Neiva Rafael, Caulino-Rocha Ana, Ferreirinha Fátima, Lobo Maria Graça, Correia-de-Sá Paulo
Laboratório de Farmacologia e Neurobiologia - Departamento de Imuno-Fisiologia e Farmacologia, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Porto, Portugal.
Center for Drug Discovery and Innovative Medicines (MedInUP), Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Porto, Portugal.
Front Mol Neurosci. 2020 Aug 5;13:146. doi: 10.3389/fnmol.2020.00146. eCollection 2020.
Corticosteroids exert a dual role in eukaryotic cells through their action via (1) intracellular receptors (slow genomic responses), or (2) membrane-bound receptors (fast non-genomic responses). Highly vulnerable regions of the brain, like the hippocampus, express high amounts of corticosteroid receptors, yet their actions on ionic currents and neurotransmitters release are still undefined. Here, we investigated the effect of methylprednisolone (MP) on GABA and glutamate (Glu) release from isolated nerve terminals of the rat hippocampus. MP favored both spontaneous and depolarization-evoked [C]Glu release from rat hippocampal nerve terminals, without affecting [H]GABA outflow. Facilitation of [C]Glu release by MP is mediated by a Na-dependent Ca-independent non-genomic mechanism relying on the activation of membrane-bound glucocorticoid (GR) and mineralocorticoid (MR) receptors sensitive to their antagonists mifepristone and spironolactone, respectively. The involvement of Na-dependent high-affinity EAAT transport reversal was inferred by blockage of MP-induced [C]Glu release by DL-TBOA. Depolarization-evoked [H]GABA release in the presence of MP was partially attenuated by the selective P2X7 receptor antagonist A-438079, but this compound did not affect the release of [C]Glu. Data indicate that MP differentially affects GABA and glutamate release from rat hippocampal nerve terminals via fast non-genomic mechanisms putatively involving the activation of membrane-bound corticosteroid receptors. Facilitation of Glu release strengthen previous assumptions that MP may act as a cognitive enhancer in rats, while crosstalk with ATP-sensitive P2X7 receptors may promote a therapeutically desirable GABAergic inhibitory control during paroxysmal epileptic crisis that might be particularly relevant when extracellular Ca levels decrease below the threshold required for transmitter release.
（1）通过细胞内受体（缓慢的基因组反应），或（2）通过膜结合受体（快速的非基因组反应）。大脑中高度易损区域，如海马体，表达大量的皮质类固醇受体，但其对离子电流和神经递质释放的作用仍不明确。在此，我们研究了甲基强的松龙（MP）对大鼠海马体分离神经末梢中γ-氨基丁酸（GABA）和谷氨酸（Glu）释放的影响。MP促进了大鼠海马体神经末梢自发的和去极化诱发的[C]Glu释放，而不影响[H]GABA外流。MP对[C]Glu释放的促进作用是由一种依赖钠但不依赖钙的非基因组机制介导的，该机制依赖于分别对其拮抗剂米非司酮和螺内酯敏感的膜结合糖皮质激素（GR）和盐皮质激素（MR）受体的激活。通过DL-TBOA阻断MP诱导的[C]Glu释放，推断出依赖钠的高亲和力兴奋性氨基酸转运体（EAAT）转运逆转的参与。在MP存在的情况下，选择性P2X7受体拮抗剂A-438079部分减弱了去极化诱发的[H]GABA释放，但该化合物不影响[C]Glu的释放。数据表明，MP通过可能涉及膜结合皮质类固醇受体激活的快速非基因组机制，对大鼠海马体神经末梢中GABA和谷氨酸的释放产生不同影响。Glu释放的促进作用强化了之前的假设，即MP可能在大鼠中作为一种认知增强剂，而与ATP敏感性P2X7受体的相互作用可能在阵发性癫痫发作期间促进治疗上理想的GABA能抑制控制，这在细胞外钙水平降至低于递质释放所需阈值时可能尤为重要。
