Chen Ying, Holland Katherine D, Shertzer Howard G, Nebert Daniel W, Dalton Timothy P
Department of Environmental and Public Health Sciences, Center for Environmental Genetics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT 06520, USA.
Antioxidants (Basel). 2023 Feb 10;12(2):448. doi: 10.3390/antiox12020448.
Reduced glutathione (GSH) and ascorbic acid (AA) are the two most abundant low-molecular-weight antioxidants in mammalian tissues. knockout mice lack the gene encoding the modifier subunit of the rate-limiting enzyme in GSH biosynthesis; mice exhibit 10-40% of normal tissue GSH levels and show no overt phenotype. knockout mice, lacking a functional gene encoding L-gulono-γ-lactone oxidase, cannot synthesize AA and depend on dietary ascorbic acid for survival. To elucidate functional crosstalk between GSH and AA in vivo, we generated the / double-knockout (DKO) mouse. DKO mice exhibited spontaneous epileptic seizures, proceeding to death between postnatal day (PND)14 and PND23. Histologically, DKO mice displayed neuronal loss and glial proliferation in the neocortex and hippocampus. Epileptic seizures and brain pathology in young DKO mice could be prevented with AA supplementation in drinking water (1 g/L). Remarkably, in AA-rescued adult DKO mice, the removal of AA supplementation for 2-3 weeks resulted in similar, but more severe, neocortex and hippocampal pathology and seizures, with death occurring between 12 and 21 days later. These results provide direct evidence for an indispensable, yet underappreciated, role for the interplay between GSH and AA in normal brain function and neuronal health. We speculate that the functional crosstalk between GSH and AA plays an important role in regulating glutamatergic neurotransmission and in protecting against excitotoxicity-induced brain damage.
还原型谷胱甘肽（GSH）和抗坏血酸（AA）是哺乳动物组织中含量最丰富的两种低分子量抗氧化剂。基因敲除小鼠缺乏编码GSH生物合成限速酶修饰亚基的基因；这些小鼠的组织GSH水平仅为正常水平的10%-40%，且无明显表型。基因敲除小鼠缺乏编码L-古洛糖酸-γ-内酯氧化酶的功能基因，无法合成AA，依赖饮食中的抗坏血酸生存。为了阐明体内GSH和AA之间的功能相互作用，我们培育了/双基因敲除（DKO）小鼠。DKO小鼠表现出自发性癫痫发作，在出生后第14天（PND）至第23天之间死亡。组织学检查显示，DKO小鼠的新皮层和海马体出现神经元丢失和神经胶质细胞增殖。给幼龄DKO小鼠饮用添加AA（1 g/L）的水可预防癫痫发作和脑病理变化。值得注意的是，在补充AA后存活的成年DKO小鼠中，停止补充AA 2-3周会导致类似但更严重的新皮层和海马体病理变化及癫痫发作，12至21天后死亡。这些结果为GSH和AA之间的相互作用在正常脑功能和神经元健康中发挥不可或缺但未得到充分认识的作用提供了直接证据。我们推测，GSH和AA之间的功能相互作用在调节谷氨酸能神经传递和预防兴奋性毒性诱导的脑损伤中起重要作用。
