Departamento de Farmacología y Terapéutica, Facultad de Medicina, Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain.
Servicio de Neurobiología-Investigación, Hospital Ramón y Cajal, IRYCIS, Madrid, Spain.
Transl Stroke Res. 2024 Dec;15(6):1070-1087. doi: 10.1007/s12975-023-01192-y. Epub 2023 Sep 27.
The contribution of excitatory amino acids (AA) to ischemic brain injury has been widely described. In addition, we reported that a mixture of non-excitatory AA at plasmatic concentrations turns irreversible the depression of synaptic transmission caused by hypoxia. Here, we describe that the presence of seven non-excitatory AA (L-alanine, L-glutamine, glycine, L-histidine, L-serine, taurine, and L-threonine) during hypoxia provokes an irreversible neuronal membrane depolarization, after an initial phase of hyperpolarization. The collapse of the membrane potential correlates with a great increase in fiber volley amplitude. Nevertheless, we show that the presence of all seven AA is not necessary to cause the irreversible loss of fEPSP after hypoxia and that the minimal combination of AA able to provoke a solid, replicable effect is the mixture of L-alanine, glycine, L-glutamine, and L-serine. Additionally, L-glutamine seems necessary but insufficient to induce these harmful effects. We also prove that the deleterious effects of the AA mixtures on field potentials during hypoxia depend on both the identity and concentration of the individual AA in the mixture. Furthermore, we find that the accumulation of AA in the whole slice does not determine the outcome caused by the AA mixtures on the synaptic transmission during hypoxia. Finally, results obtained using pharmacological inhibitors and specific substrates of AA transporters suggest that system N and the alanine-serine-cysteine transporter 2 (ASCT2) participate in the non-excitatory AA-mediated deleterious effects during hypoxia. Thus, these AA transporters might represent therapeutical targets for the treatment of brain ischemia.
兴奋性氨基酸（AA）对缺血性脑损伤的贡献已被广泛描述。此外，我们还报道，在血浆浓度下混合非兴奋性 AA 可使缺氧引起的突触传递抑制变为不可逆。在这里，我们描述了在缺氧期间，七种非兴奋性 AA（L-丙氨酸、L-谷氨酰胺、甘氨酸、L-组氨酸、L-丝氨酸、牛磺酸和 L-苏氨酸）的存在会引起神经元膜的不可逆去极化，继初始超极化阶段之后。膜电位的崩溃与纤维爆发幅度的大幅增加相关。然而，我们表明，在缺氧后引起 fEPSP 不可逆丧失并不需要所有七种 AA 的存在，并且能够引起稳定、可重复效果的最小 AA 组合是 L-丙氨酸、甘氨酸、L-谷氨酰胺和 L-丝氨酸的混合物。此外，L-谷氨酰胺似乎是必需的，但不足以引起这些有害影响。我们还证明，AA 混合物在缺氧期间对场电位的有害影响取决于混合物中单个 AA 的身份和浓度。此外，我们发现 AA 在整个切片中的积累并不能决定 AA 混合物在缺氧期间对突触传递的影响。最后，使用药理学抑制剂和 AA 转运体的特异性底物获得的结果表明，系统 N 和丙氨酸-丝氨酸-半胱氨酸转运体 2（ASCT2）参与了缺氧期间非兴奋性 AA 介导的有害作用。因此，这些 AA 转运体可能成为治疗脑缺血的治疗靶点。
