Brawek B, Löffler M, Weyerbrock A, Feuerstein T J
Section of Clinical Neuropharmacology, Neurozentrum, University of Freiburg, 79106, Freiburg, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 2009 Apr;379(4):361-9. doi: 10.1007/s00210-008-0370-z. Epub 2008 Nov 11.
One site of action of the anticonvulsant, analgesic, and anxiolytic drugs gabapentin and pregabalin is the alpha(2)delta-subunit of voltage-sensitive Ca(2+) channels (VSCC). We therefore analyzed the effects of gabapentin and pregabalin on K(+)-evoked release of (3)H-gamma-aminobutyric acid (GABA) and (3)H-glutamate from superfused human neocortical synaptosomes. These neurotransmitters are released by Ca(2+)-dependent exocytosis and by Ca(2+)-independent uptake reversal. When a GABA transport inhibitor was present throughout superfusion to isolate exocytotic conditions, gabapentin and pregabalin (100 microM each) reduced K(+)-evoked (3)H-GABA release by 39% and 47%, respectively. These effects were antagonized by the alpha(2)delta-ligand L: -isoleucine (1 microM) suggesting the alpha(2)delta-subunit of terminal VSCC to mediate the reduction of exocytosis. Both drugs had no effect on exocytotic (3)H-glutamate release and also failed to modulate the release of (3)H-GABA and (3)H-glutamate caused by reversed uptake in the absence of external Ca(2+). Thus, an inhibition of glutamate release by gabapentin and pregabalin as main anticonvulsant principle is not supported by our experiments. An anticonvulsant mode of action of both drugs may be the reduction of a proconvulsant exocytotic GABA release.
抗惊厥药、镇痛药和抗焦虑药加巴喷丁和普瑞巴林的一个作用位点是电压敏感性钙通道（VSCC）的α(2)δ亚基。因此，我们分析了加巴喷丁和普瑞巴林对从人新皮层突触体中钾离子诱发的(3)H-γ-氨基丁酸（GABA）和(3)H-谷氨酸释放的影响。这些神经递质通过钙依赖的胞吐作用和钙非依赖的摄取逆转而释放。当在整个灌流过程中存在GABA转运抑制剂以分离胞吐条件时，加巴喷丁和普瑞巴林（各100微摩尔）分别使钾离子诱发的(3)H-GABA释放减少了39%和47%。这些作用被α(2)δ配体L-异亮氨酸（1微摩尔）拮抗，提示终末VSCC的α(2)δ亚基介导了胞吐作用的减少。两种药物对胞吐性(3)H-谷氨酸释放均无影响，并且在无细胞外钙的情况下也未能调节由摄取逆转引起的(3)H-GABA和(3)H-谷氨酸释放。因此，我们的实验不支持加巴喷丁和普瑞巴林作为主要抗惊厥原理对谷氨酸释放的抑制作用。两种药物的抗惊厥作用方式可能是减少惊厥性的胞吐性GABA释放。
