In vivo activity of ajoene against rodent malaria

Abstract

Ajoene (4,5,9-trithiadodeca-1,6,11-triene 9-oxide), a product initially isolated from extracts of garlic (Alium sativum), was tested for its antimalarial activity in vivo in a well-characterized murine model. A single ajoene dose of 50 mg/kg, on the day of infection, suppressed the development of parasitemia; there were no obvious acute toxic effects from the tested dose. The combination of ajoene (50 mg/kg) and chloroquine (4.5 mg/kg), given as a single dose on the day of the infection, completely prevented the subsequent development of parasitemia in treated mice.Malaria parasites resistant to various drugs are widespread in South America, Asia, and Africa (15). In particular, the chloroquine (CQ)-resistant strains of Plasmodium falciparum have become a major public health problem around the world (11,15). Hence, the search for new antimalarial therapies is a high-priority task for the control of the disease. Ajoene (4,5,9-trithiadodeca-1,6,11-triene 9-oxide), an organosulfur compound derived from garlic (Allium sativum) (1, 7), is a well-known inhibitor of platelet activation (2-4) and also has significant antifungal (10, 12, 16), antitrypanosomal (14), and antiviral (13) activities.We investigated the potential anti-Plasmodium berghei activity of ajoene in vivo. The results show that when used alone, ajoene displays a moderate anti-P. berghei activity. However, when used in combination with a noneffective dose of CQ, ajoene synergistically enhances the susceptibility of the parasite to this drug. MATERUILS AND METHODSAjoene. Synthetic ajoene (Mr, 234) was prepared as previously described (1, la, 3), dissolved in ethanol, and diluted eightfold with Intralipid (200 g of fractionated soybean, 12 g of fractionated egg phospholipids, 22 g of glycerol USP, 1,000 ml of water q.s.p) (Kavi Vitrum, Stockholm, Sweden). The final concentration of ethanol was less than 1% (vol/vol Animal experiments. All experimental mice were infected at random before being divided into groups of 7 to 10. Mice were treated by intraperitoneal injection of ajoene given on the day of inoculation (day 0). The time between the inoculation of parasites and drug injection was 60 min. The effectiveness of CQ alone at a dose of 4.5 mg/kg (8) or in combination with various concentrations of ajoene was studied by using the same experimental protocol described for ajoene. CQ diphosphate (CQ; Sigma Chemical Co.) was diluted in 0.9% (wt/vol) NaCl to give the dose required in 0.1 ml for 10 g of mouse and was administered intraperitoneally. Experiments were repeated at least three times. Data from a representative experiment are given. RESULTSDrug toxicity. On the basis of the results of a set of preliminary experiments, ajoene doses of up to 50 mg/kg were used. No signs of toxicity were observed in 30 days.Inhibition of parasite growth by ajoene. In BALB/c mice infected with 105 parasitized erythrocytes, systemic parasitemia became apparent (1%) on day 2 and increased to 24 ± 2.8% infected cells on day 6 after the inoculation. Ajoene (50 mg/kg) given ...

Potential antimalarials from Nigerian plants: A review

“…lactone, Tagitinin C, present in the leaves of Tithonia diversifolia was active against Plasmodium falciparum (Goffin et al, 2002); (e) Ajoene, a metabolite of Allium sativum, was active against Plasmodium berghei in mice (Perez et al, 1994); (f) Simalikalactone D was identified to be responsible for the antimalarial activity of Quassia amara leaves (Bertani et al, 2006). However, the possibility that the in vitro data presented in the studies with these phytochemicals could be misleading cannot be overlooked because certain natural products are metabolized and the pharmacokinetics of the individual natural products are often totally ignored.…”

Medicinal plants used by the people of Northeast India for curing malaria

“…Quinine isolated from Cinchona sp. bark and artimisinin from the Chinese plant Artimesia annua are established drugs against malaria (Agtmael et al, 1999;Perez et al, 1994). Apart from this currently cryptolepine derived from Cryptolepis sanguinolenta and tazospine purified from Madagascarian plant Strychnopsis thouarsii are potential antimalarial lead compounds (Cimanga et al, 1997;8, Carraz et al, 2006).…”

Natural products as potential antiparasitic drugs

“…Ajoenes metabolites ( 7) are a good example with the naturally occuring allicin that has proved to be active against rodent malaria and Trypanosoma cruzi. These sulfur containing aliphatics, initially isolated from garlic (Allium sativum, Liliaceae), showed significant suppression of Trypanosoma parasitemia in vivo with daily doses of 50 mg/kg over 12 days [37]. Gallwitz et al [38] identified ajoenes also as potential drugs effecting thiol metabolism by acting as a covalent inhibitor as well as a substrate of human glutathione reductase (GR) and secondly of the Trypanosoma cruzi trypanothione reductase (TR).…”