Antisense knockdown of the glial glutamate transporter GLT-1, but not the neuronal glutamate transporter EAAC1, exacerbates transient focal cerebral ischemia-induced neuronal damage in rat brain.
Transient focal cerebral ischemia leads to extensive neuronal damage in cerebral cortex and striatum. Normal functioning of glutamate transporters clears the synaptically released glutamate to prevent excitotoxic neuronal death. This study evaluated the functional role of the glial (GLT-1) and neuronal (EAAC1) glutamate transporters in mediating ischemic neuronal damage after transient middle cerebral artery occlusion (MCAO). Transient MCAO in rats infused with GLT-1 antisense oligodeoxynucleotides (ODNs) led to increased infarct volume (45 +/- 8%; p < 0.05), worsened neurological status, and increased mortality rate, compared with GLT-1 sense/random ODN-infused controls. Transient MCAO in rats infused with EAAC1 antisense ODNs had no significant effect on any of these parameters. This study suggests that GLT-1, but not EAAC1, knockdown exacerbates the neuronal death and thus neurological deficit after stroke.
Department of Neurological Surgery and Cardiovascular Research Center, University of Wisconsin-Madison, Madison, Wisconsin 53792, USA. Vemugant@neurosurg.wisc.edu
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Rao
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Dogan
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Todd
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Bowen
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Kim
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Rothstein
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Dempsey
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D027322:Amino Acid Transport System X-AG; D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002540:Cerebral Cortex / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003342:Corpus Striatum / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D050580:Excitatory Amino Acid Transporter 3; D050491:Glutamate Plasma Membrane Transport Proteins; D018698:Glutamic Acid / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery; D002546:Ischemic Attack, Transient / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D015996:Survival Rate; D027981:Symporters
D018528:ATP-Binding Cassette Transporters; D027322:Amino Acid Transport System X-AG; D002352:Carrier Proteins; D050580:Excitatory Amino Acid Transporter 3; D050491:Glutamate Plasma Membrane Transport Proteins; D016376:Oligonucleotides, Antisense; C493398:Slc1a1 protein, rat; D027981:Symporters; D018698:Glutamic Acid