Anticonvulsive and neuroprotective actions of a potent agonist (DCG-IV) for Group II metabotropic glutamate receptors against intraventricular kainate in the rat

Abstract

Anticonvulsive and neuroprotective effects of (2 S,1′ R,2′ R,3′ R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV), a potent agonist for Group II metabotropic glutamate receptors, were examined in vivo against the excitotoxicity of kainic acid in the rat. Intraventricular injection of kainic acid (2 nmol) induced circling behavior and wet-dog shakes soon after injection, followed by episodes of limbic motor seizures at intervals of several minutes (sporadic limbic motor seizures). The frequency of sporadic limbic motor seizures gradually increased until seizures occurred incessantly (continuous limbic motor seizures). Intraventricular kainic acid also caused severe selective neuron damage in the hippocampal CA3 region, limbic lobe and medial geniculate body. Prolonged intraventricular infusion of DCG-IV (24–240 pmol/h) for 17 h before and 7 h after the application of kainic acid decreased the incidence of the continuous limbic motor seizures and the degree of neuronal damage in circumscribed brain areas. However, the behavioral changes observed immediately after the administration of kainic acid were unaffected by prolonged intraventricular infusion with DCG-IV (8–2400 pmol/h). Similarly, the occurrence of sporadic limbic motor seizures was only slightly reduced by the administration of DCG-IV (8–800 pmol/h). High doses of DCG-IV, greater than 800 pmol/h, afforded no protection against kainate-induced lesions; rather, the degradation of hippocampal CA1 pyramidal neurons was increased under such conditions. Single injections of DCG-IV (10–300 pmol/rat) in the lateral ventricle did not affect kainate neurotoxicity. Thus, prolonged infusion of DCG-IV showed a bell-shaped dose–response relationship with regard to protection against kainate-induced neurotoxicity.