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Effects of endotoxin and dexamethasone on cerebral malaria in mice
Abstract:
CBA/T6 and DBA/2J mice inoculated with Plasmodium berghei ANKA (PbA) develop cerebral involvement 6-8 days post-inoculation, from which the CBA mice almost invariably die and the DBA mice recover. Dexamethasone (DXM; 80 mg/kg) given to inoculated CBA mice twice, on day 3 and again within 48 h, reduced the cerebral symptoms and prevented death from cerebral malaria. Plasma tumour necrosis factor (TNF) levels, which increased at the time of the cerebral symptoms, were also reduced in these DXM-treated mice. Intravenously administered Evans Blue, a dye which binds to albumin, diffused extensively across the blood-brain barrier only during the period of cerebral symptoms, in proportion to the severity of the cerebral symptoms and the disease. In PbA-infected CBA mice, cerebral symptoms and the amounts of Evans Blue diffusing into the brain tissue were both reduced by DXM treatment, but only if the steroid was given on day 3 and again within 48 h. Endotoxin injected intravascularly into PbA-infected DBA mice after day 5 resulted in an exaggeration of cerebral symptoms and death between days 6 and 9. Plasma TNF and the amount of Evans Blue in the brain parenchyma increased above normal levels in these mice. Endotoxin injections had only minor effects on the severity of the cerebral symptoms in PbA-infected CBA mice and did not cause the animals to die sooner.
Insights
Dexamethasone (DXM) treatment effectively prevents death from cerebral malaria in CBA mice infected with Plasmodium berghei ANKA (PbA). This treatment reduces cerebral symptoms and lowers plasma tumor necrosis factor (TNF) levels.
Area of Science:
- Immunology
- Infectious Diseases
- Neuroscience
Background:
- Plasmodium berghei ANKA (PbA) infection causes cerebral malaria in susceptible CBA/T6 mice, leading to high mortality.
- DBA/2J mice, while infected with PbA, typically recover from cerebral involvement.
Purpose of the Study:
- To investigate the efficacy of Dexamethasone (DXM) in preventing and treating cerebral malaria in a murine model.
- To explore the role of tumor necrosis factor (TNF) and blood-brain barrier (BBB) permeability in PbA-induced cerebral malaria.
Main Methods:
- CBA/T6 and DBA/2J mice were inoculated with PbA.
- Dexamethasone (DXM) was administered at specific time points to infected CBA mice.
- Plasma TNF levels and Evans Blue dye extravasation into the brain were measured.
- Endotoxin was administered to assess its effect on disease severity.
Main Results:
- DXM treatment significantly reduced cerebral symptoms and prevented mortality in PbA-infected CBA mice when administered early.
- DXM treatment lowered elevated plasma TNF levels during cerebral malaria.
- Evans Blue diffusion across the BBB correlated with cerebral symptom severity and was reduced by DXM.
- Endotoxin exacerbated cerebral symptoms and mortality in DBA/2J mice but had minimal effect on CBA mice.
Conclusions:
- Early DXM intervention is a promising strategy for managing cerebral malaria by mitigating neuroinflammation and BBB breakdown.
- TNF and BBB permeability are critical factors in the pathogenesis of PbA-induced cerebral malaria.
- Differential responses to endotoxin suggest distinct immune mechanisms in CBA and DBA/2J mice during PbA infection.