title: Contrasting effects of Na+, K+-ATPase activation on seizure activity in acute versus chronic models.
abstract: Epilepsy is a life-shortening brain disorder affecting approximately 1% of the worldwide population. Most epilepsy patients are refractory to currently available antiepileptic drugs (AEDs). Knowledge about the mechanisms underlying seizure activity and probing for new AEDs is fundamental to the discovery of new therapeutic strategies. Brain Na(+), K(+)-ATPase activity contributes to the maintenance of the electrochemical gradients underlying neuronal resting and action potentials as well as the uptake and release of neurotransmitters. Accordingly, a decrease of Na(+), K(+)-ATPase increases neuronal excitability and may predispose to appearing of seizure activity. In the present study, we tested the hypothesis that activation of Na(+), K(+)-ATPase activity with a specific antibody (DRRSAb) raised against a regulatory site in the α subunit would decrease seizure susceptibility. We found that incubation of hippocampal homogenates with DRRSAb (1 μM) increased total and α1 Na(+), K(+)-ATPase activities. A higher concentration (3 μM) increased total, α1 and α2/α3 Na(+), K(+)-ATPase activities. Intrahippocampal injection of DRRSAb decreased the susceptibility of post status epilepticus animals to pentylenetetrazol (PTZ)-induced myoclonic seizures. In contrast, administration of DRRSAb into the hippocampus of naïve animals facilitated the appearance of PTZ-induced seizures. Quantitative analysis of hippocampal electroencephalography (EEG) recordings revealed that DRRSAb increased the percentage of total power contributed by the delta frequency band (0-3 Hz) to a large irregular amplitude pattern of hippocampal EEG. On the other hand, we found no DRRSAb-induced changes regarding the theta functional state. Further studies are necessary to define the potential of Na(+), K(+)-ATPase activation as a new therapeutic approach for seizure disorders.
authors.affiliation: Graduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, Brazil.
authors.forename: V R
authors.initials: VR
authors.lastname: Funck
authors.affiliation: Graduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, Brazil.
authors.forename: L R
authors.initials: LR
authors.lastname: Ribeiro
authors.affiliation: Graduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, Brazil.
authors.forename: L M
authors.initials: LM
authors.lastname: Pereira
authors.affiliation: Graduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, Brazil.
authors.forename: C V
authors.initials: CV
authors.lastname: de Oliveira
authors.affiliation: Graduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, Brazil.
authors.forename: J
authors.initials: J
authors.lastname: Grigoletto
authors.affiliation: Graduate Program in Biological Sciences: Biochemistry, Federal University of Santa Maria, Santa Maria, Brazil.
authors.forename: I D
authors.initials: ID
authors.lastname: Della-Pace
authors.affiliation: Graduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, Brazil; Graduate Program in Biological Sciences: Biochemistry, Federal University of Santa Maria, Santa Maria, Brazil.
authors.forename: M R
authors.initials: MR
authors.lastname: Fighera
authors.affiliation: Graduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, Brazil; Graduate Program in Biological Sciences: Biochemistry, Federal University of Santa Maria, Santa Maria, Brazil.
authors.forename: L F F
authors.initials: LF
authors.lastname: Royes
authors.affiliation: Graduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, Brazil.
authors.forename: A F
authors.initials: AF
authors.lastname: Furian
authors.affiliation: Panorama Research Institute, 1230 Bordeaux Drive, Sunnyvale, CA 94089, United States.
authors.forename: J W
authors.initials: JW
authors.lastname: Larrick
authors.affiliation: Graduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, Brazil; Graduate Program in Biological Sciences: Biochemistry, Federal University of Santa Maria, Santa Maria, Brazil. Electronic address: ms.oliveira@ufsm.br.
authors.forename: M S
authors.initials: MS
authors.lastname: Oliveira
mesh_terms: D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D000927:Anticonvulsants / Q000627:therapeutic use; D058256:Brain Waves / Q000187:drug effects; D003292:Convulsants / Q000633:toxicity; D004195:Disease Models, Animal; D004569:Electroencephalography; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D010433:Pentylenetetrazole / Q000633:toxicity; D010862:Pilocarpine / Q000633:toxicity; D051381:Rats; D000254:Sodium-Potassium-Exchanging ATPase / Q000276:immunology / Q000378:metabolism*; D018709:Statistics, Nonparametric; D013226:Status Epilepticus / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D013997:Time Factors
chemical_list: D000906:Antibodies; D000927:Anticonvulsants; D003292:Convulsants; D010862:Pilocarpine; D000254:Sodium-Potassium-Exchanging ATPase; D010433:Pentylenetetrazole
keywords: EEG; epilepsy; pilocarpine; seizure; sodium pump