Effects of autacoid inhibitors and of an antagonist on malaria infection in mice.

E.O Iwalewa,E.O Agbani

doi:10.1590/s0100-879x2004000800010

Abstract

The effects of p-chlorophenylalanine, an inhibitor of serotonin synthesis, indomethacin, an inhibitor of prostaglandin synthesis, cyproheptadine, a serotonin, bradykinin and histamine antagonist, were assessed separately and in combination with chloroquine (CQ) in Vom strains of Swiss albino mice (18-22 g) of either sex infected intraperitoneally with 1 x 10(7) Plasmodium yoelii nigeriensis-induced malaria. As prophylactic, these agents reduced from 31.9 +/- 4.5 to 16.1 +/- 8.1% the level of parasitemia relative to control but had no appreciable activity as curative agents when administered subcutaneously once daily for 4 days after 72 h of parasites innoculum in vivo. However, CQ alone and the combination of these agents with CQ in curative and prophylactic treatments significantly reduced (from 50.3 +/- 5.8 to 4.9 +/- 0.75%) the level of parasitemia (P < 0.05), which was taken only once 72 h after the parasites innoculum. The prophylactic result was shown to produce better results than the curative treatment. The data indicate that inhibitors and an antagonist can reduce the parasitemia load (the extent of damage and the severity of infection) as well as enhance the effects of CQ when combined with it for malaria therapy. The study reveals that the production of autacoids in established infection renders autacoid inhibitors and an antagonist ineffective for radical cure in malarial mice; however, selective inhibition of local hormones implicated in the pathological manifestations of malaria infection by autacoid inhibitors and an antagonist may be a possible pathway to reduce the severity of infection and the associated tissue damage and to enhance the efficacy of available anti-malarials.

Highlights

Malaria is a major disease in tropical climates, with high mortality rates
The curative experiments (Figure 1) indicate that the autacoid inhibitors and the antagonist p-CPA, indomethacin cyproheptadine (a 5-HT, bradykinin and histamine antagonist) used had no curative effect on an established malaria infection, perhaps because they lack radical killing or suppressant activity on the parasites in monotherapy or on the various pharmacologically active substances produced by the parasite that enhance tissue damage and hamper the immune response [13]
Evidence suggests that acute malaria infection induces a temporal reduction of the immune response via autacoids [8,13]; for example, during infection with a plasmodium parasite, circulating Tcells are reduced in number, accompanied by a decrease in lymphoproliferative response and cytokine release by peripheral blood mononuclear cells when stimulated by malaria antigens [7]

Summary

Introduction

Malaria is a major disease in tropical climates, with high mortality rates. Despite serious efforts to eradicate the disease, malaria is reemerging to take its toll among the inhabitants of tropical developing countries. According to the World Health Organization (WHO) [1], approximately 300-500 million individuals are infected with malaria, with death totals ranging from 1.5 to 3.5 million annually. The development of new drugs and the evaluation of the efficacy of available drugs for the treatment of malaria infection have been effective in controlling the spread of malaria. The malaria parasite Plasmodium yoelii nigeriensis used in the present study belongs to a group of four plasmodium species that infect murine rodents in central Africa [2,3]. Malaria infection is known to produce inflammatory responses by the release of a num-

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Conclusion