Imipramine Is an Orally Active Drug against Both Antimony Sensitive and Resistant Leishmania donovani Clinical Isolates in Experimental Infection

Abstract

BackgroundIn an endeavor to find an orally active and affordable antileishmanial drug, we tested the efficacy of a cationic amphiphilic drug, imipramine, commonly used for the treatment of depression in humans. The only available orally active antileishmanial drug is miltefosine with long half life and teratogenic potential limits patient compliance. Thus there is a genuine need for an orally active antileishmanial drug. Previously it was shown that imipramine, a tricyclic antidepressant alters the protonmotive force in promastigotes, but its in vivo efficacy was not reported.Methodology/Principal FindingsHere we show that the drug is highly active against antimony sensitive and resistant Leishmania donovani in both promastigotes and intracellular amastigotes and in LD infected hamster model. The drug was found to decrease the mitochondrial transmembrane potential of Leishmania donovani (LD) promastigotes and purified amastigotes after 8 h of treatment, whereas miltefosine effected only a marginal change even after 24 h. The drug restores defective antigen presenting ability of the parasitized macrophages. The status of the host protective factors TNF α, IFN γ and iNOS activity increased with the concomitant decrease in IL 10 and TGF β level in imipramine treated infected hamsters and evolution of matured sterile hepatic granuloma. The 10-day therapeutic window as a monotherapy, showing about 90% clearance of organ parasites in infected hamsters regardless of their SSG sensitivity.ConclusionsThis study showed that imipramine possibly qualifies for a new use of an old drug and can be used as an effective orally active drug for the treatment of Kala-azar.

Imipramine Exploits Histone Deacetylase 11 To Increase the IL-12/IL-10 Ratio in Macrophages Infected with Antimony-Resistant Leishmania donovani and Clears Organ Parasites in Experimental Infection

“…Imipramine offers several advantages: it is a drug in use (18), it is orally active, it kills intracellular Sb S LD and Sb R LD parasites (21), and it is immunostimulatory (22). Previously, we showed that infection of Mfs with Sb R LD, but not with Sb S LD, produces IL-10, which in turn upregulates MDR-1 (4).…”

“…There is a recent report that histone deacetylase (HDAC)11, one of the newly added members of the HDAC family, regulates IL-10 expression in mouse and human APCs (31). We showed that hamsters infected with Sb R LD show a decreased IL-12/IL-10 ratio that is reversed upon oral imipramine treatment (21). The mechanism by which imipramine activates the Sb R LDinfected host to increase IL-12 levels with a concomitant decrease in IL-10 is a matter of considerable interest.…”

“…Similar to phenothiazines, imipramine, another antipsychotic drug used for treating depression (18) and pediatric nocturnal enuresis (19), alters the proton motive force in Leishmania donovani promastigotes (20) and kills antimony-sensitive (Sb S ) and Sb R intracellular amastigotes without affecting the host cell viability. Additionally, oral treatment of imipramine clears organ parasites in hamsters (21). Imipramine is a potent inducer in macrophages (Mfs) of TNF-a (22), which is an important cytokine for antileishmanial defense (23) and is a competitive inhibitor of trypanothione reductase, an enzyme upregulated in Sb R L. donovani (Sb R LD) (8).…”

Antimony-ResistantLeishmania donovaniExploits miR-466i To Deactivate Host MyD88 for Regulating IL-10/IL-12 Levels during Early Hours of Infection

“…Although there was increased sinusoidal dilation, numerous parasitized KC within immature granuloma in Sb R LD-infected MyD88 KD mice, Sb R LD infection of WT BALB/c mice resulted in numerous capsulated MGs with few L. donovani bodies, pointing to a nonpersistent infection. Previously, MG formation has been associated with clearance of Leishmania infection (36). An earlier report also suggested that the level of IL-12 might act as a critical factor in determining the nature of granuloma formation during experimental infection with VL (47).…”

“…Each group contained five mice (n = 5) that were sacrificed 4 wk p.i. The parasite burdens in the liver and spleen were enumerated and expressed in Leishman-Donovan units (36). Each experiment was performed three times.…”