Published Online
on March 11, 2004

A more recent version of this article appeared on May 1, 2004

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Submitted on October 22, 2003
Revised on January 8, 2004
Accepted on January 9, 2004

Volume-Regulated Anion Channels are the Predominant Contributors to Release of Excitatory Amino Acids in the Ischemic Cortical Penumbra

Paul J. Feustel PhD^*; Yiqiang Jin MS; and Harold K. Kimelberg PhD

From the Center for Neuropharmacology and Neuroscience (P.J.F.), Albany Medical College, Albany, New York and Ordway Research Institute (Y.J., H.K.K.), Albany, New York.

^* To whom correspondence should be addressed. E-mail: feustep{at}mail.amc.edu.

Background and Purpose--Release of excitatory amino acids (EAA) is considered a cause of neuronal damage in ischemia. We investigated the sources and mechanisms of EAA release using microdialysis in regions of incomplete ischemia where perfusion was reduced by 50% to 80%, by applying inhibitors of volume-regulated anion channels (VRACs) and the GLT-1 glutamate transporter.

Methods--Reversible middle cerebral artery occlusion (rMCAo) was induced in anesthetized rats using the intraluminal suture technique. Microdialysate concentrations of glutamate, aspartate, and taurine were measured before, during 2 hours of rMCAo, and for 2 hours after rMCAo. Vehicle, dihydrokainate (DHK, 1 mmol/L), a GLT-1 inhibitor, or tamoxifen (50 µmol/L), a VRAC inhibitor, were administered continuously via the dialysis probes starting one hour prior to ischemia.

Results--During incomplete ischemia, dialysate glutamate levels averaged 1.74±0.31 µmol/L (SEM) in the control group (n=8), 2.08±0.33 µmol/L in the DHK group (n=7), and were significantly lower at 0.88±0.30 µmol/L in the tamoxifen group (n=9; P<0.05). As perfusion returned toward baseline levels, EAA levels declined in the vehicle and tamoxifen-treated animals but they remained elevated in the DHK-treated animals.

Conclusion--In contrast to previous results in severely ischemic regions, DHK did not reduce EAA release in less severely ischemic brain, suggesting a diminished role for transporter reversal in these areas. These findings also support the hypothesis that in regions of incomplete ischemia, release of EAAs via VRACs may play a larger role than reversal of the GLT-1 transporter.

Key words: cerebral ischemia • astrocytes • anion transport • rats • reversible middle cerebral artery occlusion

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