Sánchez-Cano Fredy, Hernández-Kelly Luisa C, Ortega Arturo
Laboratorio de Neurotoxicología, Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Av. IPN 2508, San Pedro Zacatenco, 07300 CDMX, México.
Neurotox Res. 2024 Mar 4;42(2):20. doi: 10.1007/s12640-024-00696-1.
Glutamate is the major excitatory amino acid in the vertebrate brain, playing an important role in most brain functions. It exerts its activity through plasma membrane receptors and transporters, expressed both in neurons and glia cells. Overstimulation of neuronal glutamate receptors is linked to cell death in a process known as excitotoxicity, that is prevented by the efficient removal of the neurotransmitter through glutamate transporters enriched in the glia plasma membrane and in the components of the blood-brain barrier (BBB). Silica nanoparticles (SiO-NPs) have been widely used in biomedical applications and directed to enter the circulatory system; however, little is known about the potential adverse effects of SiO-NPs exposure on the BBB transport systems that support the critical isolation function between the central nervous system (CNS) and the peripheral circulation. In this contribution, we investigated the plausible SiO-NPs-mediated disruption of the glutamate transport system expressed by BBB cell components. First, we evaluated the cytotoxic effect of SiO-NPs on human brain endothelial (HBEC) and Uppsala 87 Malignant glioma (U-87MG) cell lines. Transport kinetics were evaluated, and the exposure effect of SiO-NPs on glutamate transport activity was determined in both cell lines. Exposure of the cells to different SiO-NP concentrations (0.4, 4.8, 10, and 20 µg/ml) and time periods (3 and 6 h) did not affect cell viability. We found that the radio-labeled D-aspartate ([H]-D-Asp) uptake is mostly sodium-dependent, and downregulated by its own substrate (glutamate). Furthermore, SiO-NPs exposure on endothelial and astrocytes decreases [H]-D-Asp uptake in a dose-dependent manner. Interestingly, a decrease in the transporter catalytic efficiency, probably linked to a diminution in the affinity of the transporter, was detected upon SiO-NPs. These results favor the notion that exposure to SiO-NPs could disrupt BBB function and by these means shed some light into our understanding of the deleterious effects of air pollution on the CNS.
谷氨酸是脊椎动物大脑中的主要兴奋性氨基酸，在大多数脑功能中发挥着重要作用。它通过质膜受体和转运体发挥作用，这些受体和转运体在神经元和神经胶质细胞中均有表达。神经元谷氨酸受体的过度刺激与细胞死亡有关，这一过程被称为兴奋性毒性，而通过富含神经胶质细胞质膜和血脑屏障（BBB）成分中的谷氨酸转运体有效清除神经递质可预防这种情况。二氧化硅纳米颗粒（SiO-NPs）已广泛应用于生物医学领域，并直接进入循环系统；然而，关于暴露于SiO-NPs对支持中枢神经系统（CNS）与外周循环之间关键隔离功能的血脑屏障转运系统的潜在不利影响，我们知之甚少。在本研究中，我们调查了SiO-NPs对血脑屏障细胞成分所表达的谷氨酸转运系统可能的破坏作用。首先，我们评估了SiO-NPs对人脑内皮细胞（HBEC）和乌普萨拉87恶性胶质瘤（U-87MG）细胞系的细胞毒性作用。评估了转运动力学，并确定了SiO-NPs对两种细胞系中谷氨酸转运活性的暴露效应。将细胞暴露于不同浓度（0.4、4.8、10和20μg/ml）的SiO-NPs以及不同时间段（3小时和6小时），均未影响细胞活力。我们发现放射性标记物D-天冬氨酸（[H]-D-Asp）的摄取主要依赖于钠，并且会被其自身底物（谷氨酸）下调。此外，暴露于SiO-NPs会使内皮细胞和星形胶质细胞中的[H]-D-Asp摄取呈剂量依赖性降低。有趣的是，在SiO-NPs作用下，检测到转运体催化效率降低，这可能与转运体亲和力降低有关。这些结果支持了以下观点：暴露于SiO-NPs可能会破坏血脑屏障功能，从而有助于我们理解空气污染对中枢神经系统的有害影响。
