Co-stimulation of cyclic-AMP-linked metabotropic glutamate receptors in rat striatum attenuates excitotoxin-induced nuclear factor-kappa B activationand apoptosis

Interactions between glutamatergic mechanisms mediated by receptors of the ionotropic and metabotropic classes in the central nervous system are compl ex and incompletely understood. To explore the consequences of these intera ctions on excitotoxicity, we examined the influence of group II and group I II selective metabotropic glutamate receptor agonists on the N-methyl-D-asp artate-induced apoptotic destruction of GABAergic neurons in rat striatum. The intrastriatal administration of a group III metabotropic glutamate rece ptor agonist (amino-4-phosphonobutyric acid, 900-1800 nmol), but not of a g roup II agonist [(2S,1'S,2'S)-(carboxycyclopropyl)glycine, 100-1800 nmol] p roduced internucleosomal DNA fragmentation. Similarly, amino-4-phosphonobut yric acid (600 nmol) but not (2S,1'S,2'S)-(carboxycyclopropyl)glycine (100- 1800 nmol) destroyed some striatal neurons as indicated by a loss of D1 dop amine receptors and 67,000 mel, wt glutamate decarboxylase (glutamate decar boxylase-67) messenger RNA. On the other hand, the intensity of internucleo somal DNA fragmentation induced by N-methyl-D-aspartate (150 nmol) was subs tantially decreased by the intrastriatal co-administration of either (2S,1' S,2'S)-(carboxycyclopropyl)glycine or amino-4-phosphonobutyric acid (100-60 0 nmol). Both (2S,1'S,2'S)-(carboxycyclopropyl)glycine and amino-4-phosphon obutyric acid also reduced the N-methyl-D-aspartate-induced loss of striata l D1 dopamine receptors by 67% and 68% (both P < 0.001), and glutamate deca rboxylase-67 messenger RNA by 68% and 61%, respectively. Furthermore, both (2S, 1'S,2'S)(carboxycyclopropyl)glycine and amino-4-phosphonobutyric acid also attenuated the N-methyl-D-aspartate-induced decline in striatal I kapp a B-alpha protein levels by 62% and 37%, as well as the increase in nuclear transcription factor nuclear factor-kappa B binding activity by 135% and 9 4% (both P < 0.001), and the subsequent rise in p53 and c-Myc protein level s. These results suggest that stimulation of cyclic-AMP-linked metabotropic gl utamate receptors inhibits ionotropic glutamate receptor-mediated activatio n of apoptotic cascades involving I kappa B-alpha degradation and nuclear f actor-kappa B nuclear translocation, as well as p53 and c-Myc induction. Ce rtain selective metabotropic glutamate receptor agonists might thus find ut ility as adjuncts to N-methyl-D-aspartate antagonists in the protection aga inst the neurotoxicity initiated by excessive ionotropic glutamate receptor stimulation. Published by Elsevier Science Ltd.