The novel non-competitive N-methyl-D-aspartate antagonist gacyclidine blocks the glutamate-induced release of hydroxyl radicals in the striatum under conditions in which dizocilpine does not. A microdialysis study in rats.
Gacyclidine, a new neuroprotectant aimed to non-competitively antagonize N-methyl-D-aspartate (NMDA) receptors, and dizocilpine blocked the hydroxyl radical response to toxic amounts of glutamate, perfused through a microdialysis implanted in the striatum of conscious rats. Furthermore, the hydroxyl radical response resulting from the infusion of lower doses of glutamate, which could not be inhibited by the same amounts of dizocilpine nor by acute alcohol exposure, still remained sensitive to gacyclidine inhibition. Thus, oxidative stress resulting from a glutamate discharge involves the activation of both NMDA receptors, and of non-NMDA mechanism(s) which, with moderate glutamate levels, were still antagonized by gacyclidine. Enhanced blockage of toxic hydroxyl radicals might explain the different and possibly higher neuroprotective property of gacyclidine as compared with other non-competitive NMDA antagonists.
Laplanche
L
L
CRBM, CNRS UPR 1086, Ecole Nationale Supérieure de Chimie de, Montpellier, France.
Kamenka
J M
JM
Barbanel
G
G
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D003510:Cyclohexanes / Q000494:pharmacology*; D053138:Cyclohexenes; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005971:Glutamates / Q000494:pharmacology*; D017665:Hydroxyl Radical / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
D003510:Cyclohexanes; D053138:Cyclohexenes; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D018696:Neuroprotective Agents; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D017665:Hydroxyl Radical; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; C070707:gacyclidine