Synaptic Vesicle Glycoprotein 2A Ligands in the Treatment of Epilepsy and Beyond.
CNS Drugs
; 30(11): 1055-1077, 2016 11.
Article
in En
| MEDLINE
| ID: mdl-27752944
ABSTRACT
The synaptic vesicle glycoprotein SV2A belongs to the major facilitator superfamily (MFS) of transporters and is an integral constituent of synaptic vesicle membranes. SV2A has been demonstrated to be involved in vesicle trafficking and exocytosis, processes crucial for neurotransmission. The anti-seizure drug levetiracetam was the first ligand to target SV2A and displays a broad spectrum of anti-seizure activity in various preclinical models. Several lines of preclinical and clinical evidence, including genetics and protein expression changes, support an important role of SV2A in epilepsy pathophysiology. While the functional consequences of SV2A ligand binding are not fully elucidated, studies suggest that subsequent SV2A conformational changes may contribute to seizure protection. Conversely, the recently discovered negative SV2A modulators, such as UCB0255, counteract the anti-seizure effect of levetiracetam and display procognitive properties in preclinical models. More broadly, dysfunction of SV2A may also be involved in Alzheimer's disease and other types of cognitive impairment, suggesting potential novel therapies for levetiracetam and its congeners. Furthermore, emerging data indicate that there may be important roles for two other SV2 isoforms (SV2B and SV2C) in the pathogenesis of epilepsy, as well as other neurodegenerative diseases. Utilization of recently developed SV2A positron emission tomography ligands will strengthen and reinforce the pharmacological evidence that SV2A is a druggable target, and will provide a better understanding of its role in epilepsy and other neurological diseases, aiding in further defining the full therapeutic potential of SV2A modulation.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Synaptic Vesicles
/
Membrane Glycoproteins
/
Epilepsy
/
Anticonvulsants
Limits:
Animals
/
Humans
Language:
En
Journal:
CNS Drugs
Journal subject:
FARMACOLOGIA
/
NEUROLOGIA
/
TERAPIA POR MEDICAMENTOS
Year:
2016
Document type:
Article
Affiliation country:
Alemania