Prevention and antagonism of acute carbofuran intoxication by memantine and atropine

Male Sprague-Dawley rats administered with a sublethal acute dose of carbofuran (1.5 mg/kg, sc) developed the observable toxic signs of anticholinesterase nature within 5-7 min. The toxic signs with increasing propensity to maximal severity including tremors, generalized muscle fasciculations, and convulsions were evident during 15 min to 1 h and lasted for 2 h. Thereafter, signs were seen up to 3 h with reduced intensity. By the end of 3.5 h toxic signs were completely subsided. Maximal acetylcholinesterase (AChE) inactivation occurred at 1 h in discrete brain regions (cortex, stem, striatum, and hippocampus) and hemidiaphragm muscle when most severe signs of toxicity were also evident. A single sc dose of memantine HCl (MEM, 18 mg/kg) and atropine sulfate (ATS, 16 mg/kg) 60 and 15 min, respectively, prior to carbofuran administration completely prevented the expected gross toxic signs and significantly (p less than .01) attenuated the carbofuran-induced inhibition of AChE activity. When given therapeutically, this combined treatment completely reversed the clinical evidence of carbofuran toxicity within 15 min and also markedly reduced AChE inactivation. Memantine or atropine when given alone was less effective compared to their combined administration. The results of this study suggested that, in addition to cholinolytic effects of atropine, memantine may prevent and antagonize the acute toxicity of carbofuran by (a) protection of AChE activity and its rapid reactivation from inhibition and (b) rapid elimination of carbofuran.