Blockade of both epileptogenesis and glutamate release by (1S,3S)-ACPD, a presynaptic glutamate receptor agonist.
The influence of intracerebrally focally administered doses of a presynaptic metabotropic glutamate receptor agonist, (1S,3S)-ACPD, and of the post-synaptically targeted competitive NMDA receptor antagonist, D-CPPene (SDZ EAA 494), was tested on the development of amygdaloid kindling. The actions of these drugs, compared to that of D-CPP, was also tested on fully developed stage 5 amygdala kindled seizures. Both (1S,3S)-ACPD and D-CPPene dose-dependently increased the generalised seizure threshold in fully kindled animals. They showed a similar potency, with (1S,3S)-ACPD acting presynaptically and D-CPPene postsynaptically. Both drugs reversibly inhibited epileptogenesis at 10 nmol in 0.5 microliter of injection vehicle, keeping the kindling stage at or below stage 2. All animals reached stage 5 after withdrawal of the 2 drugs. Whereas (1S,3S)-ACPD inhibited depolarisation-induced release of [3H]L-glutamate and [3H]D-aspartate from cortical synaptosomes (IC50 63 microM and 50 microM, respectively), D-CPPene (postsynaptically active) was without effect. These findings suggest a new approach to the development of clinically effective anticonvulsants through the development of presynaptic glutamate receptor agonists which could be administered systemically to control the extent of synaptic release of glutamate.
Attwell
P J
PJ
Department of Biochemistry, Imperial College of Science, Technology and Medicine, London, UK.
Kaura
S
S
Sigala
G
G
Bradford
H F
HF
Croucher
M J
MJ
Jane
D E
DE
Watkins
J C
JC
D000818:Animals; D003515:Cycloleucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004827:Epilepsy / Q000378:metabolism / Q000517:prevention & control*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013574:Synaptosomes / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; D010879:Piperazines; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; C065286:SDZ EAA 494; D018698:Glutamic Acid