Spergulin-A strives intra-macrophage leishmanicidal activity by regulating the host P2X7R-P38MAPK axis

Abstract

Current drugs are inadequate for the treatment of visceral leishmaniasis an immunosuppressive ailment caused by Leishmania donovani. Regrettably, there is no plant-origin antileishmanial drug present. P2X7R is constitutively present on macrophage surfaces and can be a putative therapeutic target in intra-macrophage pathogens with function attributes towards inflammation, host cell apoptosis, altered redox, and phagolysosomal maturation by activating p38MAPK. Here we demonstrated that the initial interaction of Spergulin-A (SpA), a triterpenoid saponin with RAW 264.7 macrophages was mediated through P2X7R involving the signaling cascade intermediates Ca++, P38MAPK, and NF-{kappa}{beta}. P38MAPK involvement is shown to have specific and firm importance in leishmanial killing with increased NF-{kappa}Bp65. Phago-lysosomal maturation by Sp A also campaigns for another contribution of P2X7R. In vivo evaluation of the anti-leishmanial activity of Sp A was monitored through expression analyses of P2X7R, P38MAPK, and NF-{kappa}{beta} in murine spleen and bone-marrow macrophages and advocated Sp A of being a natural compound of leishmanicidal functions which acted through the P2X7R-P38MAPK axis. SIGNIFICANCE OR IMPORTANCEPreciously, this manuscript demonstrated previously unreported initial interaction of Spergulin-A, a triterpenoid saponin isolated from Glinus oppositifolius with macrophages through P2X7R involving the signaling cascade intermediates Ca++, P38MAPK, and NF-{kappa}{beta}. Signaling interaction is shown to have specific importance in the leishmanial killing. Phago-lysosomal maturation also campaigns for another contribution of P2X7R. In vivo evaluation was monitored through P2X7R, P38MAPK, and NF-{kappa}{beta} in murine spleen and bone-marrow macrophages and advocated Sp A of being a natural compound of leishmanicidal functions which acted through the P2X7R-P38MAPK axis. The result supports that Spergulin-A can provide new lead molecules for the development of alternative drugs against VL. We feel very strongly that this work can be very interesting as it describes a detailed evaluation of leishmanicidal effect by Sp A and thus has every potential to attract a lot of workers especially in the fields of pharmacology, drug development, immunology, as well as parasitology.