Brivaracetam prevents astroglial l-glutamate release associated with hemichannel through modulation of synaptic vesicle protein - 16/04/21
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Abstract |
The antiepileptic/anticonvulsive action of brivaracetam is considered to occur via modulation of synaptic vesicle protein 2A (SV2A); however, the pharmacological mechanisms of action have not been fully characterised. To explore the antiepileptic/anticonvulsive mechanism of brivaracetam associated with SV2A modulation, this study determined concentration-dependent effects of brivaracetam on astroglial L-glutamate release associated with connexin43 (Cx43), tumour-necrosis factor-α (TNFα) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/glutamate receptor of rat primary cultured astrocytes using ultra-high-performance liquid chromatography. Furthermore, interaction among TNFα, elevated extracellular K+ and brivaracetam on expression of SV2A and Cx43 was determined using capillary immunoblotting. TNFα and elevated extracellular K+ predominantly enhanced astroglial L-glutamate release associated with respective AMPA/glutamate receptor and hemichannel. These effects were enhanced by a synergistic effect of TNFα and elevated extracellular K+ in combination. The activation of astroglial L-glutamate release, and expression of SV2A and Cx43 in the plasma membrane was suppressed by subchronic brivaracetam administration but were unaffected by acute administration. These results suggest that migration of SV2A to the astroglial plasma membrane by hyperexcitability activates astroglial glutamatergic transmission, perhaps via hemichannel activation. Subchronic brivaracetam administration suppressed TNFα-induced activation of AMPA/glutamate receptor and hemichannel via inhibition of ectopic SV2A. These findings suggest that combined inhibition of vesicular and ectopic SV2A functions contribute to the antiepileptic/anticonvulsive mechanism of brivaracetam action.
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Highlights |
• | Synaptic vesicle protein 2A (SV2A) has been considered to be a major target of brivaracetam. |
• | Hyperexcitability migrates SV2A to plasma membrane. |
• | Migrated SV2A enhances astroglial glutamatergic transmission through possibly activation of hemichannel. |
• | Brivaracetam suppresses epileptic discharges due to inhibition of vesicular and ectopic SV2A functions. |
Abbreviations : SV2A, IFNγ, TNFα, fDMEM, N-fDMEM, MK-fDMEM, FCHK-ACSF, Cx43, DIV, AMPA
Keywords : Astrocytes, Brivaracetam, Epilepsy, Synaptic vesicle protein 2A, Hemichannel, Connexin43
Esquema
Vol 138
Artículo 111462- juin 2021 Regresar al númeroBienvenido a EM-consulte, la referencia de los profesionales de la salud.
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