Neuronal death associated with cerebral ischemia and hypoglycemia is related to increased release of excitatory amino acids (EAA) and energy failure. The intrahippocampal administration of the glycolysis inhibitor, iodoacetate (IOA), induces the accumulation of EAA and neuronal death. We have investigated by microdialysis the role of exocytosis, glutamate transporters and volume-sensitive organic anion channel (VSOAC) on IOA-induced EAA release. Results show that the early component of EAA release is inhibited by riluzole, a voltage-dependent sodium channel blocker, and by the VSOAC blocker, tamoxifen, while the early and late components are blocked by the glutamate transport inhibitors, L-trans-pyrrolidine 2,4-dicarboxylate (PDC) and DL-threo-beta-benzyloxyaspartate (DL-TBOA); and by the VSOAC blocker 4,4'-dinitrostilbene-2,2'-disulfonic acid (DNDS). Riluzole, DL-TBOA and tamoxifen did not prevent IOA-induced neuronal death, while PDC and DNDS did. The VSOAC blockers 5-nitro-2-(3-phenylpropyl-amino) benzoic acid (NPPB) and phloretin had no effect either on EAA efflux or neuronal damage. Results suggest that acute inhibition of glycolytic metabolism promotes the accumulation of EAA by exocytosis, impairment or reverse action of glutamate transporters and activation of a DNDS-sensitive mechanism. The latest is substantially involved in the triggering of neuronal death. To our knowledge, this is the first study to show protection of neuronal death by DNDS in an in vivo model of neuronal damage, associated with deficient energy metabolism and EAA release, two conditions involved in some pathological states such as ischemia and hypoglycemia.

译文

:与脑缺血和低血糖有关的神经元死亡与兴奋性氨基酸(EAA)释放增加和能量衰竭有关。海马内糖酵解抑制剂碘乙酸盐(IOA)的给药可诱导EAA积累和神经元死亡。我们已经通过微透析研究了胞吐作用,谷氨酸转运蛋白和体积敏感性有机阴离子通道(VSOAC)对IOA诱导的EAA释放的作用。结果表明,EAA释放的早期组分被电压依赖性钠通道阻滞剂利鲁唑和VSOAC阻断剂他莫昔芬抑制,而谷氨酸转运抑制剂L-反式吡咯烷2则阻断了早期和晚期组分。 ,4-二羧酸盐(PDC)和DL-苏-β-苄氧基天冬氨酸(DL-TBOA);通过VSOAC阻滞剂4,4'-二硝基二苯乙烯-2,2'-二磺酸(DNDS)。利鲁唑,DL-TBOA和他莫昔芬不能预防IOA诱导的神经元死亡,而PDC和DNDS可以预防。 VSOAC阻滞剂5-硝基-2-(3-苯基丙基-氨基)苯甲酸(NPPB)和荧光素对EAA流出或神经元损伤均无影响。结果表明,糖酵解代谢的急性抑制可通过胞吐作用,谷氨酸转运蛋白的损伤或逆作用以及DNDS敏感机制的激活来促进EAA的积累。最新消息实质上涉及神经元死亡的触发。据我们所知,这是第一个在体内神经元损伤模型中由DNDS保护神经元死亡的研究,该模型与能量代谢不足和EAA释放有关,这是某些病理状态(例如局部缺血和低血糖)的两个条件。

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