Lidocaine exhibits antileishmanial and immunomodulatory activities in an in vitro model of tegumentary leishmaniasis

Local anesthetics have been shown to inhibit or delay the progression of tegumentary leishmaniasis (TL) in hamster models, although the mechanisms underlying this clinical improvement remain unclear. This study aimed to determine whether lidocaine reduces intracellular parasitism through a direct antiparasitic effect and/or by modulating macrophage functions. To achieve this, Leishmania (L.) amazonensis promastigotes were exposed to increasing concentrations (0.078 to 5.0 mg/mL) of lidocaine for up to 72 hours, followed by assessments of parasite proliferation and viability. Next, human macrophages were incubated for 24 and 72 hours with escalating concentrations (0.078 to 5.0 mg/mL) of lidocaine to determine the maximum non-cytotoxic concentration (MNCC). Subsequently, L. (L.) amazonensis-infected human macrophages were treated with the MNCC of lidocaine for 24 and 72 hours, and the infection index, nitric oxide (NO) and cytokine levels, and intracellular parasite viability were measured. The results showed that lidocaine caused a dose-dependent reduction in the proliferation and viability of L. (L.) amazonensis promastigotes. The IC₅₀ values for proliferation decreased from 0.69 mg/mL at 24 hours to 0.13 mg/mL at 72 hours, while the IC₅₀ values for viability declined from 1.08 mg/mL at 24 hours to 0.30 mg/mL at 72 hours. These findings indicate that prolonged exposure enhances the parasite’s susceptibility to lidocaine’s antiproliferative and cytotoxic effects. The MNCC of lidocaine for human macrophages was determined to be 0.625 mg/mL. After incubating infected macrophages with this concentration, the mean ± standard deviation of the infection index was reduced by over 66% after both 24-hour and 72-hour treatments. Additionally, after 72 hours of exposure to lidocaine, there was an 89.6% increase in NO production by infected macrophages. Infected macrophages exposed to lidocaine produced 7.9-fold less IL-1β after 24 hours of treatment, and 35.2-fold, 12.9-fold, and 1.6-fold less TNF-α, IL-6, and IL-8, respectively, after 72 hours of treatment. The number of promastigotes that proliferated from intracellular amastigotes was significantly lower following treatment with lidocaine for both 24 and 72 hours, indicating that lidocaine significantly reduces the viability of intracellular parasites. In conclusion, lidocaine exhibits potent anti-Leishmania activity and modulates macrophage functions crucial to the immunity against Leishmania and immunopathogenesis of TL. These findings support its potential as an alternative or adjunctive therapeutic strategy for the treatment of this disease.