Sunday, May 10, 2015

Brivaracetam, An Anticonvulsant Drug Shows Promise In Alzheimer's Disease Treatment

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.


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.