Probing the Aphrodisiac Potential of Waltheria indica: Characterization, In Silico, In Vivo, and Mechanistic Studies

Background: The root extracts of Waltheria indica L. (Malvaceae) are used in African traditional medicine to treat erectile dysfunction (ED). This use, however, is not supported by compelling scientific data or linked to any characterized active constituent(s). Therefore, our aim was to determine the major active compound(s) in the ethanol root extract of Waltheria indica (EEWI) responsible for the possible aphrodisiac action and the probable mechanism(s) involved. Methods: Unbiased screening by high-performance liquid chromatography was used to identify the phenolic compounds in the EEWI. These compounds were docked with phosphodiesterase-5 (PDE-5), arginase II, and aromatase to predict aphrodisiac-related mechanisms of action. Rutin (15, 30, and 60 mg/kg), the top in silico hit, was evaluated, along with EEWI (100, 200, and 400 mg/kg), for aphrodisiac properties in rats in vivo and the possible mechanisms underlying its actions. Results: Rutin demonstrated strong PDE-5 binding affinity (docking score: −11.048 kcal/mol). EEWI and rutin significantly reduced mount latency and increased mount frequency, intromission latency, intromission frequency, ejaculatory latency, and post-ejaculatory interval. Rutin but not EEWI significantly reduced penile PDE-5 levels. EEWI and rutin both significantly increased penile cGMP levels. EEWI (400 mg/kg) and all doses of rutin significantly increased testicular and plasma testosterone levels. All doses of EEWI and rutin reduced plasma prolactin levels but did not affect testicular cholesterol levels. Neither whole-body weight nor penile or testicular weights were affected by the treatment. Conclusions: EEWI and its rutin constituent possess aphrodisiac properties. As a mechanism, rutin lowers penile PDE-5 levels, and both rutin and EEWI increase cGMP and testosterone levels but reduce prolactin levels. Therefore, our study offers empirical evidence that highlights the potential aphrodisiac effect of EEWI.