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

Nygaard HB, Kaufman AC, Sekine-Konno T, Huh LL, Going H, Feldman SJ, Kostylev MA, Strittmatter SM - Alzheimers Res Ther (2015)

Bottom Line: The antiepileptic drugs ethosuximide and brivaracetam were tested for their ability to suppress epileptiform activity and to reverse memory impairments and synapse loss in APP/PS1 mice.Our data confirm an intriguing therapeutic role of anticonvulsant drugs targeting synaptic vesicle protein 2A across AD mouse models.Chronic ethosuximide dosing did not reverse spatial memory impairments in APP/PS1 mice, despite reduction of SWDs.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Yale University School of Medicine, 800 Howard Avenue, New Haven, CT 06510 USA ; Cellular Neuroscience, Neurodegeneration, and Repair Program (CNNR), Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536 USA ; Division of Neurology, The University of British Columbia, Djavad Mowafaghian Centre for Brain Health, 2215 Wesbrook Mall, Vancouver, BC V6T 1Z3 Canada.

ABSTRACT

Introduction: Recent studies have shown that several strains of transgenic Alzheimer's disease (AD) mice overexpressing the amyloid precursor protein (APP) have cortical hyperexcitability, and their results have suggested that this aberrant network activity may be a mechanism by which amyloid-β (Aβ) causes more widespread neuronal dysfunction. 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.

Methods: Transgenic AD mice (APP/PS1 and 3xTg-AD) were chronically implanted with dural electroencephalography electrodes, and epileptiform activity was correlated with spatial memory function and transgene-specific pathology. The antiepileptic drugs ethosuximide and brivaracetam were tested for their ability to suppress epileptiform activity and to reverse memory impairments and synapse loss in APP/PS1 mice.

Results: We 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. Both ethosuximide and brivaracetam reduce mouse SWDs, but only brivaracetam reverses memory impairments in APP/PS1 mice.

Conclusions: Our data confirm an intriguing therapeutic role of anticonvulsant drugs targeting synaptic vesicle protein 2A across AD mouse models. Chronic ethosuximide dosing did not reverse spatial memory impairments in APP/PS1 mice, despite reduction of SWDs. Our data indicate that SWDs are not a reliable surrogate marker of appropriate target engagement for reversal of memory dysfunction in APP/PS1 mice.

No MeSH data available.


Related in: MedlinePlus

Brivaracetam, but not ethosuximide, reverses impairments in spatial memory in APP/PS1 mice. Aged APP/PS1 mice were administered brivaracetam by osmotic minipump or continuous delivery of ethosuximide (ETX) via drinking water. Four-week administration of brivaracetam (Briva) fully reversed memory impairments in APP/PS1 mice in the Morris water maze (A) and Probe Trial (B). Chronic (7-week) administration of ethosuximide did not improve performance in the Morris water maze or probe trial in APP/PS1 mice (C, D). For the Briva cohort, wild-type (WT) + vehicle: n = 11; WT + Briva: n = 11, APP/PS1 + vehicle: n = 15, APP/PS1 + Briva: n = 16. For chronic ETX therapy, WT + vehicle: n = 7, WT + ETX: n = 7, APP + vehicle: n = 6, APP + ETX: n = 7. *P < 0.05, ***P < 0.001, repeated-measures analysis of variance with post hoc comparisons. V1 through V4 indicate visible platform swim trials. + Indicates drug therapy; - indicates vehicle.
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Fig5: Brivaracetam, but not ethosuximide, reverses impairments in spatial memory in APP/PS1 mice. Aged APP/PS1 mice were administered brivaracetam by osmotic minipump or continuous delivery of ethosuximide (ETX) via drinking water. Four-week administration of brivaracetam (Briva) fully reversed memory impairments in APP/PS1 mice in the Morris water maze (A) and Probe Trial (B). Chronic (7-week) administration of ethosuximide did not improve performance in the Morris water maze or probe trial in APP/PS1 mice (C, D). For the Briva cohort, wild-type (WT) + vehicle: n = 11; WT + Briva: n = 11, APP/PS1 + vehicle: n = 15, APP/PS1 + Briva: n = 16. For chronic ETX therapy, WT + vehicle: n = 7, WT + ETX: n = 7, APP + vehicle: n = 6, APP + ETX: n = 7. *P < 0.05, ***P < 0.001, repeated-measures analysis of variance with post hoc comparisons. V1 through V4 indicate visible platform swim trials. + Indicates drug therapy; - indicates vehicle.

Mentions: Having demonstrated that both brivaracetam and ethosuximide significantly reduce SWDs, we tested whether this reduction in epileptiform activity could accurately predict therapeutic reversal of impairments in spatial memory in aged APP/PS1 mice. To assess the role of brivaracetam in APP/PS1 mouse phenotypes, we treated 13-month-old mice chronically, measuring the effect of drug therapy on spatial memory, Aβ levels, synapse loss and hippocampal calbindin D28 immunoreactivity. ALZET osmotic minipumps were implanted into the APP/PS1 and WT mice, and the mice received continuous IP dosing of 8.5 mg/kg/day of brivaracetam versus saline. After 28 days, mice were tested in the Morris water maze while drug delivery was continued. Chronic brivaracetam therapy fully reversed memory impairments in APP/PS1 mice (Figure 5A,B; Additional file 2: Figure S2), but it did not change the brain concentration of soluble Aβ or insoluble plaque (Figure 6A,B). Despite the improved memory performance with brivaracetam, synapse density was not recovered (Figure 6C). Treatment with brivaracetam did not affect hippocampal calbindin D28 immunoreactivity (data not shown).Figure 5


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

Nygaard HB, Kaufman AC, Sekine-Konno T, Huh LL, Going H, Feldman SJ, Kostylev MA, Strittmatter SM - Alzheimers Res Ther (2015)

Brivaracetam, but not ethosuximide, reverses impairments in spatial memory in APP/PS1 mice. Aged APP/PS1 mice were administered brivaracetam by osmotic minipump or continuous delivery of ethosuximide (ETX) via drinking water. Four-week administration of brivaracetam (Briva) fully reversed memory impairments in APP/PS1 mice in the Morris water maze (A) and Probe Trial (B). Chronic (7-week) administration of ethosuximide did not improve performance in the Morris water maze or probe trial in APP/PS1 mice (C, D). For the Briva cohort, wild-type (WT) + vehicle: n = 11; WT + Briva: n = 11, APP/PS1 + vehicle: n = 15, APP/PS1 + Briva: n = 16. For chronic ETX therapy, WT + vehicle: n = 7, WT + ETX: n = 7, APP + vehicle: n = 6, APP + ETX: n = 7. *P < 0.05, ***P < 0.001, repeated-measures analysis of variance with post hoc comparisons. V1 through V4 indicate visible platform swim trials. + Indicates drug therapy; - indicates vehicle.
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Related In: Results  -  Collection

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Fig5: Brivaracetam, but not ethosuximide, reverses impairments in spatial memory in APP/PS1 mice. Aged APP/PS1 mice were administered brivaracetam by osmotic minipump or continuous delivery of ethosuximide (ETX) via drinking water. Four-week administration of brivaracetam (Briva) fully reversed memory impairments in APP/PS1 mice in the Morris water maze (A) and Probe Trial (B). Chronic (7-week) administration of ethosuximide did not improve performance in the Morris water maze or probe trial in APP/PS1 mice (C, D). For the Briva cohort, wild-type (WT) + vehicle: n = 11; WT + Briva: n = 11, APP/PS1 + vehicle: n = 15, APP/PS1 + Briva: n = 16. For chronic ETX therapy, WT + vehicle: n = 7, WT + ETX: n = 7, APP + vehicle: n = 6, APP + ETX: n = 7. *P < 0.05, ***P < 0.001, repeated-measures analysis of variance with post hoc comparisons. V1 through V4 indicate visible platform swim trials. + Indicates drug therapy; - indicates vehicle.
Mentions: Having demonstrated that both brivaracetam and ethosuximide significantly reduce SWDs, we tested whether this reduction in epileptiform activity could accurately predict therapeutic reversal of impairments in spatial memory in aged APP/PS1 mice. To assess the role of brivaracetam in APP/PS1 mouse phenotypes, we treated 13-month-old mice chronically, measuring the effect of drug therapy on spatial memory, Aβ levels, synapse loss and hippocampal calbindin D28 immunoreactivity. ALZET osmotic minipumps were implanted into the APP/PS1 and WT mice, and the mice received continuous IP dosing of 8.5 mg/kg/day of brivaracetam versus saline. After 28 days, mice were tested in the Morris water maze while drug delivery was continued. Chronic brivaracetam therapy fully reversed memory impairments in APP/PS1 mice (Figure 5A,B; Additional file 2: Figure S2), but it did not change the brain concentration of soluble Aβ or insoluble plaque (Figure 6A,B). Despite the improved memory performance with brivaracetam, synapse density was not recovered (Figure 6C). Treatment with brivaracetam did not affect hippocampal calbindin D28 immunoreactivity (data not shown).Figure 5

Bottom Line: The antiepileptic drugs ethosuximide and brivaracetam were tested for their ability to suppress epileptiform activity and to reverse memory impairments and synapse loss in APP/PS1 mice.Our data confirm an intriguing therapeutic role of anticonvulsant drugs targeting synaptic vesicle protein 2A across AD mouse models.Chronic ethosuximide dosing did not reverse spatial memory impairments in APP/PS1 mice, despite reduction of SWDs.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Yale University School of Medicine, 800 Howard Avenue, New Haven, CT 06510 USA ; Cellular Neuroscience, Neurodegeneration, and Repair Program (CNNR), Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536 USA ; Division of Neurology, The University of British Columbia, Djavad Mowafaghian Centre for Brain Health, 2215 Wesbrook Mall, Vancouver, BC V6T 1Z3 Canada.

ABSTRACT

Introduction: Recent studies have shown that several strains of transgenic Alzheimer's disease (AD) mice overexpressing the amyloid precursor protein (APP) have cortical hyperexcitability, and their results have suggested that this aberrant network activity may be a mechanism by which amyloid-β (Aβ) causes more widespread neuronal dysfunction. 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.

Methods: Transgenic AD mice (APP/PS1 and 3xTg-AD) were chronically implanted with dural electroencephalography electrodes, and epileptiform activity was correlated with spatial memory function and transgene-specific pathology. The antiepileptic drugs ethosuximide and brivaracetam were tested for their ability to suppress epileptiform activity and to reverse memory impairments and synapse loss in APP/PS1 mice.

Results: We 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. Both ethosuximide and brivaracetam reduce mouse SWDs, but only brivaracetam reverses memory impairments in APP/PS1 mice.

Conclusions: Our data confirm an intriguing therapeutic role of anticonvulsant drugs targeting synaptic vesicle protein 2A across AD mouse models. Chronic ethosuximide dosing did not reverse spatial memory impairments in APP/PS1 mice, despite reduction of SWDs. Our data indicate that SWDs are not a reliable surrogate marker of appropriate target engagement for reversal of memory dysfunction in APP/PS1 mice.

No MeSH data available.


Related in: MedlinePlus