Effects of NMDA receptor antagonists with different subtype selectivities on retinal spreading depression.

Abstract

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. Immunoblotting was applied to the chick retina for NMDA receptor subunit protein analysis, and an efficient in vitro chick retinal model used with SD imaging for NMDA receptor pharmacology. 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. 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.