Effectiveness of donepezil, rivastigmine, and (+/-)huperzine A in counteracting the acute toxicity of organophosphorus nerve agents: comparison with galantamine.

Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.89). 10/2009; 331(3):1014-24. DOI: 10.1124/jpet.109.160028
Source: PubMed

ABSTRACT Galantamine, a centrally acting cholinesterase (ChE) inhibitor and a nicotinic allosteric potentiating ligand used to treat Alzheimer's disease, is an effective and safe antidote against poisoning with nerve agents, including soman. Here, the effectiveness of galantamine was compared with that of the centrally active ChE inhibitors donepezil, rivastigmine, and (+/-)huperzine A as a pre- and/or post-treatment to counteract the acute toxicity of soman. In the first set of experiments, male prepubertal guinea pigs were treated intramuscularly with one of the test drugs and 30 min later challenged with 1.5 x LD(50) soman (42 microg/kg s.c.). All animals that were pretreated with galantamine (6-8 mg/kg), 3 mg/kg donepezil, 6 mg/kg rivastigmine, or 0.3 mg/kg (+/-)huperzine A survived the soman challenge, provided that they were also post-treated with atropine (10 mg/kg i.m.). However, only galantamine was well tolerated. In subsequent experiments, the effectiveness of specific treatment regimens using 8 mg/kg galantamine, 3 mg/kg donepezil, 6 mg/kg rivastigmine, or 0.3 mg/kg (+/-)huperzine A was compared in guinea pigs challenged with soman. In the absence of atropine, only galantamine worked as an effective and safe pretreatment in animals challenged with 1.0 x LD(50) soman. Galantamine was also the only drug to afford significant protection when given to guinea pigs after 1.0 x LD(50) soman. Finally, all test drugs except galantamine reduced the survival of the animals when administered 1 or 3 h after the challenge with 0.6 or 0.7 x LD(50) soman. Thus, galantamine emerges as a superior antidotal therapy against the toxicity of soman.

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    ABSTRACT: Galantamine, a drug currently approved for treatment of Alzheimer's disease, has recently emerged as an effective pretreatment against the acute toxicity and delayed cognitive deficits induced by organophosphorus (OP) nerve agents, including soman. Since cognitive deficits can result from impaired glutamatergic transmission in the hippocampus, the present study was designed to test the hypothesis that hippocampal glutamatergic transmission declines following an acute exposure to soman and that this effect can be prevented by galantamine. To test this hypothesis, spontaneous excitatory postsynaptic currents (EPSCs) were recorded from CA1 pyramidal neurons in hippocampal slices obtained at 1h, 24 h, or 6-9 days after guinea pigs were injected with: (i) 1xLD50 soman (26.3μg/kg, s.c.); (ii) galantamine (8mg/kg, i.m.) followed 30min later by 1xLD50 soman, (iii) galantamine (8mg/kg, i.m.), or (iv) saline (0.5ml/kg, i.m.). In soman-injected guinea pigs that were not pretreated with galantamine, the frequency of EPSCs was significantly lower than that recorded from saline-injected animals. There was no correlation between the severity of soman-induced acute toxicity and the magnitude of soman-induced reduction of EPSC frequency. Pretreatment with galantamine prevented the reduction of EPSC frequency observed at 6-9 days after the soman challenge. Prevention of soman-induced long-lasting reduction of hippocampal glutamatergic synaptic transmission may be an important determinant of the ability of galantamine to counter cognitive deficits that develop long after an acute exposure to the nerve agent.
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    ABSTRACT: The toxicity of organophosphorus compounds (OPs) results primarily from the irreversible inhibition of acetylcholinesterase (AChE). Huperzine A (HupA) is a reversible inhibitor of AChE and HupA sustained-release microspheres (HSMs) steadily release HupA, resulting in the continual inhibition of AChE activity for 14 days in mice. The present study aimed to investigate the preventive effects of HSMs on the toxicity of methyl parathion (MP). The mice were pretreated with HSMs followed by MP exposure. Subsequently, the median lethal dose (LD50) and survival of the mice were determined. A histopathological examination of the brain, liver, lungs, heart, kidneys and intercostal muscles was also performed. The results revealed that the LD50 was 51.4 mg/kg in the control group and 70.0, 67.5, 63.4 and 53.5 mg/kg at 2 h, 5, 10 and 15 days after pretreatment with HSMs, respectively. Pretreatment with HSMs at 2 h, 5 days and 10 days prior to an acute challenge with 1.2 × LD50 MP was sufficient to counteract the lethality and acute toxicity of MP. HSM pretreatment also attenuated the pulmonary edema induced by MP. The results demonstrated that pretreatment with HSMs may be an effective method to counteract MP poisoning. To the best of our knowledge, the present study was the first to demonstrate that pretreatment with an AChE reversible inhibitor sustained-release agent may be a novel approach to effective protection against OP toxicity.
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