Role of glutamate excitotoxicity and glutamate transporter EAAT2 in epilepsy: Opportunities for novel therapeutics development.
Astrocytes
EAAT2
Epilepsy
Excitotoxicity
Glutamate
Glutamate transporter
Journal
Biochemical pharmacology
ISSN: 1873-2968
Titre abrégé: Biochem Pharmacol
Pays: England
ID NLM: 0101032
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
received:
24
06
2021
revised:
21
09
2021
accepted:
22
09
2021
pubmed:
28
9
2021
medline:
7
1
2022
entrez:
27
9
2021
Statut:
ppublish
Résumé
Epilepsy is a complex neurological syndrome characterized by seizures resulting from neuronal hyperexcitability and sudden and synchronized bursts of electrical discharges. Impaired astrocyte function that results in glutamate excitotoxicity has been recognized to play a key role in the pathogenesis of epilepsy. While there are 26 drugs marketed as anti-epileptic drugs no current treatments are disease modifying as they only suppress seizures rather than the development and progression of epilepsy. Excitatory amino acid transporters (EAATs) are critical for maintaining low extracellular glutamate concentrations and preventing excitotoxicity. When extracellular glutamate concentrations rise to abnormal levels, glutamate receptor overactivation and the subsequent excessive influx of calcium into the post-synaptic neuron can trigger cell death pathways. In this review we discuss targeting EAAT2, the predominant glutamate transporter in the CNS, as a promising approach for developing therapies for epilepsy. EAAT2 upregulation via transcriptional and translational regulation has proven successful in vivo in reducing spontaneous recurrent seizures and offering neuroprotective effects. Another approach to regulate EAAT2 activity is through positive allosteric modulation (PAM). Novel PAMs of EAAT2 have recently been identified and are under development, representing a promising approach for the advance of novel therapeutics for epilepsy.
Identifiants
pubmed: 34571003
pii: S0006-2952(21)00402-0
doi: 10.1016/j.bcp.2021.114786
pmc: PMC8605998
mid: NIHMS1745554
pii:
doi:
Substances chimiques
Anticonvulsants
0
Excitatory Amino Acid Transporter 2
0
SLC1A2 protein, human
0
Glutamic Acid
3KX376GY7L
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
114786Subventions
Organisme : NINDS NIH HHS
ID : R01 NS111767
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
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