Glutamate transporter type 3 knockout reduces brain tolerance to focal brain ischemia in mice

J Cereb Blood Flow Metab. 2011 May;31(5):1283-92. doi: 10.1038/jcbfm.2010.222. Epub 2010 Dec 8.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehydes / metabolism
  • Animals
  • Blotting, Western
  • Brain Ischemia / metabolism*
  • Brain Ischemia / pathology*
  • Enzyme-Linked Immunosorbent Assay
  • Excitatory Amino Acid Transporter 3 / deficiency
  • Excitatory Amino Acid Transporter 3 / metabolism*
  • Glutathione / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Tyrosine / analogs & derivatives
  • Tyrosine / metabolism

Substances

  • Aldehydes
  • Excitatory Amino Acid Transporter 3
  • Slc1a1 protein, mouse
  • 3-nitrotyrosine
  • Tyrosine
  • Glutathione
  • 4-hydroxy-2-nonenal