S-Space College of Medicine/School of Medicine (의과대학/대학원) Neuroscience (뇌신경과학전공) Journal Papers (저널논문_뇌신경과학전공)
Pharmacological Induction of Ischemic Tolerance by Glutamate Transporter-1 (EAAT2) Upregulation
- 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
- American Heart Association
- Stroke. 2007 Jan;38(1):177-82. Epub 2006 Nov 22.
- Animals; Anti-Bacterial Agents/pharmacology; Astrocytes/*drug effects/metabolism; Brain/blood supply/*drug effects/physiopathology; Brain Ischemia/*drug therapy/metabolism/physiopathology; Ceftriaxone/*pharmacology; Cell Communication/drug effects/physiology; Cytoprotection/drug effects/physiology; Disease Models, Animal; Excitatory Amino Acid Transporter 2/drug effects/genetics/metabolism; Glutamic Acid/*metabolism; Male; Neurons/metabolism; Neuroprotective Agents/pharmacology; Neurotoxins/antagonists & inhibitors/metabolism; RNA, Messenger/drug effects/metabolism; Rats; Rats, Sprague-Dawley; Treatment Outcome; Up-Regulation/drug effects/physiology
- 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.
- 1524-4628 (Electronic)