Glutathione (GSH) is an essential component of intracellular antioxidant systems that plays a primordial role in the protection of cells against oxidative stress, maintaining redox homeostasis and xenobiotic detoxification. GSH synthesis in the brain is limited by the availability of cysteine and glutamate. Cystine, the disulfide form of cysteine is transported into endothelial cells of the blood-brain barrier (BBB) and astrocytes via the system x_c⁻, which is composed of xCT and the heavy chain of 4F2 cell surface antigen (4F2hc). Cystine is reduced inside the cells and the L-type amino acid transporter 1 (LAT1) transports cysteine from the endothelial cells into the brain, cysteine is transported into the neurons through the excitatory amino acid transporter 3 (EAAT3), also known as excitatory amino acid carrier 1 (EAAC1). The mechanistic/mammalian target of rapamycin (mTOR) and neurotrophins can activate signaling pathways that modulate amino acid transporters for GSH synthesis. The present study found that systemic L-buthionine-S-R-sulfoximine (BSO) administration selectively altered GSH homeostasis and EAAT3 levels in the mice cerebellum. Intraperitoneal treatment of mice with 6 mmol/kg of BSO depleted GSH and GSSG in the liver at 2 h of treatment. The cerebellum, but not other brain regions, exhibited a redox response. The mTOR and the neuronal growth factor (NGF)/tropomyosin receptor kinase A (TrkA) signaling pathways were activated and lead to an increase in the protein levels of the EAAT3 transporter, which was linked to an increase in the GSH/GSSG ratio and GSH concentration in the cerebellum at 0.5 and 2 h, respectively. Therefore, the cerebellum responds to peripheral GSH depletion via activation of the mTOR and NGF/TrkA pathways, which increase the transport of cysteine for GSH synthesis.

谷胱甘肽（GSH）是细胞内抗氧化系统的重要组成部分，在保护细胞免受氧化应激，维持氧化还原稳态和异种生物排毒中起着主要作用。半胱氨酸和谷氨酸的可用性限制了大脑中GSH的合成。胱氨酸，半胱氨酸的二硫化物形式经由系x输送到血脑屏障的（BBB）星形胶质细胞内皮细胞和_Ç ^-由xCT和4F2细胞表面抗原（4F2hc）的重链组成。胱氨酸在细胞内部被还原，L型氨基酸转运蛋白1（LAT1）将半胱氨酸从内皮细胞转运至大脑，半胱氨酸通过兴奋性氨基酸转运蛋白3（EAAT3）转运至神经元。酸性载体1（EAAC1）。雷帕霉素（mTOR）和神经营养蛋白的机械/哺乳动物靶标可以激活信号传导途径，该信号传导途径调节GSH合成的氨基酸转运蛋白。本研究发现全身性L-丁硫氨酸-SR-亚磺酰亚胺（BSO）给药可选择性改变小鼠小脑的GSH稳态和EAAT3水平。在治疗2小时后，用6 mmol / kg的BSO腹腔内治疗小鼠肝脏中的GSH和GSSG耗尽。小脑 但其他大脑区域则没有氧化还原反应。mTOR和神经元生长因子（NGF）/原肌球蛋白受体激酶A（TrkA）信号通路被激活并导致EAAT3转运蛋白的蛋白质水平升高，这与GSH / GSSG比值和GSH升高有关小脑中的浓度分别在0.5和2小时。因此，小脑通过激活mTOR和NGF / TrkA途径对周围的GSH耗竭做出反应，这会增加半胱氨酸对GSH合成的转运。这与分别在0.5和2 h时小脑中GSH / GSSG比和GSH浓度增加有关。因此，小脑通过激活mTOR和NGF / TrkA途径对周围的GSH耗竭做出反应，这会增加半胱氨酸对GSH合成的转运。这与分别在0.5和2 h时小脑中GSH / GSSG比值和GSH浓度增加有关。因此，小脑通过激活mTOR和NGF / TrkA途径对周围的GSH耗竭做出反应，这会增加半胱氨酸对GSH合成的转运。