Volume-regulated anion channels are the predominant contributors to release of excitatory amino acids in the ischemic cortical penumbra.
OBJECTIVE
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.
Feustel
Paul J
PJ
Center for Neuropharmacology and Neuroscience, MC136, Albany Medical College, Albany, New York, USA. feustep@mail.amc.edu
Jin
Yiqiang
Y
Kimelberg
Harold K
HK
D027322:Amino Acid Transport System X-AG; D000818:Animals; D027321:Anion Transport Proteins / Q000378:metabolism*; D001224:Aspartic Acid / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism; D002545:Brain Ischemia / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism*; D018846:Excitatory Amino Acids / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery; D007608:Kainic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D017551:Microdialysis; D009474:Neurons / Q000378:metabolism; D051381:Rats; D017470:Receptors, Glutamate / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D013654:Taurine / Q000378:metabolism
D027322:Amino Acid Transport System X-AG; D027321:Anion Transport Proteins; D018846:Excitatory Amino Acids; D017470:Receptors, Glutamate; D013629:Tamoxifen; D013654:Taurine; D001224:Aspartic Acid; D018698:Glutamic Acid; C020889:dihydrokainic acid; D007608:Kainic Acid