The novel non-competitive N-methyl-D-aspartate antagonist gacyclidine blocks the glutamate-induced release of hydroxyl radicals in the striatum underconditions in which dizocilpine does not. A microdialysis study in rats

Gacyclidine, a new neuroprotectant aimed to non-competitively antagonize N- methyl-D-aspartate (NM DA) receptors, and dizocilpine blocked the hydroxyl radical response to toxic amounts of glutamate, perfused through a microdia lysis implanted in the striatum of conscious rats. Furthermore, the hydroxy l radical response resulting from the infusion of lower doses of glutamate, which could not be inhibited by the same amounts of dizocilpine nor by acu te alcohol exposure, still remained sensitive to gacyclidine inhibition. Th us, oxidative stress resulting from a glutamate discharge involves the acti vation of both NMDA receptors, and of non-NMDA mechanism(s) which, with mod erate glutamate levels, were still antagonized by gacyclidine. Enhanced blo ckage of toxic hydroxyl radicals might explain the different and possibly h igher neuroprotective property of gacyclidine as compared with other non-co mpetitive NMDA antagonists. (C) 2000 Elsevier Science Ireland Ltd. All righ ts reserved.