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

Abstract

Gupta, R.C., and W.L. Kadel: Subacute toxicity of aldicarb: Prevention and treatment with memantine and atropine. Drug Dev. Res. 24:343-353, 1991. Daily administration (i.p.) of aldicarb in male Sprague-Dawley rats at various dosage levels for 21 days revealed 1) 0.1 mg/kg, nontoxic dose: 2) 0.2 mg/kg, moderately toxic dose; and 3) 0.4 mg/kg, severely toxic dose. Inhibition of acetylcholinesterase (AChE) in discrete brain regions and diaphragm muscle was dose dependent. Toxic signs were predominantly peripheral even though AChE inhibition was significantly higher in the brain (except striatum). Besides AChE inhibition, marked inactivation of carboxylesterases (false targets) was observed, suggesting a protective mechanism especially against low dosage by reducing free concentration of aldicarb. After 30 min following the 7th, 14th, or 21st dose of aldicarb, the degree of inhibition of esterase(s) remained the same, and consequently no tolerance developed to aldicarb. On day 21, administration of 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) injection provided complete protection. Therapeutic administration of these antidotes completely reversed the clinical manifestations of intoxication. The present findings indicated that memantine provided protection and reversal of AChE from inhibition in addition to reversible blockage of hyperneuromuscular activity.

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.…”

“…These authors suggested that mAChRs and nAChRs, as well as NMDA receptors, seem to play major roles in anticholinesterase-induced neurotoxicity and that combined treatment with cholinergic and NMDA antagonists might be beneficial in anticholinesterase-induced poisonings (Dekundy et al, 2001(Dekundy et al, , 2003. In similar studies, another NMDA receptor antagonist memantine, in combination with atropine, has been found equally effective against organophosphate and carbamate poisoning (Gupta, 1994;Gupta and Kadel, 1989, 1990, 1991a, 1991bMcLean et al, 1992).…”

“…Chronic exposure to carbamates causes reversible but recurring inhibition of AChE and may induce alterations in metabolic kinetics of the compounds (Tang et al, 2006), which may result in different activity of AChE independent of the dose and frequency of exposure. These factors may explain the reason for inconsistent effects of some carbamates on brain regional AChE activity following chronic exposure, while a carbamate compound like aldicarb produces consistent effect on AChE activity (Gupta and Kadel, 1991b).…”

Prevention and antagonism of acute carbofuran intoxication by memantine and atropine

“…mate compound, carbofuran, produced toxic signs involving central as well as peripheral nervous systems (Gupta and Kadel, 1989a). Memantine in combination with atropine was found equally effective against both classes of organophosphorus compounds Gupta and Kadel, 1989b). There is no single therapeutic agent yet available that can antagonize the toxic effects evoked by overstimulation of both muscarinic and nicotinic receptors.…”

“…1), an amantadme derivative, has recently been reported for the treatment of numerous central nervous system disorders, such as Parkinsonism, coma, and convulsions and seizures induced by organophosphorus compounds (Miltner, 1982;Schneider et al, 1984;Gupta and Kadel, 1989b). In a recent study, Masuo et al (1986) extended these findings to the peripheral nervous system by demonstrating that memantine reversibly blocks neuromuscular transmission.…”