title: Glutamate transporter type 3 knockout reduces brain tolerance to focal brain ischemia in mice.
abstract: Excitatory amino-acid transporters (EAATs) transport glutamate into cells under physiologic conditions. Excitatory amino-acid transporter type 3 (EAAT3) is the major neuronal EAAT and also uptakes cysteine, the rate-limiting substrate for synthesis of glutathione. Thus, we hypothesize that EAAT3 contributes to providing brain ischemic tolerance. Male 8-week-old EAAT3 knockout mice on CD-1 mouse gene background and wild-type CD-1 mice were subjected to right middle cerebral artery occlusion for 90 minutes. Their brain infarct volumes, neurologic functions, and brain levels of glutathione, nitrotyrosine, and 4-hydroxy-2-nonenal (HNE) were evaluated. The EAAT3 knockout mice had bigger brain infarct volumes and worse neurologic deficit scores and motor coordination functions than did wild-type mice, no matter whether these neurologic outcome parameters were evaluated at 24 hours or at 4 weeks after brain ischemia. The EAAT3 knockout mice contained higher levels of HNE in the ischemic penumbral cortex and in the nonischemic cerebral cortex than did wild-type mice. Glutathione levels in the ischemic and nonischemic cortices of EAAT3 knockout mice tended to be lower than those of wild-type mice. Our results suggest that EAAT3 is important in limiting ischemic brain injury after focal brain ischemia. This effect may involve attenuating brain oxidative stress.
authors.affiliation: Department of Anesthesiology, University of Virginia Health System, 1 Hospital Drive, Charlottesville, VA 22908, USA.
authors.forename: Liaoliao
authors.initials: L
authors.lastname: Li
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Zuo
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D050580:Excitatory Amino Acid Transporter 3 / Q000172:deficiency / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000447:Aldehydes; D050580:Excitatory Amino Acid Transporter 3; C493399:Slc1a1 protein, mouse; C002744:3-nitrotyrosine; D014443:Tyrosine; D005978:Glutathione; C027576:4-hydroxy-2-nonenal