Neuroprotection by a novel NMDAR functional glycine site partial agonist, GLYX-13.
GLYX-13 (threonine-proline-proline-threonine-amide) is an amidated di-pyrrolidine that acts as a functional partial agonist at the glycine site on N-methyl-D-aspartate glutamate receptors (NMDARs). GLYX-13 can both increase NMDAR conductance at NR2B-containing receptors, and reduce conductance of non-NR2B-containing receptors. Here, we report that GLYX-13 potently reduces delayed (24 h) death of CA1 pyramidal neurons produced by bilateral carotid occlusion in Mongolian gerbils, when administered up to 5 h post-ischemia. GLYX-13 also reduced delayed (24 h) neuronal death of CA1, CA3, and dentate gyrus principal neurons elicited by oxygen/glucose deprivation in in-vitro hippocampal organotypic slice cultures, when applied up to 2 h post-oxygen/glucose deprivation. The glycine site full agonist D-serine completely occluded neuroprotection, indicating that GLYX-13 acts by modulating activation of this site.
Stanton
Patric K
PK
Department of Cell Biology and Anatomy, New York Medical College, Valhalla, New York 10595, USA. patric_stanton@nymc.edu
Potter
Pamela E
PE
Aguilar
Jennifer
J
Decandia
Maria
M
Moskal
Joseph R
JR
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy; D002340:Carotid Artery Diseases / Q000188:drug therapy; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D005260:Female; D005849:Gerbillinae; D005947:Glucose / Q000172:deficiency; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D020521:Stroke / Q000188:drug therapy; D013997:Time Factors
C121001:NR2B NMDA receptor; D018696:Neuroprotective Agents; D009842:Oligopeptides; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; C507283:GLYX-13 peptide; D005947:Glucose