Protective potential of linalool against cyclophosphamide-induced interstitial cystitis: mechanistic insights from...

Interstitial cystitis (IC) is an adverse event associated with the use of cyclophosphamide (CYP), an alkylating anticancer agent, caused by oxidative stress and excessive production of proinflammatory cytokines. The bladder becomes overactive. This study aims to evaluate linalool's ability to treat CYP-induced IC. To induce IC, a 150 mg/kg intraperitoneal (i.p.) dose of CYP was administered to female Sprague Dawley rats on days 1, 4, and 7. To assess the protective potential of linalool, macroscopic evaluation, nociception response, Evans blue dye test, and the role of antioxidant and inflammatory mediators were investigated. Linalool is an acyclic monoterpene tertiary alcohol. It makes up almost 70% of the terpenoids found in flower fragrances. In this study, oral linalool at doses of 25, 50, and 100 mg/kg significantly reduced inflammation (P < 0.05). Compared to the CYP-treated group, linalool markedly increased mRNA expression (P < 0.05) of superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GSH), and interleukin-10 (IL-10) levels, while decreasing mRNA expression of inducible nitrous oxide synthase (iNOS), tissue growth factor-β1 (TGF-β1), and tissue necrosis factor-α (TNF-α). The anti-inflammatory and antioxidant properties of linalool were further confirmed by molecular docking with specific protein targets. Linalool reduced CYP-induced bladder overactivity by blocking muscarinic 3 (M₃) receptors, ATP-sensitive potassium channels, calcium channels, and the cyclooxygenase (COX) enzyme, without affecting beta-adrenergic receptors. Thus, by reducing oxidative stress, inflammation, and bladder smooth muscle hyperexcitability, our results demonstrate that linalool offers significant protection against CYP-induced IC. Therefore, in CYP-based chemotherapy regimens, linalool presents as a potential adjuvant drug.