Conventional and experimental treatment of cerebral malaria

Golenser, Jacob; McQuillan, James A.; Hee, L.; Mitchell, Andrew J.; Hunt, Nicholas H.

doi:10.1016/j.ijpara.2006.02.009

Cited by 47 publications

(47 citation statements)

References 95 publications

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“…It has been suggested that the early production of IFN-␥ may be able to divert the disease course from the development of CM (47). Mice deficient in IFN-␥ (i.e., IFN-␥ Ϫ/Ϫ mice) do not develop CM (27,59), and neutralizing anti-IFN-␥ antibodies administered in the early course of infection also provide protection (24). The relevance of these observations to human CM has been suggested by studies of the induction of IFN-␥ in human peripheral blood mononuclear cells (PBMC) by Plasmodium falciparum (2).…”

Section: Resultsmentioning

confidence: 99%

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Differential MicroRNA Expression in Experimental Cerebral and Noncerebral Malaria

et al. 2011

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MicroRNAs (miRNAs) are posttranscriptional regulatory molecules that have been implicated in the regulation of immune responses, but their role in the immune response to Plasmodium infection is unknown. We studied the expression of selected miRNAs following infection of CBA mice with Plasmodium berghei ANKA (PbA), which causes cerebral malaria (CM), or Plasmodium berghei K173 (PbK), which causes severe malaria but without cerebral complications, termed non-CM. The differential expression profiles of selected miRNAs (let-7i, miR-27a, miR-150, miR-126, miR-210, and miR-155) were analyzed in mouse brain and heart tissue by quantitative reverse transcription-PCR (qRT-PCR). We identified three miRNAs that were differentially expressed in the brain of PbA-infected CBA mice: let7i, miR-27a, and miR-150. In contrast, no miRNA changes were detected in the heart, an organ with no known pathology during acute malaria. To investigate the involvement of let-7i, miR-27a, and miR-150 in CM-resistant mice, we assessed the expression levels in gamma interferon knockout (IFN-␥ ؊/؊ ) mice on a C57BL/6 genetic background. The expression of let-7i, miR-27a, and miR-150 was unchanged in both wild-type (WT) and IFN-␥ ؊/؊ mice following infection. Overexpression of these three miRNAs during PbA, but not PbK, infection in WT mice may be critical for the triggering of the neurological syndrome via regulation of their potential downstream targets. Our data suggest that in the CBA mouse at least, miRNA may have a regulatory role in the pathogenesis of severe malaria.

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Section: Resultsmentioning

confidence: 99%

“…Despite promising therapeutic agents, no treatment provides complete amelioration in humans or mice (24,67). Mouse models have been an invaluable tool for the study of the underlying pathogenesis of CM (20,31,32).…”

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confidence: 99%

Differential MicroRNA Expression in Experimental Cerebral and Noncerebral Malaria

et al. 2011

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“…This might be a hint to consider drug combinations that also include components that reduce oxidant stress. In addition, immunomodulators that could alleviate CM should be considered for adjunctive therapy due to the inflammatory etiological nature of CM (and severe malaria in general) in both human malaria and experimental models (16,22,26,29,30,41). Obviously, an adjunctive drug also should be examined in combination with the antiplasmodial drugs to exclude any deleterious antagonistic effects.…”

Section: Discussionmentioning

confidence: 99%

Synthesis of Artemiside and Its Effects in Combination with Conventional Drugs against Severe Murine Malaria

Guo

Guiguemde

Bentura-Marciano

et al. 2012

Antimicrob Agents Chemother

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This research describes the use of novel antimalarial combinations of the new artemisinin derivative artemiside, a 10-alkylamino artemisinin. It is a stable, highly crystalline compound that is economically prepared from dihydroartemisinin in a one-step process. Artemiside activity was more pronounced than that of any antimalarial drug in use, both in Plasmodium falciparum culture and in vivo in a murine malaria model depicting cerebral malaria (CM). In vitro high-throughput testing of artemiside combinations revealed a large number of conventional antimalarial drugs with which it was additive. Following monotherapy in mice, individual drugs reduced parasitemias to nondetectable levels. However, after a period of latency, parasites again were seen and eventually all mice became terminally ill. Treatment with individual drugs did not prevent CM in mice with recrudescent malaria, except for piperaquine at high concentrations. Even when CM was prevented, the mice developed later of severe anemia. In contrast, most of the mice treated with drug combinations survived. A combination of artemiside and mefloquine or piperaquine may confer an optimal result because of the longer half life of both conventional drugs. The use of artemiside combinations revealed a significant safety margin of the effective artemiside doses. Likewise, a combination of 1.3 mg/kg of body weight artemiside and 10 mg/kg piperaquine administered for 3 days from the seventh day postinfection was completely curative. It appears possible to increase drug concentrations in the combination therapy without reaching toxic levels. Using the drug combinations as little as 1 day before the expected death of control animals, we could prevent further parasite development and death due to CM or anemic malaria. Earlier treatment may prevent cognitive dysfunctions which might occur after recovery from CM.

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“…7,11,28,33,41 Quinine, MFQ, and QNX have demonstrated the ability to penetrate the blood-brain barrier; therefore, QN and MFQ are effectively used to treat malaria-causing parasites that have entered the central nervous system. 3,5,21,22,32 In addition to targeting the AFVs of P. falciparum, CQ has recently received attention for its antitumor effects, where it was shown to accumulate in the lysosomes of tumor cells, blocking autophagy and preventing the degradation of autophagosomal content. Moreover, we have recently examined the use of MFQ in breast cancer.…”

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confidence: 99%

Quinoline-based antimalarial drugs: a novel class of autophagy inhibitors

Golden

Cho²,

Hofman³

et al. 2015

FOC

150

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OBJECT Chloroquine (CQ) is a quinoline-based drug widely used for the prevention and treatment of malaria. More recent studies have provided evidence that this drug may also harbor antitumor properties, whereby CQ possesses the ability to accumulate in lysosomes and blocks the cellular process of autophagy. Therefore, the authors of this study set out to investigate whether CQ analogs, in particular clinically established antimalaria drugs, would also be able to exert antitumor properties, with a specific focus on glioma cells. METHODS Toward this goal, the authors treated different glioma cell lines with quinine (QN), quinacrine (QNX), mefloquine (MFQ), and hydroxychloroquine (HCQ) and investigated endoplasmic reticulum (ER) stress–induced cell death, autophagy, and cell death. RESULTS All agents blocked cellular autophagy and exerted cytotoxic effects on drug-sensitive and drug-resistant glioma cells with varying degrees of potency (QNX > MFQ > HCQ > CQ > QN). Furthermore, all quinoline-based drugs killed glioma cells that were highly resistant to temozolomide (TMZ), the current standard of care for patients with glioma. The cytotoxic mechanism involved the induction of apoptosis and ER stress, as indicated by poly(ADP-ribose) polymerase (PARP) cleavage and CHOP/GADD153. The induction of ER stress and resulting apoptosis could be confirmed in the in vivo setting, in which tumor tissues from animals treated with quinoline-based drugs showed increased expression of CHOP/GADD153, along with elevated TUNEL staining, a measure of apoptosis. CONCLUSIONS Thus, the antimalarial compounds investigated in this study hold promise as a novel class of autophagy inhibitors for the treatment of newly diagnosed TMZ-sensitive and recurrent TMZ-resistant gliomas.

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Conventional and experimental treatment of cerebral malaria

Cited by 47 publications

References 95 publications

Differential MicroRNA Expression in Experimental Cerebral and Noncerebral Malaria

Differential MicroRNA Expression in Experimental Cerebral and Noncerebral Malaria

Synthesis of Artemiside and Its Effects in Combination with Conventional Drugs against Severe Murine Malaria

Quinoline-based antimalarial drugs: a novel class of autophagy inhibitors

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