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(Stroke. 2007;38:177.)
© 2007 American Heart Association, Inc.

Original Contributions

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

Kon Chu, MD; Soon-Tae Lee, MD; Dong-In Sinn, MD; Song-Yi Ko, MS; Eun-Hee Kim, MS; Jeong-Min Kim, MD; Se-Jeong Kim, MS; Dong-Kyu Park, BS; Keun-Hwa Jung, MD; Eun-Cheol Song, MD; Sang Kun Lee, MD, PhD; Manho Kim, MD, PhD Jae-Kyu Roh, MD, PhD

From the Stroke &Neural Stem Cell Laboratory in the Clinical Research Institute (K.C., S.T.L., D.-I.S., S.-Y.K., E.-H.K., J.-M.K., S.-J.K., D.-K.P., K.-H.J., E.-C.S., S.K.L., M.K., J.-K.R.), Stem Cell Research Center, Department of Neurology, Seoul National University Hospital, Seoul, South Korea; the Program in Neuroscience (K.C., S.-T.L., K.-H.J., E.-C.S., S.K.L., M.K., J.-K.R.), Neuroscience Research Institute of the SNUMRC, Seoul National University, Seoul, South Korea; and the Center for Alcohol and Drug Addiction Research (S.-T.L.), Seoul National Hospital, Seoul, South Korea.

Correspondence to Jae-Kyu Roh, MD, PhD, Department of Neurology, Seoul National University Hospital, 28, Yongon-Dong, Chongro-Gu, Seoul, 110-744, South Korea. E-mail rohjk{at}snu.ac.kr

Background and Purpose— Astrocytic glutamate transporter protein, GLT-1 (EAAT2), recovers extracellular glutamate and ensures that neurons are protected from excess stimulation. Recently, β-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-, 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.

Key Words: ceftriaxone • cerebral ischemia • excitotoxicity • ischemic tolerance • glutamate transporter-1

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