Immune-mediated parasite clearance in mice infected with Plasmodium berghei treatment with manzamine A.

Department of Biological Sciences, National University of Singapore, Singapore.
Parasitology Research (Impact Factor: 2.1). 10/2001; 87(9):715-21. DOI: 10.1007/s004360000366
Source: PubMed


Manzamine A, a sponge-derived alkaloid, was recently shown to possess in vivo antimalarial activity against the blood stages of the rodent malaria parasite Plasmodium berghei. A single intraperitoneal dose of 100 micromol/kg of manzamine A suppressed parasite growth but was followed by parasite recrudescence. Forty percent of mice with recrudescing parasites were able to recover and clear the fulminating parasitaemia. Examination of sera from these mice revealed that infected mice treated with manzamine A had a suppressed IFN-gamma production but an increase in their IL-10 and IgG production. The prolonged survival of infected mice treated with manzamine A and the eventual clearance of recrudescing parasites in some of these mice involve a down-regulation of Thl responses and a switch to antibody dependent-Th2 responses.

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    • "The biological activities of new metabolites from sponges have been reported in hundreds of scientific papers. Sponges have the potential to provide future drugs against important diseases such as cancer (Bai et al. 1993; Blackburn et al. 1999; Hood et al. 2002; Molinski et al. 2009), inflammation (Tan et al. 1997; Pope et al. 1999; Festaa et al. 2012), cardiovascular (Maryanoff et al. 1993; Shuman et al. 1993; Chackalamannil 2001), viral (Müller et al. 1987; Ford et al. 1999; Wellington et al. 2000), plasmodial (Ang et al. 2001) and bacterial (D_Ambrosio et al. 1996). Previous work on another species of the genus Dragmacidon collected from Andaman Sea in Thailand resulted in the isolation of a number of b-carboline alkaloids; some of them are characterised by possessing potent anti-inflammatory and antitumour activities (Pedpradab et al. 2004). "
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    ABSTRACT: Chemical investigation of the Red Sea sponge Dragmacidon coccinea led to the isolation of a new nucleoside, dragmacidoside (1), along with eight known compounds: adenosine (2), inosine (3), deoxycytidine (4), methyl-α-d-glucopyranoside (5), clionasterol (6), stigmasterol (7), campesterol (8) and brassicasterol (9). The compounds were isolated from chloroform and ethyl acetate fractions of the methanolic extract of the sponge, and their structures were established based on various spectroscopic data including MS, 1D and 2D NMR (COSY, HSQC and HMBC). Biological testing revealed that the chloroform fraction possesses significant anti-inflammatory activity in the carrageenan-induced hind paw oedema in rats.
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    • "IL-10 has also been shown to play a crucial role in the protection of experimental cerebral malaria due to P. berghei ANKA strain by co-infection with non-lethal malaria parasite [30]. The recovery of 40% of recrudescing P.berghei-infected animals under conditions of the alkaloid manzamine A treatment has also been shown to be correlated with increased IL-10 levels in sera [31]. "
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    ABSTRACT: Earlier studies in this laboratory have shown the potential of artemisinin-curcumin combination therapy in experimental malaria. In a parasite recrudescence model in mice infected with Plasmodium berghei (ANKA), a single dose of alpha,beta-arteether (ART) with three oral doses of curcumin prevented recrudescence, providing almost 95% protection. The parasites were completely cleared in blood with ART-alone (AE) or ART+curcumin (AC) treatments in the short-term, although the clearance was faster in the latter case involving increased ROS generation. But, parasites in liver and spleen were not cleared in AE or AC treatments, perhaps, serving as a reservoir for recrudescence. Parasitemia in blood reached up to 60% in AE-treated mice during the recrudescence phase, leading to death of animals. A transient increase of up to 2-3% parasitemia was observed in AC-treatment, leading to protection and reversal of splenomegaly. A striking increase in spleen mRNA levels for TLR2, IL-10 and IgG-subclass antibodies but a decrease in those for INFγ and IL-12 was observed in AC-treatment. There was a striking increase in IL-10 and IgG subclass antibody levels but a decrease in INFγ levels in sera leading to protection against recrudescence. AC-treatment failed to protect against recrudescence in TLR2(-/-) and IL-10(-/-) animals. IL-10 injection to AE-treated wild type mice and AC-treated TLR2(-/-) mice was able to prolong survival. Blood from the recrudescence phase in AE-treatment, but not from AC-treatment, was able to reinfect and kill naïve animals. Sera from the recrudescence phase of AC-treated animals reacted with several parasite proteins compared to that from AE-treated animals. It is proposed that activation of TLR2-mediated innate immune response leading to enhanced IL-10 production and generation of anti-parasite antibodies contribute to protective immunity in AC-treated mice. These results indicate a potential for curcumin-based combination therapy to be tested for prevention of recrudescence in falciparum and relapse in vivax malaria.
    Full-text · Article · Jan 2012 · PLoS ONE
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    • "Youssaf et al., 2002). This antimalarial effect of manzamine-A is due to an enhanced immune response (Ang et al., 2001). "
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    ABSTRACT: Malaria, which is caused by multiplication of the protozoan parasite Plasmodium falciparum in erythrocytes, is a major health problem in many southern countries. There is an urgent need to discover new antimalarials, due to the spread of chloroquinine resistance and the limited number of available drugs. Among marine invertebrates, Porifera (sponges) are potential source of novel bioactive compounds to provide future drugs against malaria, cancer and a range of viral diseases. A number of sponge-derived antimalarials have been discovered during the last decade. The compounds are mostly nitrogen containing ones (proteins, pyridines, tyrosine-based metabolites, alkaloids, indoles and amides) and also non-nitrogenous compounds (terpenes, polyketides and polysaccharides).
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