Effects of memantine and its metabolite Mrz 2/373 on soman-induced inhibition of acetylcholinesterase in vitro.

Memantine is the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, used in the treatment of Alzheimer's disease. It is also known that memantine pretreatment assured protection of skeletal muscles from poisoning with nerve agents and an interaction between memantine and AChE was proposed. In the study presented we examined interactions of memantine and its main metabolite (1-amino-3-hydroxymethyl-5-methyl adamantine, Mrz 2/373) with AChE in vitro as well as their effect on kinetics of the soman-induced AChE inhibition and aging. The results have shown that memantine and Mrz 2/373 exerted concentration-dependent inhibition of AChE, with Mrz 2/373 being a more potent inhibitor than the parent compound. Addition of soman 7.5 nmol/l induced gradual AChE inhibition that became almost complete after 20 min. Memantine (0.1, 0.5 and 1 mmol/l) and Mrz 2/373 (0.1, 0.5 and 1 mmol/l) concentration-dependently slowed down the AChE inhibition. After 30 min of incubation of AChE with soman, 5 min of aging and 20 min of reactivation by asoxime (HI-6 dichloride), AChE activity was 8.1% in control medium, 30.7% and 41.9% after addition of 1 and 10 mmol/l memantine, and 16.1% after addition of 1 mmol/l Mrz 2/373. It was concluded that it is possible that memantine and Mrz 2/373 can prevent AChE from inhibition by soman, which could, along with known memantine's neuroprotective activity, explain its potent antidotal effect in soman poisoning. The potential effect on aging of the soman-AChE complex warrants further studies.

Efficacy of trimedoxime in mice poisoned with dichlorvos, heptenophos or monocrotophos.

The aim of the study was to examine antidotal potency of trimedoxime in mice poisoned with three direct dimethoxy-substituted organophosphorus inhibitors. In order to assess the protective efficacy of trimedoxime against dichlorvos, heptenophos or monocrotophos, median effective doses and efficacy half-times were calculated. Trimedoxime (24 mg/kg intravenously) was injected 5 min. before 1.3 LD50 intravenously of poisons. Activities of brain, diaphragmal and erythrocyte acetylcholinesterase, as well as of plasma carboxylesterases were determined at different time intervals (10, 40 and 60 min.) after administration of the antidotes. Protective effect of trimedoxime decreased according to the following order: monocrotophos > heptenophos > dichlorvos. Administration of the oxime produced a significant reactivation of central and peripheral acetylcholinesterase inhibited with dichlorvos and heptenophos, with the exception of erythrocyte acetylcholinesterase inhibited by heptenophos. Surprisingly, trimedoxime did not induce reactivation of monocrotophos-inhibited acetylcholinesterase in any of the tissues tested. These organophosphorus compounds produced a significant inhibition of plasma carboxylesterase activity, while administration of trimedoxime led to regeneration of the enzyme activity. The same dose of trimedoxime assured survival of experimental animals poisoned by all three organophosphorus compounds, although the biochemical findings were quite different.