Non-competitive AMPA glutamate receptors antagonism by perampanel as a strategy to counteract hippocampal hyper-excitability and cognitive deficits in cerebral amyloidosis.
Animals
Mice
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Amyloid beta-Peptides
/ metabolism
Cognition
/ drug effects
Excitatory Amino Acid Antagonists
/ pharmacology
Hippocampus
/ drug effects
Receptors, AMPA
/ antagonists & inhibitors
Cerebral Amyloid Angiopathy
/ therapy
Cognitive Dysfunction
/ therapy
AMPAR antagonism
Alzheimer's disease
Aβ-oligomers
Epilepsy
Neuronal hyperexcitability
Perampanel
Synaptic plasticity
Journal
Neuropharmacology
ISSN: 1873-7064
Titre abrégé: Neuropharmacology
Pays: England
ID NLM: 0236217
Informations de publication
Date de publication:
01 03 2023
01 03 2023
Historique:
received:
25
06
2022
revised:
26
11
2022
accepted:
07
12
2022
pubmed:
13
12
2022
medline:
11
1
2023
entrez:
12
12
2022
Statut:
ppublish
Résumé
Pathological accumulation of Aβ oligomers has been linked to neuronal networks hyperexcitability, potentially underpinned by glutamatergic AMPA receptors (AMPARs) dysfunction. We aimed to investigate whether the non-competitive block of AMPARs was able to counteract the alteration of hippocampal epileptic threshold, and of synaptic plasticity linked to Aβ oligomers accumulation, being this glutamate receptor a valuable specific therapeutic target. In this work, we showed that the non-competitive AMPARs antagonist perampanel (PER) which, per se, did not affect physiological synaptic transmission, was able to counteract Aβ-induced hyperexcitability. Moreover, AMPAR antagonism was able to counteract Aβ-induced hippocampal LTP impairment and hippocampal-based cognitive deficits in Aβ oligomers-injected mice, while retaining antiseizure efficacy. Beside this, AMPAR antagonism was also able to reduce the increased expression of proinflammatory cytokines in this mice model, also suggesting the presence of an anti-inflammatory activity. Thus, targeting AMPARs might be a valuable strategy to reduce both hippocampal networks hyperexcitability and synaptic plasticity deficits induced by Aβ oligomers accumulation.
Identifiants
pubmed: 36502868
pii: S0028-3908(22)00432-4
doi: 10.1016/j.neuropharm.2022.109373
pii:
doi:
Substances chimiques
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
77521-29-0
Amyloid beta-Peptides
0
Excitatory Amino Acid Antagonists
0
perampanel
H821664NPK
Receptors, AMPA
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
109373Informations de copyright
Copyright © 2022 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest Emilio Russo has received speaker fees or fundings and has participated in advisory boards for Angelini, Arvelle Therapeutics, Eisai, Kolfarma, Pfizer, GW Pharmaceuticals, UCB, Lundbeck. Rita Citraro has received speaker fees or fundings from Clicon Srl, Daiichy Sankyo, Kolfarma. Antonio Leo has received research fundings, from, Eisai Europe Limited and GW Pharmaceuticals. Cinzia Costa has received research support, speaker honoraria, travel expenses from Bial, Eisai Europe Limited, GW Pharma, Lusopharma, PIAM Pharma, and UCB Pharma. Massimiliano Di Filippo participated on advisory boards for and received speaker or writing honoraria, funding for travelling and research support from Bayer, Biogen Idec, Sanofi, Merck, Mylan, Novartis, Roche, Teva and Viatris.