Specific group II metabotropic glutamate receptor activation inhibits the development of kindled epilepsy in rats.
The effects of intracerebral administration of the group II metabotropic glutamate receptor agonist, 2R,4R-APDC, were tested on both the development of amygdaloid kindling and on fully developed stage 5 amygdala kindled seizures. The development of amygdaloid kindling was significantly retarded in 2R,4R-APDC (10 nmol in 0.5 microl) treated animals compared to control animals over a period of 8 days. At a low dose, 2R,4R-APDC (0.1 nmol) caused a 42.5+/-26.6% increase of the generalised seizure threshold in fully kindled animals. As higher doses were administered, however, the changes in generalised seizure threshold were less marked, and even a small decrease in the threshold was seen (-19.6+/-5.36% at 10 nmol). The agonist 2R,4R-APDC inhibited depolarization-induced release of [3H]d-aspartate from cortical synaptosomes with an IC50 value of 0. 29 microM. This effect was maximal at 1 microM, and decreased with dose thereafter. These findings suggest that the selective activation of the group II metabotropic glutamate receptors by agonists such as 2R,4R-APDC may be of therapeutic potential in the treatment of seizure disorders.
Attwell
P J
PJ
Department of Biochemistry, Imperial College of Science, Technology and Medicine, London SW7 2AZ, UK.
Koumentaki
A
A
Abdul-Ghani
A S
AS
Croucher
M J
MJ
Bradford
H F
HF
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001921:Brain / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000473:pathology / Q000517:prevention & control*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism; D007696:Kindling, Neurologic / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009004:Monosaccharide Transport Proteins; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D000927:Anticonvulsants; D018690:Excitatory Amino Acid Agonists; D009004:Monosaccharide Transport Proteins; D018094:Receptors, Metabotropic Glutamate; D018698:Glutamic Acid; D011392:Proline