Hanaya Ryosuke, Sasa Masashi, Kiura Yoshihiro, Serikawa Tadao, Kurisu Kaoru
Department of Neurosurgery, Hiroshima University School of Medicine, Japan.
Epilepsy Res. 2002 Aug;50(3):223-31. doi: 10.1016/s0920-1211(02)00002-5.
Vigabatrin, a gamma-amino butyric acid (GABA) transaminase inhibitor, is known to inhibit partial epilepsy in humans. The spontaneously epileptic rat (SER), a double mutant (zi/zi, tm/tm), exhibits both tonic convulsion and absence-like seizures from the age of 8 weeks. Hippocampal CA3 pyramidal neurons in SER show a long-lasting depolarization shift with accompanying repetitive firing when a single stimulus is delivered to the mossy fibers in slice preparations. The effects of vigabatrin on the abnormal excitability of hippocampal CA3 pyramidal neurons in SER were examined to elucidate the mechanism underlying the antiepileptic action of the drug. Intracellular recordings were performed in 24 hippocampal slice preparations of 20 SER aged 8-17 weeks old. Bath application of vigabatrin (1 mM) inhibited the depolarizing shifts with repetitive firing induced by mossy fiber stimulation in 15 min without affecting the first spike and resting membrane potentials in hippocampal CA3 neurons of SER. A higher dose of vigabatrin (10 mM) sometimes inhibited the first spike. However, vigabatrin at doses up to 10 mM did not significantly affect the single action potential elicited by stimulation of the mossy fibers in the hippocampal CA3 neurons of age-matched Wistar rats. In addition, application of vigabatrin (10 mM) did not significantly affect the firing induced by depolarizing pulse applied in the CA3 neurons of the SER, nor the miniature excitatory postsynaptic potential (mEPSP) recorded in the CA3 neurons of SER. The inhibitory effect of vigabatrin (1 mM) on the mossy fiber stimulation-induced depolarization shift with repetitive firing was blocked by concomitant application of bicuculline (10 microM), a GABA(A) receptor antagonist. These findings strongly suggested that GABA increased by inhibition of GABA transaminase with vigabatrin inhibits abnormal excitation of hippocampal CA3 neurons of SER via GABA(A) receptors, although the possibility that the drug acted directly on the GABA(A) receptors of CA3 neurons could not be completely excluded.
氨己烯酸是一种γ-氨基丁酸（GABA）转氨酶抑制剂，已知可抑制人类的部分性癫痫。自发性癫痫大鼠（SER）是一种双突变体（zi/zi，tm/tm），从8周龄开始出现强直性惊厥和失神样发作。当在脑片制备中向苔藓纤维施加单个刺激时，SER中的海马CA3锥体神经元会出现持久的去极化偏移并伴有重复放电。研究了氨己烯酸对SER中海马CA3锥体神经元异常兴奋性的影响，以阐明该药物抗癫痫作用的潜在机制。对20只8-17周龄SER的24个海马脑片制备进行了细胞内记录。浴用氨己烯酸（1 mM）在15分钟内抑制了苔藓纤维刺激诱导的伴有重复放电的去极化偏移，而不影响SER海马CA3神经元的第一个动作电位和静息膜电位。更高剂量的氨己烯酸（10 mM）有时会抑制第一个动作电位。然而，高达10 mM剂量的氨己烯酸对年龄匹配的Wistar大鼠海马CA3神经元中苔藓纤维刺激引发的单个动作电位没有显著影响。此外，应用氨己烯酸（10 mM）对SER的CA3神经元中去极化脉冲诱导的放电以及SER的CA3神经元中记录的微小兴奋性突触后电位（mEPSP）均无显著影响。氨己烯酸（1 mM）对苔藓纤维刺激诱导的伴有重复放电的去极化偏移的抑制作用被同时应用GABA(A)受体拮抗剂荷包牡丹碱（10 microM）所阻断。这些发现强烈表明，氨己烯酸通过抑制GABA转氨酶增加的GABA通过GABA(A)受体抑制SER海马CA3神经元的异常兴奋，尽管不能完全排除该药物直接作用于CA3神经元GABA(A)受体的可能性。
