Volume-regulated anion channels are the predominant contributors to release of excitatory amino acids in the ischemic cortical penumbra.

Abstract

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 micromol/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 micromol/L (SEM) in the control group (n=8), 2.08+/-0.33 micromol/L in the DHK group (n=7), and were significantly lower at 0.88+/-0.30 micromol/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.

CONCLUSIONS:

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.

• Authors: Paul J Feustel, Yiqiang Jin, Harold K Kimelberg
• Journal: Stroke (Stroke) Vol. 35 Issue 5 Pg. 1164-8 (May 2004) ISSN: 1524-4628 [Electronic] United States
• PMID: 15017010 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Amino Acid Transport System X-AG
• Anion Transport Proteins
• Excitatory Amino Acids
• Receptors, Glutamate
• Tamoxifen
• Taurine
• Aspartic Acid
• Glutamic Acid
• dihydrokainic acid
• Kainic Acid

Topics

• Amino Acid Transport System X-AG
• Animals
• Anion Transport Proteins (metabolism)
• Aspartic Acid (metabolism)
• Astrocytes (metabolism)
• Brain Ischemia (metabolism)
• Cerebral Cortex (metabolism)
• Excitatory Amino Acids (metabolism)
• Glutamic Acid (metabolism)
• Infarction, Middle Cerebral Artery
• Kainic Acid (analogs & derivatives, pharmacology)
• Microdialysis
• Neurons (metabolism)
• Rats
• Receptors, Glutamate (metabolism)
• Tamoxifen (pharmacology)
• Taurine (metabolism)