Potent antileishmanial and synergic effects of phellandrene through its immunomodulation, modulating oxidant/antioxidant, and apoptotic induction.

The primary pharmaceutical treatments for the cutaneous leishmaniasis (CL) are linked to a range of negative complications. The development of innovative pharmacological agents aimed at enhancing cellular immune responses could denote a promising therapeutic approach for CL therapy. Here, the present study investigated the impact of phellandrene (PR), a cyclic monoterpene found in various plant species, on Leishmania tropica, focusing on its antileishmanial properties, immunomodulatory effects, antioxidant activity, and capacity to induce apoptosis. The antileishmaial and synergistic properties effects of PR alone and in conjunction with glucantime (GCT) on L. tropica promastigote and amastigote forms were investigated. As well, the influence of PR on the immunomodulatory-associated genes, antioxidant-associated genes, plasma membrane integrity, ROS generation, apoptosis induction, and nitric oxide (NO) production was assessed. We found that PR principally in conjunction with GCT notably reduced by the number of promastigote and amastigote forms within macrophages a dose-dependent reduction (p%lt;0.001). We found a significant upregulation in the expression of the iNOS, interferon gamma (IFN-g), and tumor necrosis factor (TNF-a) genes in infected macrophages subsequent to treatment with RP, particularly in conjunction with GCT. Conversely, there was a notable downregulation in the expression of interleukin 10 (IL-10), superoxide dismutase (SOD), and catalase (CAT) genes; whereas, results in a substantial rise in NO release in macrophage cells (p<0.001). PR, GCT, PR+GCT resulted in a dose-dependent enhancement of caspase-3 activity, increase in plasma membrane integrity, and reactive oxygen species (ROS) production (p<0.001). The findings indicate that the PR mainly along with GCT has a substantial effect on the inhibition and elimination of Leishmania parasites in controlled laboratory environments. Although certain cellular mechanisms of action have been recognized, including immune modulation cellular immunity response, the induction of apoptosis, ROS and NO production, reducing the antioxidant activity, and affecting membrane integrity in response to Leishmania, additional research is required to interpret its effectiveness in both animal models and human participants.