title: Effects of Glycyrrhetinic Acid on GSH Synthesis Induced by Realgar in the Mouse Hippocampus: Involvement of System [Formula: see text], System [Formula: see text], MRP-1, and Nrf2.
abstract: Realgar, a type of mineral drug-containing arsenic, exhibits neurotoxicity. Brain glutathione (GSH) is crucial to protect the nervous system and to resist arsenic toxicity. Therefore, the main aim of this study was to explore the neurotoxic mechanisms of realgar and the protective effects of glycyrrhetinic acid (GA) by observing the effects of GA on the hippocampal GSH biosynthetic pathway after exposure to realgar. Institute of Cancer Research (ICR) mice were randomly divided into five groups: a control group, a GA control group, a realgar alone group, a low-dose GA intervention group, and a high-dose GA intervention group. Cognitive ability was tested using an object recognition task (ORT). The ultrastructures of the hippocampal neurons and synapses were observed. mRNA and protein levels of EAAT1, EAAT2, EAAT3, xCT, Nrf2, HO-1, γ-GCS (GCLC, GCLM), and MRP-1 were measured, as was the cellular localization of EAAT3, xCT, MRP-1, and Nrf2. The levels of GSH in the hippocampus, the levels of glutamate (Glu) and cysteine (Cys) in the extracellular fluid of hippocampal CA1 region, and the levels of active sulfur in the brain were also investigated. The results indicate that realgar lowered hippocampal GSH levels, resulting in ultrastructural changes in hippocampal neurons and synapses and deficiencies in cognitive ability, ultimately inducing neurotoxicity. GA could trigger the expression of Nrf2, HO-1, EAAT1, EAAT2, EAAT3, xCT, MRP-1, GCLC, and GCLM. Additionally, the expression of γ-GT and the supply levels of Glu and Cys increased, ultimately causing a significant increase in hippocampal GSH to alleviate realgar-induced neurotoxicity. In conclusion, the findings from our study indicate that GA can antagonize decreased brain GSH levels induced by realgar and can lessen the neurotoxicity of realgar.
authors.affiliation: Department of Health Laboratory Technology, School of Public health, China Medical University, Shenyang, 110122, People's Republic of China.|School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, 063009, People's Republic of China.
authors.forename: Yan-Lei
authors.initials: YL
authors.lastname: Wang
authors.affiliation: Department of Health Laboratory Technology, School of Public health, China Medical University, Shenyang, 110122, People's Republic of China.
authors.forename: Mo
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Health Laboratory Technology, School of Public health, China Medical University, Shenyang, 110122, People's Republic of China.
authors.forename: Tao-Guang
authors.initials: TG
authors.lastname: Huo
authors.affiliation: Department of Health Laboratory Technology, School of Public health, China Medical University, Shenyang, 110122, People's Republic of China.
authors.forename: Ying-Hua
authors.initials: YH
authors.lastname: Zhang
authors.affiliation: Department of Health Laboratory Technology, School of Public health, China Medical University, Shenyang, 110122, People's Republic of China.|School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, 116600, People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Department of Health Laboratory Technology, School of Public health, China Medical University, Shenyang, 110122, People's Republic of China.
authors.forename: Cong
authors.initials: C
authors.lastname: Feng
authors.affiliation: Department of Health Laboratory Technology, School of Public health, China Medical University, Shenyang, 110122, People's Republic of China.|School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, People's Republic of China.
authors.forename: Shou-Yun
authors.initials: SY
authors.lastname: Wang
authors.affiliation: Department of Health Laboratory Technology, School of Public health, China Medical University, Shenyang, 110122, People's Republic of China. jianghong@mail.cmu.edu.cn.
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000378:metabolism*; D027182:Amino Acid Transport System y+ / Q000378:metabolism*; D000818:Animals; D001152:Arsenicals / Q000494:pharmacology*; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D006034:Glycyrrhetinic Acid / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013440:Sulfides / Q000494:pharmacology*; D013455:Sulfur / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D027322:Amino Acid Transport System X-AG; D027182:Amino Acid Transport System y+; D001152:Arsenicals; D005978:Glutathione; D006034:Glycyrrhetinic Acid; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D051267:NF-E2-Related Factor 2; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D013440:Sulfides; D013455:Sulfur; C058317:arsenic disulfide; C421109:multidrug resistance-associated protein 1
keywords: Arsenic; Glutathione; Glycyrrhetinic acid; MRP-1; Nrf2; Realgar; System