Perillic Acid Synergizes With the Miltefosine Leishmanicidal Effect Against Leishmania amazonensis

Perillic acid (PA), a monocyclic monoterpene derived from limonene, was evaluated for its leishmanicidal activity alone and in combination with miltefosine, as well as in its microemulsion-based formulation. PA demonstrated synergistic activity with miltefosine and was effective against both promastigote and amastigote forms of Leishmania amazonensis. Its anti-amastigote effect was independent of nitric oxide production but was partially associated with reduced arginase activity in stimulated macrophages. In a murine model of cutaneous leishmaniasis, topical treatment with a PA-loaded microemulsion resulted in a marked reduction in parasite burden, achieving a 99% reduction in L. amazonensis infections. PA also showed efficacy in vivo across different administration routes and showed significant skin permeation when formulated in a microemulsion. These findings highlight PA as a promising leishmanicidal agent and support its potential application in the treatment of cutaneous leishmaniasis.