Anticonvulsant and glutamate release-inhibiting properties of the highly potent metabotropic glutamate receptor agonist (2S,2'R, 3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV).
The anticonvulsant effects of intracerebral administration of the highly potent group II metabotropic glutamate receptor agonist, DCG-IV, were tested in fully kindled rats following daily electrical stimulation of the basolateral amygdala. The agonist caused a dose-dependent increase in the generalized seizure threshold (GST) of these seizure susceptible animals within the dose range tested (0. 01-1.0 nmol). The estimated GST100 value (dose causing a 100% increase in GST) for this effect was 0.22 nmol. The anti-seizure activity of DCG-IV was fully inhibited in the presence of the group II metabotropic glutamate receptor antagonist (2S,1'S, 2'S)-2-methyl-2-(carboxycyclopropyl)glycine (MCCG; 40 nmol), while MCCG alone showed no significant inhibitory effect on seizure activity. DCG-IV also powerfully inhibited depolarization-induced release of [3H]D-aspartate from rat cerebrocortical synaptosomes, with an IC50 value of 0.39 microM. In this respect, DCG-IV was approximately 70-fold more potent than the clinically effective anticonvulsant drug lamotrigine (IC50=27.7 microM), a proposed neurotransmitter release inhibitor known to inhibit glutamate release, also tested in this assay. These findings demonstrate the high potency of DCG-IV as an anticonvulsant agent and confirm a key role for group II metabotropic glutamate receptors in the control of seizure activity via their modulatory action on neuronal glutamate release.
Attwell
P J
PJ
Department of Biochemistry, Imperial College of Science, Technology and Medicine, London SW7 2AZ, UK. p.attwell@ucl.ac.uk
Singh Kent
N
N
Jane
D E
DE
Croucher
M J
MJ
Bradford
H F
HF
D000679:Amygdala / Q000502:physiology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001224:Aspartic Acid / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D003521:Cyclopropanes / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism*; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007696:Kindling, Neurologic / Q000502:physiology; D000077213:Lamotrigine; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D012640:Seizures / Q000503:physiopathology; D013574:Synaptosomes / Q000378:metabolism; D014227:Triazines / Q000494:pharmacology
D000927:Anticonvulsants; D003521:Cyclopropanes; D018094:Receptors, Metabotropic Glutamate; D014227:Triazines; C082313:2-(2,3-dicarboxycyclopropyl)glycine; D001224:Aspartic Acid; D018698:Glutamic Acid; D005998:Glycine; D000077213:Lamotrigine