Low plasma arginine concentrations in children with cerebral malaria and decreased nitric oxide production

Lopansri, Bert K.; Anstey, Nicholas M.; Weinberg, J. Brice; Stoddard, Gregory J.; Hobbs, Maurine R.; Levesque, Marc C.; Mwaikambo, Esther D.; Granger, Donald L.

doi:10.1016/s0140-6736(03)12564-0

Cited by 157 publications

(147 citation statements)

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“…Tregs inhibit the Th1 response by modifying DC function, producing IL-10, and inducing CD4 + T cell apoptosis (Slade and Langhorne 1989;Zheng et al 2009), which facilitates immune evasion by the parasite (Hisaeda et al 2004). Previous studies have shown that Tregs contributed to determining the incidence and outcome of CM in Pb ANKA-infected mice by altering the balance of pro-(IFN-γ, TNF-α, IL-6, IL-17, and NO) and anti-inflammatory (IL-10) responses (Lopansri et al 2003;Amante et al 2007;Yeo et al 2008b). Therefore, we assessed the effect of L-Arg on the percentage of Tregs and the production of the anti-inflammatory cytokine IL-10.…”

Section: Discussionmentioning

confidence: 99%

L-Arginine Exacerbates Experimental Cerebral Malaria by Enhancing Pro-Inflammatory Responses

Feng

Chen³

et al. 2015

Tohoku J. Exp. Med.

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L-Arginine (L-Arg), the substrate for nitric oxide (NO) synthase, has been used to treat malaria to reverse endothelial dysfunction in adults. However, the safety and efficacy of L-Arg remains unknown in malaria patients under the age of five, who are at the greatest risk of developing cerebral malaria (CM), a severe malaria complication. Here, we tested effects of L-Arg treatment on the outcomes of CM using a mouse model. Experimental cerebral malaria (ECM) was induced in female C57BL/6 mice infected with Plasmodium berghei ANKA, and L-Arg was administrated either prophylactically or after parasite infection. ) in the spleen. The levels of pro-inflammatory cytokines, IFN-γ and TNF-α, in splenocyte cultures were also increased by L-Arg treatment. The above changes were accompanied with a rise in the number of dendritic cells (DCs) and an increase in their maturation. However, L-Arg did not affect the population of regulatory T cells or the level of IL-10 in the spleen. Taken together, these data suggest that L-Arg may enhance the Th1 immune response, which is essential for a protective response in uncomplicated malaria but could be lethal in CM patients. Therefore, the prophylactic use of L-Arg to treat CM, based on the assumption that restoring the bioavailability of endothelial NO improves the outcome of CM, may need to be reconsidered especially for children.

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Section: Discussionmentioning

confidence: 99%

L-Arginine Exacerbates Experimental Cerebral Malaria by Enhancing Pro-Inflammatory Responses

Feng

Chen³

et al. 2015

Tohoku J. Exp. Med.

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“…The short half-life of nitric oxide, as well as its ability to diffuse quickly makes direct measurement difficult. However, decreased future science group levels of the precursor to nitric oxide, l-arginine, have been shown to correlate with malaria disease severity in children [81]. Based on these data, as well as encouraging results showing that increased nitric oxide may lead to disease protection in a mouse model of CM [82], there are two ongoing randomized controlled trials of inhaled nitric oxide as adjunctive treatment of CM taking place in Uganda [83,84].…”

Section: Inhaled Nitric Oxidementioning

confidence: 99%

Pediatric Cerebral Malaria: A Scourge of Africa

et al. 2012

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Cerebral malaria, defined as an otherwise unexplained coma in a patient with Plasmodium falciparum parasitemia, affects up to 1 million people per year, the vast majority of them being children living in sub-Saharan Africa. Despite optimal treatment, this condition kills 15% of those affected and leaves 30% of survivors with neurologic sequelae. The clinical diagnosis is hampered by its poor specificity, but the presence or absence of a malarial retinopathy in cerebral malaria has proven to be important in the differentiation of underlying coma etiology. Both antimalarials and intense supportive care are necessary for optimal treatment. As of yet, clinical trials of adjunctive therapies have not improved the high rates of mortality and morbidity. Survivors are at high risk of neurologic sequelae including epilepsy, neurodisabilities and cognitive–behavioral problems. The neuroanatomic and functional bases of these sequelae are being elucidated. Although adjunctive therapy trials continue, the best hope for African children may lie in disease prevention. Strategies include bednets, chemoprophylaxis and vaccine development.

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“…These toxic molecules might contribute to the pathogenesis of severe and cerebral malaria (Clark, Hunt et al 1986;Clark, Rockett et al 1991). However, recent clinical and experimental studies in CM have failed to support this belief (Lopansri, Anstey et al 2003;Gramaglia, Sobolewski et al 2006;Weinberg, Lopansri et al 2008). Indeed, they did find good evidence for the protective role of NO in human CM (Lopansri, Anstey et al 2003;Gramaglia, Sobolewski et al 2006;Weinberg, Lopansri et al 2008).…”

Section: Arginine/nitric Oxide Signaling Pathwaymentioning

confidence: 99%

“…However, recent clinical and experimental studies in CM have failed to support this belief (Lopansri, Anstey et al 2003;Gramaglia, Sobolewski et al 2006;Weinberg, Lopansri et al 2008). Indeed, they did find good evidence for the protective role of NO in human CM (Lopansri, Anstey et al 2003;Gramaglia, Sobolewski et al 2006;Weinberg, Lopansri et al 2008). Some investigators proposed that severe malaria is associated with reduced NO production and low blood levels of L-arginine, the substrate for NO synthase (Yeo, Rooslamiati et al 2008).…”

Section: Arginine/nitric Oxide Signaling Pathwaymentioning

confidence: 99%