Na+, K+-ATPase Activating Antibody Displays in vitro and in vivo Beneficial Effects in the Pilocarpine Model of Epilepsy

•DRRSAb decreased glutamate release in slices of slices from epileptic mice.•Reduced uptake of glucose was not detected in DRRSAb-treated slices.•In vivo injection of DRRSAb restored crossing activity of epileptic mice. Na+, K+-ATPase is an important regulator of brain excitability. Accordingly, com...

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Published in:Neuroscience 2018-05, Vol.377, p.98-104
Main Authors: Freitas, Mayara Lütchemeyer de, Oliveira, Clarissa Vasconcelos de, Mello, Fernanda Kulinski, Funck, Vinícius Rafael, Fighera, Michele Rechia, Royes, Luiz Fernando Freire, Furian, Ana Flávia, Larrick, James W., Oliveira, Mauro Schneider
Format: Article
Language:English
Subjects:
Animals
Anticonvulsants - pharmacology
Caspase 3 - metabolism
Disease Models, Animal
Drug Evaluation, Preclinical
epilepsy
Epilepsy - drug therapy
Epilepsy - metabolism
excitotoxicity
Glucose - metabolism
Glutamic Acid - metabolism
Hippocampus - drug effects
Hippocampus - metabolism
hypometabolism
Male
Mice, Inbred C57BL
Oxidation-Reduction - drug effects
Pilocarpine
sodium pump
Sodium-Potassium-Exchanging ATPase - immunology
Sodium-Potassium-Exchanging ATPase - metabolism
Tissue Culture Techniques
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Summary:•DRRSAb decreased glutamate release in slices of slices from epileptic mice.•Reduced uptake of glucose was not detected in DRRSAb-treated slices.•In vivo injection of DRRSAb restored crossing activity of epileptic mice. Na+, K+-ATPase is an important regulator of brain excitability. Accordingly, compelling evidence indicates that impairment of Na+, K+-ATPase activity contributes to seizure activity in epileptic mice and human with epilepsy. In addition, this enzyme is crucial for plasma membrane transport of water, glucose and several chemical mediators, including glutamate, the major excitatory transmitter in the mammalian brain. Since glucose hypometabolism and increased glutamate levels occur in clinical and experimental epilepsy, we aimed the present study to investigate whether activation of Na+, K+-ATPase activity with specific antibody (DRRSAb) would improve glucose uptake and glutamate release in pilocarpine-treated mice. We found decreased uptake of the glucose fluorescent analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-il)amino]-2-desoxi-d-glucose (2-NBDG) in cerebral slices from pilocarpine-treated animals. Interestingly, decreased 2-NBDG uptake was not detected in DRRSAb-treated slices, suggesting a protective effect of the Na+, K+-ATPase activator. Moreover, DRRSAb prevented the increase in glutamate levels in the incubation media of slices from pilocarpine-treated mice. In addition, in vivo intrahippocampal injection of DRRSAb restored crossing activity of pilocarpine-treated mice in the open-field test. Overall, the present data further support the hypothesis that activation of the Na+, K+-ATPase is a promising therapeutic strategy for epilepsy.
ISSN:0306-4522
1873-7544
DOI:10.1016/j.neuroscience.2018.02.044