Induction of heat-shock protein (HSP72) in the cingulate and retrosplenial cortex by drugs that antagonize the effects of excitatory amino acids.
To address the issue of the cytotoxicity of glutamate antagonists, we administered representative agents to rats and used HSP72 immunocytochemistry as a measure of neuronal injury in the brain. The doses studied spanned the reported neuroprotective range for each compound. Some, but not all, glutamate antagonists induce neuronal injury in the brain. The non-competitive NMDA antagonists (MK801 and dextrorphan) demonstrate maximum toxicity. Competitive NMDA antagonists (CGS 19755 and MDL 100,453) may or may not induce neuronal injury depending on the particular compound. The polyamine site (SL 82.0715-10) antagonist does not result in neuronal injury. Cingulate and retrosplenial cortex neurotoxicity is not a ubiquitous feature of neuroprotective agents that block excitotoxcity, but is limited to NMDA antagonists and may depend upon the duration and completeness of the blockade of the NMDA receptor.
Lan
J Q
JQ
Department of Neurology, University of Pittsburgh, PA 15261, USA.
Chen
J
J
Sharp
F R
FR
Simon
R P
RP
Graham
S H
SH
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006179:Gyrus Cinguli / Q000187:drug effects* / Q000378:metabolism; D050884:HSP72 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000096:biosynthesis* / Q000187:drug effects; D007150:Immunohistochemistry; D008297:Male; D010875:Pipecolic Acids / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D018691:Excitatory Amino Acid Antagonists; D050884:HSP72 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D010875:Pipecolic Acids; C053672:selfotel; D016291:Dizocilpine Maleate