Brivaracetam prevents astroglial L-glutamate release associated with hemichannel through modulation of synaptic vesicle protein

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-? (TNF?) and ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/glutamate receptor of rat primary cultured astrocytes using ultra-highperformance liquid chromatography. Furthermore, interaction among TNF?, elevated extracellular K+ and brivaracetam on expression of SV2A and Cx43 was determined using capillary immunoblotting. TNF? 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 TNF? 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 TNF?-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.

Automated summary

The study investigated the effects of brivaracetam on astroglial L-glutamate release and the interaction with SV2A and Cx43 expression. The results suggest that suppression of TNF-α-induced neuronal excitability by inhibiting ectopic SV2A contributes to the antiepileptic/anticonvulsive mechanism of brivaracetam action.