Prevention and antagonism of acute carbofuran intoxication by memantine and atropine

Abstract

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.

Memantine does not influence AChE inhibition in rat brain by donepezil or rivastigmine but does with DFP and metrifonate in in vivo studies

“…These findings are further strengthened by the recent observations with rivastigmine in in vitro and in vivo studies [Enz and Gentsch, 2004]. However, numerous in vivo studies have demonstrated that at higher doses MEM attenuates AChE inhibition against several organophosphate (OP) nerve agents (soman, sarin, tabun, and VX), an OP prototype compound (DFP) and an insecticide (methyl parathion), and carbamate insecticides (carbofuran, aldicarb, oxamyl, and methomyl) [Gupta and Kadel, 1989, 1990, 1991Gupta and Dettbarn, 1992;McLean et al, 1992;Gupta, 1994;Gupta and Goad, 2000]. Both in vitro and in vivo studies [McLean et al, 1992;Stojiljkovic et al, 2002;Antonijevic et al, 2002] further confirmed that MEM pretreatment protects AChE in rat and mice brain against soman-induced AChE inhibition.…”

“…AChE activity was determined in brain region (cortex and hippocampus) homogenates according to the modified method of Hestrin [Gupta and Kadel, 1989;. The enzyme activity was determined and calculated as micromole substrate (ACh iodide) hydrolyzed/g/h and was expressed in terms of percent remaining activity compared to controls (100%).…”

“…Memantine (MEM) is a specific, uncompetitive, voltage-dependent NMDA receptor antagonist with low-to moderate-affinity, strong voltage dependency, and rapid blocking/unblocking receptor kinetics and is effective in moderate to severe cases of dementia Reisberg et al, 2003;Wilcock, 2003]. Numerous data demonstrate that at higher doses, MEM induced attenuation of in vitro/in vivo AChE inhibition by organophosphates and carbamates [Gupta and Kadel, 1989, 1990, 1991Gupta and Dettbarn, 1992;McLean et al, 1992;Gupta, 1994]. In an in vitro study, Wenk et al [2000] found no interaction of MEM with AChE inhibitors, including donepezil, tacrine, and galantamine.…”

Subacute toxicity of aldicarb: Prevention and treatment with memantine and atropine

“…In addition to protection of AChE, MEM also provided protection of CarbE (Fig. 2), which might have facilitated the bioelimination of aldicarb similar to that reported in acute intoxication by carbofuran, methyl parathion, or aldicarb [Gupta and Kadel, 1989b, 1990b.…”

Acetylcholinesterase and Acetylcholine Receptors: Brain Regional Heterogeneity

“…In contrast to the organophosphates, recovery of AChE activity after a carbamate (e.g., carbofuran)-induced inhibition is quite rapid since recovery simply requires the spontaneous hydrolysis of the covalent bond between the methyl carbamyl moiety and the enzyme (Ferguson et al, 1984;Gupta and Kadel, 1989). This observation is also true for several other carbamate pesticides, including aldicarb, methomyl, and propoxur (Gupta, 1994(Gupta, , 2004Gupta and Kadel, 1990, 1991a, 1991b.…”