Brivaracetam, but not ethosuximide, reverses memory impairments in an Alzheimer's disease mouse model


BIBLIOGRAPHIC THERAPEUTIC AGENT ANIMAL MODEL EXPERIMENTAL DESIGN OUTCOMES

Bibliographic

Year of Publication:
2015
Contact PI Name:
Stephen M. Strittmatter
Contact PI Affiliation:
Yale University School of Medicine, New Haven, Connecticut, USA
Co-Authors:
Haakon B. Nygaard, Adam C. Kaufman, Tomoko Sekine-Konno, Linda L. Huh, Hilary Going, Samantha J. Feldman, Mikhail A. Kostylev
Primary Reference (PubMED ID):
Funding Source:
Falk Medical Research Trust
Alzheimer's Association
BrightFocus Foundation
UCB Pharma
National Institutes of Health (NIH)
Study Goal and Principal Findings:

This study aimed at demonstrating the efficacy of two antiepileptic drugs (AEDs)  brivaracetam and ethosuximide in treating impairments in spatial memory in two AD mouse models. Using continuous in vivo electroencephalography (EEG) recording, coupled with spatial memory testing, the authors studied whether epileptiform discharges in transgenic AD mice could be used as a marker of drug efficacy for memory improvement.  The authors report that, in two transgenic mouse models of AD (APP/PS1 and 3xTg-AD), the presence of spike-wave discharges (SWDs) correlated with impairments in spatial memory,although a weaker correlation was seen in 3xTg-AD mice. Both ethosuximide and brivaracetam reduced mouse SWDs, but only brivaracetam reversed memory impairments in APP/PS1 mice. Biochemical and immunohistochemical analyses indicated that epileptiform discharges were not associated with changes in Aβ metabolism or deposition.  Data showed that, similar to levetiracetam, brivaracetam interacts with synapticvesicle protein 2A (SV2A), and confirm that targeting SV2A,  which results in broad-spectrum anticonvulsant action, reverses memory impairments in the APP/PS1 model of AD. Finally, while  SWDs in APP/PS1 mice correlate with impairments in spatial memory, the reduction of these discharges is not a reliable surrogate marker of preclinical drug efficacy in the APP/PS1 AD mouse model.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Brivaracetam
Therapeutic Target:
Synaptic Vesicle Protein 2A (SV2A)
Therapy Type:
Small Molecule
Therapeutic Agent:
Ethosuximide
Therapeutic Target:
T-Type Calcium Channel/CaV3 Channel

Animal Model

Model Information:
Species:
Mouse
Model Type:
APPxPS1
Strain/Genetic Background:
C57BL/6 x C3H)F2
Species:
Mouse
Model Type:
APPxPS1xTau
Strain/Genetic Background:
C57BL/6J × 129/Sv

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Biomarkers
Dose
Formulation
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest

Outcomes

Outcome Measured
Outcome Parameters
Behavioral
Morris Water Maze
Histopathology
beta Amyloid Load
Biochemical
Brain-beta Amyloid Peptide-Total
Amyloid Precursor Protein (APP) Metabolites
Immunochemistry
Postsynaptic Density Protein 95 (PSD95)
Electrophysiology
Electroencephalogram (EEG) Spike Wave Discharge

Source URL: http://alzped.nia.nih.gov/brivaracetam-not-ethosuximide