Cerebral Malaria Causes Enduring Behavioral and Molecular Changes in Mice Brain Without Causing Gross Histopathological Damage

• Published in: Neuroscience 2018-01, Vol.369, p.66-75
• Main Authors: Souza, Thaíze Lopes de, Grauncke, Ana Claudia Beck, Ribeiro, Leandro Rodrigo, Mello, Fernanda Kulinski, Oliveira, Sara Marchesan, Brant, Fátima, Machado, Fabiana S., Oliveira, Mauro Schneider
• Format: Article
• Language: English
• Subjects: Animals; Behavior, Animal; Calcium-Binding Proteins - metabolism; Cerebral Cortex - metabolism; chloroquine; cognitive deficits; Female; Flunitrazepam - metabolism; Fluoresceins - metabolism; GABAA receptor; Hippocampus - metabolism; Malaria, Cerebral - metabolism; Malaria, Cerebral - parasitology; Malaria, Cerebral - pathology; Malaria, Cerebral - psychology; Mice; Microfilament Proteins - metabolism; Na+,K+-ATPase; oxidative stress; Plasmodium berghei - pathogenicity; Plasmodium berghei ANKA; Protein Carbonylation; Radioligand Assay; Receptors, GABA-A - metabolism; Silver Compounds - metabolism; Sodium-Potassium-Exchanging ATPase - immunology; Sodium-Potassium-Exchanging ATPase - metabolism; Tritium - metabolism
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2017.10.043

[Display omitted] •Nest and marble burying tests remained altered after CM recovery.•Phosphorylated Na+,K+-ATPase α subunit at Ser943 levels were increased after infection.•CM decreased α2/α3 Na+,K+-ATPase activity and GABAA binding capacity.•Protein carbonyl remains increased 46 days after PbA infection. Malaria, parasitic disease considered a major health public problem, is caused by Plasmodium protozoan genus and transmitted by the bite of infected female Anopheles mosquito genus. Cerebral malaria (CM) is the most severe presentation of malaria, caused by P. falciparum and responsible for high mortality and enduring development of cognitive deficits which may persist even after cure and cessation of therapy. In the present study we evaluated selected behavioral, neurochemical and neuropathologic parameters after rescue from experimental cerebral malaria caused by P. berghei ANKA in C57BL/6 mice. Behavioral tests showed impaired nest building activity as well as increased marble burying, indicating that natural behavior of mice remains altered even after cure of infection. Regarding the neurochemical data, we found decreased α2/α3 Na+,K+-ATPase activity and increased immunoreactivity of phosphorylated Na+,K+-ATPase at Ser943 in cerebral cortex after CM. In addition, [3H]-Flunitrazepam binding assays revealed a decrease of benzodiazepine/GABAA receptor binding sites in infected animals. Moreover, in hippocampus, dot blot analysis revealed increased levels of protein carbonyls, suggesting occurrence of oxidative damage to proteins. Interestingly, no changes in the neuropathological markers Fluoro-Jade C, Timm staining or IBA-1 were detected. Altogether, present data indicate that behavioral and neurochemical alterations persist even after parasitemia clearance and CM recovery, which agrees with available clinical findings. Some of the molecular mechanisms reported in the present study may underlie the behavioral changes and increased seizure susceptibility that persist after recovery from CM and may help in the future development of therapeutic strategies for CM sequelae.