Selected peptides targeted to the NMDA receptor channel protect neurons from excitotoxic death

Excitotoxic neuronal death, associated with neurodegeneration and stroke, is triggered primarily by massive Ca2+ influx arising from overactivation of glutamate receptor channels of the N-methyl-D-aspartate (NMDA) subtype. To search for channel blockers, synthetic combinatorial libraries were assaye...

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Bibliographic Details
Published inNature biotechnology Vol. 16; no. 3; pp. 286 - 291
Main Authors Ferrer-Montiel, Antonio V, Merino, Jaime M, Blondelle, Sylvie E, Perez-Paya, Enrique, Houghten, Richard A, Montal, Mauricio
Format Journal Article
LanguageEnglish
Published New York, NY Nature 01.03.1998
Subjects
Animals
Arginine
Binding, Competitive
Biological and medical sciences
Cell Death - drug effects
Drug Design
Drug Evaluation, Preclinical
Female
Hippocampus - cytology
Hippocampus - drug effects
Humans
Medical sciences
Neurons - drug effects
Neuropharmacology
Neuroprotective agent
Oocytes - physiology
Peptides - metabolism
Peptides - pharmacology
Pharmacology. Drug treatments
Rats
Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors
Receptors, N-Methyl-D-Aspartate - metabolism
Substrate Specificity
Xenopus
Design
Neuron
Peptides
Cell death
Combinatorial chemistry
Glutamate receptor
Ionic channel
Neuroprotective agent
Antagonist
NMDA receptor
Protection
Research and development
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Summary:Excitotoxic neuronal death, associated with neurodegeneration and stroke, is triggered primarily by massive Ca2+ influx arising from overactivation of glutamate receptor channels of the N-methyl-D-aspartate (NMDA) subtype. To search for channel blockers, synthetic combinatorial libraries were assayed for block of agonist-evoked currents by the human NR1-NR2A NMDA receptor subunits expressed in amphibian oocytes. A set of arginine-rich hexapeptides selectively blocked the NMDA receptor channel with IC50 approximately 100 nM, a potency similar to clinically tolerated blockers such as memantine, and only marginally blocked on non-NMDA glutamate receptors. These peptides prevent neuronal cell death elicited by an excitotoxic insult on hippocampal cultures.
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ISSN:1087-0156
1546-1696
DOI:10.1038/nbt0398-286