Introduction
Researchers
have known the following facts from various scientific reports:
1. It is
now well established that patients with Alzheimer’s disease (AD) have an
increased risk of seizures. In sporadic AD, the frequency of seizures vary
considerably between studies, with more recent reports estimating an incidence
of approximately 4 to 5 per 1,000 persons per year.
2.
Epilepsy is common in familial AD, with an incidence as high as 83% in these
patients.
3.
Several strains of transgenic AD mice overexpressing the amyloid precursor
protein (APP) have cortical hyperexcitability, and these results have suggested
that this aberrant network activity may be a mechanism by which amyloid-ß (Aß)
causes more widespread neuronal dysfunction.
4.
Specific anticonvulsant therapy reverses memory impairments in various
transgenic mouse strains, but it is not known whether reduction of epileptiform
activity might serve as a surrogate marker of drug efficacy for memory
improvement in AD mouse models.
5. Two
previous studies in J20 and APP/PS1 mice have shown clear benefits of
Levetiracetam in reversing memory impairments in this model, suggesting that
targeting synaptic vesicle protein 2A (SV2A) alleviates AD symptoms across
AD models.
These findings have led to the hypothesis that amyloid-ß
(Aß), the peptide derived from APP and widely believed to play a critical role
in AD pathogenesis, may trigger neuronal hyperexcitability, seizures, and
ultimately worsen neuronal dysfunction in AD. This hypothesis was partly tested
in two recent studies where transgenic AD mice underwent chronic treatment with
the antiepileptic drug (AED) levetiracetam.
In view of the above findings, Brivaracetam (structure
homologue of Levetiracetam), an anticonvulsant drug for epilepsy treatment, along with ethosuximide were tested for their ability
to suppress epileptiform activity and to reverse memory impairments and synapse
loss in APP/PS1 mice. Both
Levetiracetam and Brivaracetam show affinity for synaptic vesicle protein 2A (SV2A), with Brivaracetam has activity that is ten-fold
above that of Levetiracetam
 |
| Brivaracetam |
Experiment
Each mouse received a single intraperitoneal (IP) injection
of drug as indicated. All drugs were dissolved in normal saline. Each mouse
underwent a 1-week washout with verification of a return to baseline SWD
frequency prior to subsequent drug injection. Each mouse first received an IP
injection of levetiracetam, followed by ethosuximide, phenytoin and
brivaracetam. Drug administartion was followed by behavioral
studies, brain tissue analysis, immunoblotting and enzyme-linked immunoassay
experiments and continuous electroencephalography video monitoring.
Following results are reported:
1. Transgenic Alzheimer’s disease mice have frequent
epileptiform discharges
2. Spike-wave discharges (SWDs) correlate with impairments in
spatial memory in APP/PS1 and 3xTg-AD mices.
3. Spike-wave discharges do not affect amyloid-ß metabolism
of plaque deposition in APP/PS1 mice
4. Ethosuximide and brivaracetam reduce spike-wave discharges
in Alzheimer’s disease mice
5. Brivaracetam, but not ethosuximide, reverses impairments
in spatial memory in APP/PS1 mice
The authors conclude as “although both ethosuximide and brivaracetam significantly reduced SWDs
in APP/PS1 mice, only the latter reversed impairments in spatial memory
performance in these mice. These findings suggest that a reduction in SWDs does
not represent a robust surrogate marker of drug efficacy in APP/PS1 mice. Our
data further emphasize the role of drugs targeting SV2A, such as levetiracetam
and brivaracetam, in reversing spatial memory impairments across several AD
mouse strains.”
While the Brivaracetam appears effective, the researchers are
unclear how it works to reverse memory loss. Researchers points out that the
current study represents very preliminary data with respect to treating
patients with Alzheimer's disease.
Article citation: Nygaard, H. B.; et. al. Brivaracetam, but not ethosuximide, reverses memory impairments in an Alzheimer’s disease mouse model. Alzheimer's Research and Therapy 2015, 7, 25.
