on March 11, 2004
Published online before print March 11, 2004, doi: 10.1161/01.STR.0000124127.57946.a1
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on October 22, 2003
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.
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*;
Key words: cerebral ischemia • astrocytes • anion transport • rats • reversible middle cerebral artery occlusion
This article has been cited by other articles:
 |
|
 |
|
  K. Chu, S.-T. Lee, D.-I. Sinn, S.-Y. Ko, E.-H. Kim, J.-M. Kim, S.-J. Kim, D.-K. Park, K.-H. Jung, E.-C. Song, et al. Pharmacological Induction of Ischemic Tolerance by Glutamate Transporter-1 (EAAT2) Upregulation Stroke, January 1, 2007; 38(1): 177 - 182. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Mulligan and B. A. MacVicar VRACs CARVe a Path for Novel Mechanisms of Communication in the CNS Sci. Signal., October 17, 2006; 2006(357): pe42 - pe42. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. F. Abdullaev, A. Rudkouskaya, G. P. Schools, H. K. Kimelberg, and A. A. Mongin Pharmacological comparison of swelling-activated excitatory amino acid release and Cl- currents in cultured rat astrocytes J. Physiol., May 1, 2006; 572(3): 677 - 689. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Chesnoy-Marchais The Estrogen Receptor Modulator Tamoxifen Enhances Spontaneous Glycinergic Synaptic Inhibition of Hypoglossal Motoneurons Endocrinology, October 1, 2005; 146(10): 4302 - 4311. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. E. Haskew-Layton, A. A. Mongin, and H. K. Kimelberg Hydrogen Peroxide Potentiates Volume-sensitive Excitatory Amino Acid Release via a Mechanism Involving Ca2+/Calmodulin-dependent Protein Kinase II J. Biol. Chem., February 4, 2005; 280(5): 3548 - 3554. [Abstract] [Full Text] [PDF]
|
|