Clotrimazole is effective, safe and tolerable for the treatment of endometriosis and functions by downregulating inducible nitric oxide synthase and modulating oxidative stress biomarkers

Endometriosis is one of the most common gynecological disorders, affecting approximately 10% of reproductive-aged women, up to 50% of infertile women, and 21% of women hospitalized for pelvic pain, although 11% of women with endometriosis are asymptomatic (Eisenberg et al., 2018; Shafrir et al., 2018; Zondervan et al., 2020). This condition is characterized by the implantation of endometrial tissue outside the uterine cavity, which promotes persistent inflammation and other symptoms, such as chronic pelvic pain, dyspareunia, dysmenorrhea and infertility (Filip et al., 2020; Zondervan et al., 2020).

The development and maintenance of ectopic implants involves many factors, such as changes in hormone levels, inflammatory processes, immunological changes, genetic factors and background environmental factors (Filip et al., 2020; Zondervan et al., 2020; Riccio et al., 2018; Cardoso et al., 2020a, 2020b, 2021). Reactive oxygen species (ROS) are generated by continuous activation of macrophages in the peritoneal fluid and may play a role in endometrial cell proliferation and adhesion in the peritoneal cavity, which contribute to the development of endometriosis (Amreen et al., 2019; Yu et al., 2019). Oxidative stress promotes cell viability alterations, DNA damage, and biochemical responses (Scutiero et al., 2017; Jackson et al., 2005), and in endometriosis, this stress can induce permeability of the peritoneal membrane accompanied by local inflammatory expansion (Kokot et al., 2021). In addition, the nuclear transcription factor NF-kB regulates the inflammatory response and activates inducible nitric oxide synthase (iNOS), and these effects facilitate angiogenesis, decrease cell apoptosis and accelerate cell proliferation (Amreen et al., 2019; Yu et al., 2019).

Endometriosis is diagnosed mainly by surgical visualization (laparoscopy) followed by lesion removal as a treatment approach. Drug treatment is based on the combination of oral contraceptives, androgens, progestins, anti-progestins, and gonadotropin-releasing hormone (GnRH-a) analogs, which provide temporary pain relief but are not effective in eradicating ectopic lesions; furthermore, these treatments have side effects and variable efficacy (Becker et al., 2017; Rolla, 2019; Zondervan et al., 2020). Before the COVID-19 pandemic, there was already a long delay (5–12 years) in the diagnosis of endometriosis (Soliman et al., 2017; Van der Zanden et al., 2018; Cardoso et al., 2020b; Ashkenazi et al., 2022). Regardless of the treatment approach, approximately 50% of patients experience relapse of the disease symptoms at 5 years posttreatment (Becker et al., 2017; Zondervan et al., 2020). Therefore, the search for new strategies to effectively treat endometriosis is essential.

Clotrimazole (CTZ) is an antimycotic medicine widely used in the medical field to treat Candida albicans and other fungal infections (Crowley and Gallagher 2014). Recent studies have revealed the effectiveness of CTZ in significantly decreasing the growth and size of endometriotic implants in an experimental model (Machado et al., 2018, 2020). CTZ reduces ROS production and thus diminishes endometriotic cell growth and disease development (Machado et al., 2018). Thus, it is important to evaluate the oxidative-antioxidant balance during CTZ treatment (Broi et al., 2016). In this regard, superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST) and glutathione (GSH) are enzymes and proteins related to the antioxidant system (Broi et al., 2016; Güney et al., 2008), and lipid peroxidation and protein carbonylation have been implicated in the oxidative effects (Güney et al., 2008).

To explore the possible mechanisms of action of CTZ in endometriosis and its adverse effects, we investigated the effects of CTZ on reactive nitrogen species (RNS), specifically iNOS, and the ability of this drug to modulate the antioxidant defense system (CAT, SOD, GSH and GST) and oxidative stress biomarkers (lipid peroxidation – LPO; protein carbonylation – PTC) in an experimental model of endometriosis.

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