Evaluation of Nephroprotective and Immunomodulatory Activities of Antioxidants in Combination with Cisplatin against Murine Visceral Leishmaniasis

Meenakshi Sharma,Sukhbir Kaur,Rakesh Sehgal,Timothy G Geary

doi:10.1371/journal.pntd.0001629

Abstract

BackgroundMost available drugs against visceral leishmaniasis are toxic, and growing limitations in available chemotherapeutic strategies due to emerging resistant strains and lack of an effective vaccine against visceral leishmaniasis deepens the crisis. Antineoplastic drugs like miltefosine have in the past been effective against the parasitic infections. An antineoplastic drug, cisplatin (cis-diamminedichloroplatinum II; CDDP), is recognized as a DNA-damaging drug which also induces alteration of cell-cycle in both promastigotes and amastigotes leading to cell death. First in vivo reports from our laboratory revealed the leishmanicidal potential of cisplatin. However, high doses of cisplatin produce impairment of kidney, which can be reduced by the administration of antioxidants.Methodology/Principal FindingsThe present study was designed to evaluate the antileishmanial effect of cisplatin at higher doses (5 mg and 2.5 mg/kg body weight) and its combination with different antioxidants (vitamin C, vitamin E and silibinin) so as to eliminate the parasite completely and reduce the toxicity. In addition, various immunological, hematological and biochemical changes induced by it in uninfected and Leishmania donovani infected BALB/c mice were investigated.Conclusion/SignificanceA significant reduction in parasite load, higher IgG2a and lower IgG1 levels, enhanced DTH responses, and greater concentration of Th1 cytokines (IFN-γ, IL-2) with a concomitant down regulation of IL-10 and IL-4 pointed towards the generation of the protective Th1 type of immune response. A combination of cisplatin with antioxidants resulted in successful reduction of nephrotoxicity by normalizing the enzymatic levels of various liver and kidney function tests. Reduction in parasite load, increase in Th1 type of immune responses, and normalization of various biochemical parameters occurred in animals treated with cisplatin in combination with various antioxidants as compared to those treated with the drug only. The above results are promising as antioxidants reduced the potential toxicity of high doses of cisplatin, making the combination a potential anti-leishmanial therapy, especially in resistant cases.

Highlights

Pentavalent antimonial compounds like sodium stibogluconate and N-methylglucamine antimoniate have been the mainstay of antileishmanial therapy [1]
We have for the first time characterized the in vivo effect of cisplatin in murine experimental visceral leishmaniasis, but at higher doses it is nephrotoxic
Drug treatment induces a higher secretion of Th1 cytokines, diminution in parasite burden, and the supplementation of antioxidants which are antagonists of the toxicity helps in reducing the nephrotoxicity

Summary

Introduction

Pentavalent antimonial compounds like sodium stibogluconate and N-methylglucamine antimoniate have been the mainstay of antileishmanial therapy [1] They remain the conventional treatment of children and adults all over the world except in Bihar (India) where Sb is no longer useful owing to high failure rates due to resistance [2,3] and have the disadvantage of toxicity, parenteral administration and need for long duration of therapy [4]. Miltefosine (hexadecylphosphocholine) is a membrane activating alkyl phospholipid, having cure rates of approximately 90–95% It has an obvious advantage in being an active oral agent and hospitalization is not required [3] but is teratogenic in animals [3] so cannot be used in pregnant women. High doses of cisplatin produce impairment of kidney, which can be reduced by the administration of antioxidants

Methods

Results

Discussion

Conclusion