Abstract | BACKGROUND AND PURPOSE: Spreading depression (SD) is a local, temporary disruption of cellular ionic homeostasis that propagates slowly across the cerebral cortex and other neural tissues such as the retina. Spreading depolarization associated with SD occurs in different types of stroke, and this phenomenon correlates also with the initiation of classical migraine aura. The aim of this study was to investigate how NMDA receptor antagonists with different subtype selectivity alter SD. EXPERIMENTAL APPROACH: KEY RESULTS: The prominent NMDA receptor subtypes GluN1, GluN2A and GluN2B were found highly expressed in the chick retina. Nanomolar concentrations of NVP-AAM077 (GluN2A-preferring receptor antagonist) markedly suppressed high K(+) -induced SD; that is, ∼30 times more effectively than MK801. At sub-micromolar concentrations, Ro 25-6981 (GluN2B-preferring receptor antagonist) produced a moderate SD inhibition, whereas CP-101,606 (also GluN2B-preferring receptor antagonist) and UBP141 (GluN2C/2D-preferring receptor antagonist) had no effect. CONCLUSIONS AND IMPLICATIONS: The expression of major NMDA receptor subtypes, GluN1, GluN2A and GluN2B in the chick retina makes them pertinent targets for pharmacological inhibition of SD. The high efficacy of NVP-AAM077 on SD inhibition suggests a critical role of GluN2A-containing receptors in SD genesis. Such high anti-SD potency suggests that NVP-AAM077, and other GluN2A-selective drug-like candidates, could be potential anti- migraine agents.
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Authors | Minyan Wang, Paul L Chazot, Sura Ali, Stevens F Duckett, Tihomir P Obrenovitch |
Journal | British journal of pharmacology
(Br J Pharmacol)
Vol. 165
Issue 1
Pg. 235-44
(Jan 2012)
ISSN: 1476-5381 [Electronic] England |
PMID | 21699507
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society. |
Chemical References |
- Receptors, N-Methyl-D-Aspartate
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Topics |
- Animals
- Chickens
- Gene Expression Regulation
(drug effects)
- Male
- Receptors, N-Methyl-D-Aspartate
(antagonists & inhibitors, classification)
- Retina
(drug effects, metabolism)
- Retinal Diseases
(drug therapy)
- Stroke
(complications)
- Tissue Culture Techniques
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