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.
Subject(s)
Anticonvulsants/therapeutic use , Brain/metabolism , Epilepsy/drug therapy , Epilepsy/pathology , Sodium Channels/metabolism , Alzheimer Disease/complications , Alzheimer Disease/genetics , Alzheimer Disease/mortality , Amyloid beta-Protein Precursor/genetics , Animals , Anticonvulsants/pharmacology , Brain/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Electroencephalography/methods , Epilepsy/etiology , Epilepsy/mortality , Female , Gene Expression Regulation/drug effects , In Vitro Techniques , Male , Mice , Mice, Transgenic , Sodium Channel Blockers/pharmacology , Sodium Channel Blockers/therapeutic use , Spectrum Analysis , Video Recording/methodsABSTRACT
Cerebrovascular changes following status epilepticus (SE) are not well understood, yet they may contribute to epileptogenesis. We studied hemodynamic changes in the cerebral cortex and amygdala by arterial spin labeling (ASL) and dynamic susceptibility contrast (DSC) MRI at 2 days and 14 days after pilocarpine-induced SE in rats. There were no cortical hemodynamic changes, yet in the amygdala we found prolonged elevation in cerebral blood flow (CBF, 129% of control mean, day 14, p<0.01). There was a trend towards increased cerebral blood volume (CBV) during the same imaging sessions. Through immunohistochemistry, we observed increased vessel density in the amygdala (127% of control mean, day 14, p<0.05). In conclusion, epileptogenesis may involve hemodynamic changes that are associated with vascular reorganization during post-SE remodeling in the amygdaloid complex.
