title: Spontaneous epileptiform discharges in a mouse model of Alzheimer's disease are suppressed by antiepileptic drugs that block sodium channels.
abstract: Previous studies have demonstrated an increased risk of epilepsy in patients with Alzheimer's disease (AD). Also, in many mouse models of AD, animals have spontaneous seizures and frequent epileptiform discharges (EDs). Abnormal function of sodium channels has been proposed to contribute to hyperexcitability in a manner suggesting that drugs that block sodium channels might exacerbate the condition. Here we addressed this question by investigating whether common antiepileptic drugs (AEDs) that block sodium channels, including carbamazepine (CBZ), phenytoin (DPH), or valproic acid (VPA) have any effect on spontaneous seizures or EDs in APdE9 mice. Mice were successively treated with vehicle, followed by CBZ (10mg/kg, t.i.d.), DPH (10mg/kg, t.i.d.), or VPA (260 mg/kg, b.i.d.) for 3d. After wash-out and new vehicle treatment, higher doses of CBZ (40 mg/kg, t.i.d.), DPH (40 mg/kg, t.i.d.), or VPA (400mg/kg, b.i.d.) were administered for 3d (DPH) or 5d (CBZ, VPA). During the entire experiment, mice were under continuous (24/7) video-EEG monitoring. Our data show that each treatment reduced the number of spontaneous electrographic EDs. VPA was the most effective by reducing the ED frequency below 50% of that at baseline in 75% of mice. Western blot analysis of the Na(v)1.1 protein levels in the ventral temporal cortex and the hippocampus did not reveal any differences between the genotypes. Under the conditions tested, sodium channel blocking AEDs suppressed epileptiform activity in APdE9 mice with increased amyloid pathology. Whether this applies to other mouse models of AD with different APP mutations and/or genetic background remains to be explored.
authors.affiliation: Epilepsy Research Laboratory, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Sofya
authors.initials: S
authors.lastname: Ziyatdinova
authors.forename: Kestutis
authors.initials: K
authors.lastname: Gurevicius
authors.forename: Nino
authors.initials: N
authors.lastname: Kutchiashvili
authors.forename: Tamuna
authors.initials: T
authors.lastname: Bolkvadze
authors.forename: Jari
authors.initials: J
authors.lastname: Nissinen
authors.forename: Heikki
authors.initials: H
authors.lastname: Tanila
authors.forename: Asla
authors.initials: A
authors.lastname: Pitkänen
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics / Q000401:mortality; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000379:methods; D004827:Epilepsy / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality / Q000473:pathology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D026941:Sodium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D015222:Sodium Channels / Q000378:metabolism*; D013057:Spectrum Analysis; D014741:Video Recording / Q000379:methods
chemical_list: D016564:Amyloid beta-Protein Precursor; D000927:Anticonvulsants; D026941:Sodium Channel Blockers; D015222:Sodium Channels