**3. Glycyrrhizic acid**

Another constituent of licorice, which serves as an antileishmanial compound, is glycyrrhizic acid (GA) [43]. The studies using this compound showed an increase in NO production with restoration of Th1 cytokine balance and inhibition of immunosuppressive prostaglandin E2(PGE2) production. This is in line with recent evidences, which suggests that the parasite is able to induce PGE2 production via promoting inducible COX2 expression. This in turn resulted in activation of EP receptors (PGE2 receptors) on the host cell surface thereby causing Cyclic adenosine monophosphate(cAMP) induction and cytokine production [44] (**Figure 8**).

**Figure 8.** Glycyrrhizic acid mediated PGE2 inhibition and NO and proinflammatory cytokine production helps parasite suppression.

This is also anticipated as glycyrrhizic acid is readily hydrolyzed to glycyrrhetinic acid in human body [45] which is already discussed in details to have antileishmanial activities. Recent studies further shows that this compound when used in conjunction with antimonials can help in overcoming the resistance seen in the antimony resistant parasites. Extensive use of the antimonials and low follow-up of cases had led to emergence of antimonial resistant strains of the parasite [46]. The main criteria for this resistance is attributed to the overexpression and efflux activity of a class of transporters on the surface of the host cells namely P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP-1) thereby leading to efflux of the antimonials and parasite persistence. However, administration of glycyrrhizin led to suppression of these transporters and simultaneously shifted the overall anti-inflammatory milieu to the proinflammatory one [46] (**Figure 9**). Thus, this herbal compound can serve as an economical effective counterpart to its expensive counterparts like miltefosine and amphotericin B.

Further studies demonstrated the role of glycyrrhizin in mediating proliferation of T cells, thereby promoting disease resolving IFN-γ production in *Leishmania* infected cells. This was in turn an effect of suppression of COX-2 by glycyrrhizin on the myeloid-derived suppressor cells, a heterogeneous population of precursor cells, which promotes parasite survival by suppressing T cell functions [47].

**Figure 9.** Glycyyrhizic acid (GA) suppresses P-gp and MRP-1 activation leading to antimonial retention and parasite inhibition.
