NOVEL EFFECTS OF MEMANTINE IN ANTAGONIZING ACUTE ALDICARB TOXICITY - MECHANISTIC AND APPLIED CONSIDERATIONS

Administration of a single sublethal dose of aldicarb (0.4 mg/kg, i.p.) to male Sprague-Dawley rats produced the onset of hypercholinergic signs within 3-5 min. With increasing intensity the most severe signs, predominantly involving the peripheral nervous system (muscle fasciculations and convulsions), were evident within 15-30 min and lasted for about 90 min. Rats dosed with 0.1 mg/kg, i.p. did not develop intoxication while those dosed with 0.2 mg/kg, i.p. exhibited signs of moderate toxicity. A dosage of 0.6 mg/kg was found to be the minimal lethal dose (MLD). The inhibition of acetylcholinesterase (AChE) and carboxylesterase (CarbE) was dose-dependent. Significant (P < 0.01) inhibition in the activities of AChE and CarbE occurred as early as within 15 min, and the maximal effect within 30 min. Time course of CarbE activity revealed marked inhibition in different neuronal and nonneuronal tissues, suggesting tremendous nonspecific binding of aldicarb. Prophylaxis with memantine HCI (18 mg/kg, i.p.) and atropine sulfate (16 mg/kg, i.p.), 30 min and 15 min, respectively, prior to aldicarb (0.4 mg/kg), provided complete protection. Therapeutic administration of these two antidotes in combination also completely reversed the clinical signs of intoxication. It is suggested that memantine antagonized the aldicarb acute toxicity by protection/reactivation of activities of AChE and CarbE and reversible blockade of hyperneuromuscular transmission, in addition to muscarinic ACh receptor blockade by atropine.