Metabotropic receptors in excitotoxicity: (S)-4-carboxy-3-hydroxyphenylglycine ((S)-4C3HPG) protects against rat striatal quinolinic acid lesions.
Striatal quinolinate lesions mimic many of the neuropathological characteristics of Huntington's disease. This excitotoxicity is mediated by combined activity of N-methyl-D-aspartate and metabotropic glutamate receptors (mGluRs). Using recently developed phenylglycine derivatives, (S)-4-carboxy-3-hydroxyphenylglycine ((S)-4C3HPG) and (+)-alpha-methyl-4-carboxyphenylglycine ((+)-MCPG), we investigated the role of the different sub-classes of mGluRs in the in vivo excitotoxic process. (S)-4C3HPG (500 and 1000 nmol), co-injected with quinolinic acid, significantly reduced lesion volumes by 52 and 89%, respectively, whereas the same doses of (+)-MCPG had no effect on lesion size. The differential actions of these two drugs at Group 1 and Group 2 metabotropic receptors may explain their differential effects. These observations confirm the important role of mGluRs in excitotoxicity and identify them as promising targets for intervention.
Orlando
L R
LR
Department of Neurology, Massachusetts General Hospital, Boston, USA.
Standaert
D G
DG
Penney
J B
JB
Young
A B
AB
D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D017072:Neostriatum / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000494:pharmacology; D017378:Quinolinic Acid / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*
D001565:Benzoates; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D009498:Neurotoxins; D018094:Receptors, Metabotropic Glutamate; C078245:4-carboxy-3-hydroxyphenylglycine; C079694:alpha-methyl-4-carboxyphenylglycine; D017378:Quinolinic Acid; D005998:Glycine