TY - JOUR
T1 - Effects of NMDA receptor antagonists with different subtype selectivities on retinal spreading depression
AU - Wang, Minyan
AU - Chazot, Paul L.
AU - Ali, Sura
AU - Duckett, Stevens F.
AU - Obrenovitch, Tihomir P.
PY - 2012/1
Y1 - 2012/1
N2 - 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 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. 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.
AB - 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 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. 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.
KW - CP-101606
KW - GluN2A
KW - GluN2A/2B
KW - GluN2B
KW - GluN2D
KW - NMDA receptor subtypes
KW - NVP-AAM077
KW - UBP141
KW - chick retina
KW - immunoblotting
KW - spreading depression
UR - http://www.scopus.com/inward/record.url?scp=82955189736&partnerID=8YFLogxK
U2 - 10.1111/j.1476-5381.2011.01553.x
DO - 10.1111/j.1476-5381.2011.01553.x
M3 - Article
C2 - 21699507
AN - SCOPUS:82955189736
SN - 0007-1188
VL - 165
SP - 235
EP - 244
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 1
ER -