Potential utility of indomethacin in enhancing the leishmanicidal activity of glucantime
The trypanothione biosynthetic pathway is common to the trypanosomatid family of protozoa, which includes Leishmania and Trypanosoma spp. and is absent in the host systems. This pathway constitutes an important target for chemotherapy against leishmaniasis.
The trypanothione pathway combines 2 metabolic pathways: the polyamine biosynthetic pathway and the glutathione pathway. Since glutathione (GSH) is involved in a number of vital functions within cells, chiefly defence against oxidative damage, GSH inhibition is a potential means for chemotherapy against these parasites [1].
Moreover, GSH depletion in macrophages leads to increased nitric oxide production, which has leishmanicidal action. In this way, it has been shown that buthionine sulfoximine, an inhibitor of GSH synthesis, exerts an inhibitory effect on L. donovani growth [1]. On the other hand, resistance of L. donovani to sodium stibogluconate is related to the expression of host and parasite gamma-glutamylcysteine synthetase, which produces GSH [2]. Resistance of L. major and L. tropica to glucantime was also attributed to higher GSH levels [3].
Indomethacin is known to decrease cellular GSH levels [4]. Through this mechanism, it enhances the effect of chloroquine against malaria, which, like Leishmania, is an intracellular parasite [4]. Indomethacin treatment slows disease progression and enhances a type 1 helper (Th1) cell response in susceptible BALB/c mice infected with L. major [5].
In vitro indomethacin administration upregulates interleukin-12 production and polarizes the immune response towards a Th1 type in susceptible BALB/c mice infected with L. mexicana [6]. Combined treatment with interleukin-12 and indomethacin promotes increased resistance in BALB/c mice with established L. major infections [7]. Theses effects can be explained by the observations that, first, prostaglandins may play a role in the loss of interleukin-12 responsiveness observed during nonhealing of L. major infections [5] and, secondly, that prostaglandins can inhibit the development of Th1 response and enhance the development of type 2 helper (Th2) cell response [7].
Given the above facts, indomethacin, especially in the topical form, may prove to enhance the antileishmanial activity of glucantime. Clinical trials on this subject are warranted.
References
- Kapoor P, Sachdev M, Madhubala R. Inhibition of glutathione synthesis as a chemotherapeutic strategy for leishmaniasis. Tropical medicine and international health, 2000, 5(6):438–42.
- Carter KC et al. Resistance of Leishmania donovani to sodium stibogluconate is related to the expression of host and parasite gamma-glutamylcysteine synthetase. Antimicrobial agents and chemotherapy, 2006, 50(1):88–95.
- Hadighi R et al. Unresponsiveness to glucantime treatment in Iranian cutaneous leishmaniasis due to drug-resistant Leishmania tropica parasites. PLoS medicine, 2006, 3(5):e162.
- Deharo E et al. Potentiation of the antimalarial action of chloroquine in rodent malaria by drugs known to reduce cellular glutathione levels. Biochemical pharmacology, 2003, 66(5):809–17.
- De Freitas LA et al. Indomethacin treatment slows disease progression and enhances a Th1 response in susceptible BALB/c mice infected with Leishmania major. Parasite immunology, 1999, 21(5):273–7.
- Pérez-Santos JL, Talamás-Rohana P. In vitro indomethacin administration upregulates interleukin-12 production and polarizes the immune response towards a Th1 type in susceptible BALB/c mice infected with Leishmania mexicana. Parasite immunology, 2001, 23(11):599–606.
- Li J et al. Combined treatment with interleukin-12 and indomethacin promotes increased resistance in BALB/c mice with established Leishmania major infections. Infection and immunity, 2002, 70(10):5715–20.
M.R. Namazi, Department of Dermatology,
Shiraz University of Medical Sciences, Shiraz, Islamic Republic of Iran
