Anticonvulsive and
neuroprotective effects of (2S,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 doso-response relationship with regard to protection against
kainate-induced neurotoxicity.