Neonatology Department, Anhui Provincial Children's Hospital, Hefei, China.
Pulmonary Department, Anhui Provincial Children's Hospital, Hefei, China.
Neurosci Lett. 2021 Jul 27;758:136013. doi: 10.1016/j.neulet.2021.136013. Epub 2021 Jun 7.
Preterm infants often suffer from impaired postnatal brain development, and glutamate excitotoxicity is identified as a pivotal mechanism of hyperoxia-induced neurological abnormality. We aimed to investigate the effect of short time hyperoxia on glutamate homeostasis and glutamate transporters expressions in immature brain. Six-day-old (P6) rat pups were exposed to 80% oxygen for 24 h (the hyperoxia group) or placed in atmospheric air (the control group). The concentrations of glutamate and γ-aminobutyric acid (GABA) in immature cerebrum and cerebellum at P7, P14 and P21 were determined by ELISA. The mRNA levels of glutamate transporters including excitatory amino acid transporter 1 (EAAT1), EAAT2, EAAT3, vesicular glutamate transporter 1 (VGLUT1) and VGLUT2 in brain were determined by qPCR. Glutamate accumulation was induced by hyperoxia both in immature cerebrum and cerebellum at P7 but got gradually attenuated at P14 and P21, as evidenced by the changes of glutamate and GABA concentrations. Hyperoxia also induced sustained glutamatic oxidative stress in both cerebrum and cerebellum, as GSH (reduced glutathione) levels in the hyperoxia group were constantly higher than the control group at three examined time-points. Furthermore, at P7, the expressions of all glutamate transporters decreased in both cerebrum and cerebellum except that of EAAT1. At P21, VGLUT2 in cerebrum and EAAT1, EAAT3 and VGLUT2 in cerebellum still displayed significant decrease in expression levels upon hyperoxia stimulation. Taken together, our results indicate that hyperoxia induces glutamate accumulation in brain of rat pups, which is associated with increased oxidative stress and decreased expressions of glutamate transporters.
早产儿常患有出生后脑发育受损，谷氨酸兴奋性毒性被认为是高氧诱导神经异常的关键机制。我们旨在研究短暂高氧对未成熟大脑中谷氨酸稳态和谷氨酸转运体表达的影响。将 6 日龄（P6）大鼠幼仔暴露于 80%氧气中 24 小时（高氧组）或置于大气空气中（对照组）。通过 ELISA 测定 P7、P14 和 P21 时不成熟大脑和小脑中谷氨酸和γ-氨基丁酸（GABA）的浓度。通过 qPCR 测定大脑中谷氨酸转运体包括兴奋性氨基酸转运体 1（EAAT1）、EAAT2、EAAT3、囊泡谷氨酸转运体 1（VGLUT1）和 VGLUT2 的 mRNA 水平。高氧在 P7 时在不成熟的大脑和小脑中均诱导谷氨酸积累，但在 P14 和 P21 时逐渐减弱，这反映了谷氨酸和 GABA 浓度的变化。高氧还在大脑和小脑中诱导持续的谷氨酸氧化应激，因为高氧组的 GSH（还原型谷胱甘肽）水平在三个检查时间点均始终高于对照组。此外，在 P7 时，除 EAAT1 外，所有谷氨酸转运体在大脑和小脑中的表达均降低。在 P21 时，大脑中的 VGLUT2 和小脑中的 EAAT1、EAAT3 和 VGLUT2 的表达水平仍明显降低。综上所述，我们的结果表明，高氧诱导大鼠幼仔大脑中谷氨酸积累，这与氧化应激增加和谷氨酸转运体表达降低有关。
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