Effects of antiepileptic drugs on GABA release from rat and human neocortical synaptosomes

Abstract

In epilepsy, allegedly, a neurotransmitter imbalance between the inhibitory GABA and the excitatory glutamate prevails. Therefore, some antiepileptic drugs (AEDs) are thought to increase GABA release. Because little is known about corresponding presynaptic effects of AEDs in the human brain, this study investigated the effects of carbamazepine, lamotrigine, phenytoin, gabapentin, pregabalin, levetiracetam, and valproate on (3)H-GABA release from human neocortical synaptosomes preincubated with (3)H-GABA. To obtain information on possible species differences, rat neocortical synaptosomes were investigated concomitantly. Release was evoked by either veratridine (1, 3.2, or 10 μM), which prevents activated voltage-dependent Na(+) channels from closing, or elevation of extracellular [K(+)] from 3 to 15 mM. The exocytosis inhibitor tetanus toxin (TeT) or withdrawal of buffer Ca(2+) (Ca (e) (2+) ) reduced K(+)-evoked release in both species, while blockade of Na(+) channels with tetrodotoxin had no effect. K(+)-evoked release was characterized as predominant, Ca(2+)-dependent and Na(+)-independent, exocytosis. Carbamazepine and phenytoin in the rat and carbamazepine, phenytoin, lamotrigine, and valproate in human tissue reduced K(+)-evoked (3)H-GABA release. With respect to veratridine-evoked release, Ca (e) (2+) withdrawal did not reduce release in the rat; it even increased the release in human tissue. TeT was slightly inhibitory in the rat. Blockade of GABA transport diminished veratridine-evoked (3)H-GABA release in either species. This release was characterized as mediated mainly by transporter reversal. Carbamazepine, lamotrigine, and phenytoin in rat tissue and carbamazepine and phenytoin in human decreased veratridine-induced (3)H-GABA release. Interestingly, no AED increased (3)H-GABA release. The reduction by AEDs of veratridine-evoked release was more intense than that of K(+)-evoked release. In conclusion, reduction of GABA release by AEDs may be the actual objective in a pathologically altered neuronal network where GABA acts in a depolarizing fashion.

The Impact of Gabapentin Administration on Brain GABA and Glutamate Concentrations: A 7T 1H-MRS Study

“…Gabapentin is a lipophilic compound that was initially synthesized to mimic the chemical structure of GABA by addition of a cyclohexyl to its backbone (Honarmand et al, 2011). Although it is rapidly absorbed, readily crosses the blood-brain barrier and is orally active in several animal models of epilepsy, gabapentin neither binds to GABA A or GABA B receptors nor is it metabolized to GABA (Goa and Sorkin, 1993;Kammerer et al, 2011;Taylor et al, 1992). Research regarding gabapentin's effects on GABA and glutamate synthetic and metabolizing enzymes reveals a complex pattern of activity and provides an incomplete explanation for its anticonvulsant effects.…”

Mood-Stabilizing Agents

“…Also, anticonvulsants with and without activity in bipolar disorder can exert complex effects on neurotransmission mediated by the inhibitory amino acid g -aminobutyric acid (GABA), and some anticonvulsants as well as lithium can inhibit actions of the excitatory amino acid l -glutamate, often tending toward more in fl uence of GABA on cerebral function and less of glutamate [ 145,183,184 ] . Another interesting potential target is the enzyme, myristolated alanine-rich C-kinase (MARKS), which is a substrate for PKCs and a mediator of synaptic plasticity.…”

Sıçanlarda Penisilin ile Oluşturulan Epileptiform Aktivitesi Üzerine Eritropoietinin Etkileri

“…Penicillin causes acute focal epileptic activity similar to that which decreases the activity of the GABA inhibitory system in the brain and increases glutamate, which becomes the main excitatory neurotransmitter in the brain [5][6][7][8][9] . Researchers [6][7][8][9] continue to study the antiepileptic effects of agents in animal models of experimental epilepsy, but the therapeutic effectiveness of these agents may not be the same in humans [10,11] .…”