(Stroke. 1999;30:433-440.)
© 1999 American Heart Association, Inc.
Original Contributions |
Inhibition of Ischemia-Induced Glutamate Release in Rat Striatum by Dihydrokinate and an Anion Channel Blocker
From the Division of Neurosurgery, Department of Surgery (P.J.F., B.I.T., H.K.K.), and Department of Pharmacology and Neuroscience (R.W.K.), Albany Medical College, Albany, NY, and Department of Neurosurgery, Nagoya University, Nagoya, Japan (Y.S.).
Correspondence to Paul J. Feustel, PhD, Division of Neurosurgery, Department of Surgery, A-61, Albany Medical College, Albany, NY 12208. E-mail pfeustel{at}ccgateway.amc.edu
Background and Purpose—Increased activation of excitatory amino acid (EAA) receptors is considered a major cause of neuronal damage. Possible sources and mechanisms of ischemia-induced EAA release were investigated pharmacologically with microdialysis probes placed bilaterally in rat striatum.
Methods—Forebrain ischemia was induced by bilateral carotid artery occlusion and controlled hypotension in halothane-anesthetized rats. During 30 minutes of ischemia, microdialysate concentrations of glutamate and aspartate were measured in the presence of a nontransportable blocker of the astrocytic glutamate transporter GLT-1, dihydrokinate (DHK), or an anion channel blocker, 4,4'-dinitrostilben-2,2'-disulfonic acid (DNDS), administered separately or together through the dialysis probe.
Results—In control striata during ischemia, glutamate and aspartate concentrations increased 44±13 (mean±SEM) times and 19±5 times baseline, respectively, and returned to baseline values on reperfusion. DHK (1 mmol/L in perfusate; n=8) significantly attenuated EAA increases compared with control (glutamate peak, 9.6±1.7 versus control, 15.4±2.6 pmol/µL). EAA levels were similarly decreased by 10 mmol/L DHK. DNDS (1 mmol/L; n=5) also suppressed EAA peak increases (glutamate peak, 5.8±1.1 versus control, 10.1±0.7 pmol/µL). At a higher concentration, DNDS (10 mmol/L; n=7) further reduced glutamate and aspartate release and also inhibited ischemia-induced taurine release. Together, 1 mmol/L DHK and 10 mmol/L DNDS (n=5) inhibited 83% of EAA release (glutamate peak, 2.7±0.7 versus control, 10.9±1.2 pmol/µL).
Conclusions—These findings support the hypothesis that both cell swelling–induced release of EAAs and reversal of the astrocytic glutamate transporter are contributors to the ischemia-induced increases of extracellular EAAs in the striatum as measured by microdialysis.
Editorial Comment
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia
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