ACTIVATION OF CLASS-II OR CLASS-III METABOTROPIC GLUTAMATE RECEPTORS PROTECTS CULTURED CORTICAL-NEURONS AGAINST EXCITOTOXIC DEGENERATION

Trans-1-aminocyclopentane-1,3-dicarboxylic acid, a mixed agonist of al l metabotropic glutamate receptor (mGluR) subtypes, is known to produc e either neurotoxic or neuroprotective effects. We have therefore hypo thesized that individual mGluR subtypes differentially affect neurodeg enerative processes. Selective agonists of subtypes which belong to mG luR class II or III, such as (2(S),1'(R),2'(R),3'(R))-2-(2,3-dicarboxy cyclopr glycine (DCG-IV) (specific for subtypes mGluR2 or 3) or L-2-am ino-4-phosphonobutanoate and L-serine-O-phosphate (specific for subtyp es mGluR4, 6 or 7), were highly potent and efficacious in protecting c ultured cortical neurons against toxicity induced by either a transien t exposure to N-methyl-D-aspartate (NMDA) or a prolonged exposure to k ainate. In contrast, agonists that preferentially activate class I mGl uR subtypes (mGluR1 or 5), such as quisqualate or trans-azetidine-2,3- dicarboxylic acid, were inactive. DCG-IV was still neuroprotective whe n applied to cultures after the toxic pulse with NMDA. This delayed re scue effect was associated with a reduction in the release of endogeno us glutamate, a process that contributes to the maturation of neuronal damage. We conclude that agonists of class II or ill mGluRs are of po tential interest in the experimental therapy of acute or chronic neuro degenerative disorders.