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Pharmacological Induction of Ischemic Tolerance by Glutamate Transporter-1 (EAAT2) Upregulation

Cited 143 time in Web of Science Cited 151 time in Scopus
Authors
Chu, K.; Lee, S. T.; Sinn, D. I.; Ko, S. Y.; Kim, E. H.; Kim, J. M.; Kim, S. J.; Park, D. K.; Jung, K. H.; Song, E. C.; Lee, S. K.; Kim, M.; Roh, J. K.
Issue Date
2006-11-24
Publisher
American Heart Association
Citation
Stroke. 2007 Jan;38(1):177-82. Epub 2006 Nov 22.
Keywords
AnimalsAnti-Bacterial Agents/pharmacologyAstrocytes/*drug effects/metabolismBrain/blood supply/*drug effects/physiopathologyBrain Ischemia/*drug therapy/metabolism/physiopathologyCeftriaxone/*pharmacologyCell Communication/drug effects/physiologyCytoprotection/drug effects/physiologyDisease Models, AnimalExcitatory Amino Acid Transporter 2/drug effects/genetics/metabolismGlutamic Acid/*metabolismMaleNeurons/metabolismNeuroprotective Agents/pharmacologyNeurotoxins/antagonists & inhibitors/metabolismRNA, Messenger/drug effects/metabolismRatsRats, Sprague-DawleyTreatment OutcomeUp-Regulation/drug effects/physiology
Abstract
BACKGROUND AND PURPOSE: Astrocytic glutamate transporter protein, GLT-1 (EAAT2), recovers extracellular glutamate and ensures that neurons are protected from excess stimulation. Recently, beta-lactam antibiotics, like ceftriaxone (CTX), were reported to induce the upregulation of GLT-1. Here, we investigated ischemic tolerance induction by CTX in an experimental model of focal cerebral ischemia. METHODS: CTX (200 mg/kg per day, IP) was administered for 5 consecutive days before transient focal ischemia, which was induced by intraluminal thread occlusion of the middle cerebral artery for 90 minutes or permanently. RESULTS: Repeated CTX injections enhanced GLT-1 mRNA and protein expressions after 3 and 5 days of treatment, respectively. CTX-pretreated animals showed a reduction in infarct volume by 58% (reperfusion) and 39% (permanent), compared with the vehicle-pretreated animals at 24 hours postischemia (P<0.01). Lower doses of CTX (20 mg/kg per day and 100 mg/kg per day) reduced infarct volumes to a lesser degree. The injection of GLT-1 inhibitor (dihydrokainate) at 30 minutes before ischemia ameliorated the effect of CTX pretreatment. However, CTX administration at 30 minutes after ischemia produced no significant reduction in infarct volume. CTX reduced the levels of proinflammatory cytokines (tumor necrosis factor-alpha, FasL), matrix metalloproteinase (MMP)-9, and activated caspase-9 (P<0.01). In addition, CTX-pretreated animals showed better functional recovery at day 1 to week 5 after ischemia (P<0.05). CONCLUSIONS: This study presents evidence that CTX induces ischemic tolerance in focal cerebral ischemia and that this is mediated by GLT-1 upregulation.
ISSN
1524-4628 (Electronic)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17122424

https://hdl.handle.net/10371/22352
DOI
https://doi.org/10.1161/01.STR.0000252091.36912.65
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College of Medicine/School of Medicine (의과대학/대학원)Neuroscience (뇌신경과학전공)Journal Papers (저널논문_뇌신경과학전공)
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