, cardioprotective and blood-pressure lowering properties of Gomphrena perennis L. and its mechanisms of action

“… 14 Contrary, apigenin showed spasmolytic effect on bladder smooth muscle by several mechanisms including calcium channel blockade. 32 Therefore; since the contractile mechanisms of smooth muscle are similar, the apigenin glycoside found in GphT could be at least partially responsible for its intestinal relaxing effects.…”

Caftaric Acid Ameliorates Oxidative Stress, Inflammation, and Bladder Overactivity in Rats Having Interstitial Cystitis: An In Silico Study

“…The relaxant effect was decreased more significantly in control compared to diseased. It could be one of the possible mechanisms of relaxation as reported previously. , …”

Plant-Derived Polyphenols to Prevent and Treat Oral Mucositis Induced by Chemo- and Radiotherapy in Head and Neck Cancers Management

“…A recent study from 2022 in which 191 µmol APG in capsules as a dietary supplement were administered to volunteers, highlighted that neither APG nor its metabolites were detected in plasma collected until 6 h after the ingestion, whereas a total of 0.9 µmol of metabolites, equal to 0.5% of the ingested dose, were present in urine excreted within 24 h of flavone intake [109]. Despite APG was per se poorly absorbed by the gastrointestinal tract, the aforementioned APG-rich plants have been widely used for centuries as traditional medicines due to their spasmolytic [110], anti-inflammatory [111], and antimicrobic properties [112]. Considering these interesting activities, a possible application of APG as a therapeutic agent for the management of OM should be considered.…”

“…In 2016, Molina Prats et al [113] conducted a double-blind controlled pilot study comparing the effects of gavage administration of APG or Dexamethasone for the treatment of 5-FU-induced OM. The study was performed on Despite APG was per se poorly absorbed by the gastrointestinal tract, the aforementioned APG-rich plants have been widely used for centuries as traditional medicines due to their spasmolytic [110], anti-inflammatory [111], and antimicrobic properties [112]. Considering these interesting activities, a possible application of APG as a therapeutic agent for the management of OM should be considered.…”