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CGS‐19755, A competitive NMDA receptor antagonist, reduces calcium‐calmodulin binding and improves outcome after global cerebral ischemia

CGS‐19755, A competitive NMDA receptor antagonist, reduces calcium‐calmodulin binding and... We evaluated several doses of cis‐4‐(phosphonomethyl)‐2‐piperidine‐carboxylic acid (CGS‐19755), a potent competitive N‐methyl‐D‐aspartate (NMDA) receptor antagonist, systemically administered either before or after 20 to 30 minutes of global ischemia in rats. We measured outcome by mortality, histological damage by light microscopy, and learning ability on an eight‐arm maze, and determined the drug's mechanism of action by an immunohistochemical assay of calcium‐calmodulin binding. High‐dose treatment begun prior to ischemia resulted in reduced cellular damage in severely ischemic hippocampal tissue, but also caused high mortality due to respiratory depression. Treatment begun 30 minutes after ischemia resulted in little histological protection but significantly improved learning ability when tested 1 month after ischemia, and did not increase mortality. Furthermore, CGS‐19755, 10 mg/kg intraperitoneally, begun either before or after ischemia substantially reduced calcium influx into ischemic neurons as evidenced by reduced calcium‐calmodulin binding. We conclude that CGS‐19755 prevents calcium entry into ischemic neurons and may be effective therapy for very acute cerebral ischemia. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annals of Neurology Wiley

CGS‐19755, A competitive NMDA receptor antagonist, reduces calcium‐calmodulin binding and improves outcome after global cerebral ischemia

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References (33)

Publisher
Wiley
Copyright
Copyright © 1990 American Neurological Association
ISSN
0364-5134
eISSN
1531-8249
DOI
10.1002/ana.410270605
pmid
2163237
Publisher site
See Article on Publisher Site

Abstract

We evaluated several doses of cis‐4‐(phosphonomethyl)‐2‐piperidine‐carboxylic acid (CGS‐19755), a potent competitive N‐methyl‐D‐aspartate (NMDA) receptor antagonist, systemically administered either before or after 20 to 30 minutes of global ischemia in rats. We measured outcome by mortality, histological damage by light microscopy, and learning ability on an eight‐arm maze, and determined the drug's mechanism of action by an immunohistochemical assay of calcium‐calmodulin binding. High‐dose treatment begun prior to ischemia resulted in reduced cellular damage in severely ischemic hippocampal tissue, but also caused high mortality due to respiratory depression. Treatment begun 30 minutes after ischemia resulted in little histological protection but significantly improved learning ability when tested 1 month after ischemia, and did not increase mortality. Furthermore, CGS‐19755, 10 mg/kg intraperitoneally, begun either before or after ischemia substantially reduced calcium influx into ischemic neurons as evidenced by reduced calcium‐calmodulin binding. We conclude that CGS‐19755 prevents calcium entry into ischemic neurons and may be effective therapy for very acute cerebral ischemia.

Journal

Annals of Neurology – Wiley

Published: Jun 1, 1990

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