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Role of eicosanoids in the pathogenesis of murine cerebral malaria
L Xiao1, P S Patterson, C Yang
1Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30341-3724, USA.
Abstract:
Because microvascular damage is a common feature of cerebral malaria, we have examined the role eicosanoid metabolites (prostaglandins and leukotrienes) in experimental cerebral malaria. Eighty ICR mice were infected with Plasmodium berghei ANKA, with 40 uninfected mice as controls. Half of the infected mice were treated on days 4 and 5 with aspirin, a prostaglandin synthesis inhibitor. Infected mice started to die of cerebral malaria on day 6, and by day 17, all infected mice died. In contrast, all infected mice treated with aspirin died by day 12. Infected mice had increased phospholipase A2 mRNA expression in the spleen and cyclooxygenase 1 (COX1) and COX2 expression in the brain. At the peak of cerebral malaria, infected mice had higher serum leukotriene B4 levels than control mice, and aspirin-treated infected mice had higher serum leukotriene B4 levels than untreated infected mice. These results suggest that prostaglandins are protective whereas leukotrienes are detrimental in cerebral malaria.
Insights
In experimental cerebral malaria, prostaglandins appear protective, while leukotrienes are harmful. Aspirin treatment, inhibiting prostaglandin synthesis, worsened outcomes in infected mice, suggesting a complex role for these eicosanoids.
Area of Science:
- Immunology
- Parasitology
- Biochemistry
Background:
- Microvascular damage is a hallmark of cerebral malaria.
- Eicosanoid metabolites, including prostaglandins and leukotrienes, are implicated in inflammatory processes.
- Their specific roles in cerebral malaria pathogenesis remain incompletely understood.
Purpose of the Study:
- To investigate the role of prostaglandins and leukotrienes in experimental cerebral malaria.
- To determine the impact of inhibiting prostaglandin synthesis on disease progression and survival.
Main Methods:
- Induction of experimental cerebral malaria in ICR mice using Plasmodium berghei ANKA infection.
- Treatment of a subset of infected mice with aspirin, a prostaglandin synthesis inhibitor.
- Assessment of survival rates, gene expression (phospholipase A2, COX1, COX2), and serum leukotriene B4 levels.
Main Results:
- Infected mice exhibited increased phospholipase A2, COX1, and COX2 expression.
- Serum leukotriene B4 levels were elevated in infected mice compared to controls.
- Aspirin treatment accelerated mortality in infected mice and further increased leukotriene B4 levels.
- Prostaglandins demonstrated a protective effect, while leukotrienes showed detrimental effects.
Conclusions:
- Prostaglandins play a protective role in cerebral malaria.
- Leukotrienes contribute to the pathology of cerebral malaria.
- Inhibition of prostaglandin synthesis exacerbates cerebral malaria, highlighting the critical balance of eicosanoid metabolism in disease outcome.