The nerve agents soman, sarin and VX are organophosphorus compounds (OPs) chemically related to, but far more toxic than OP insecticides. Most of their acute toxicity results from the irreversible inhibition of acetylcholinesterase (AChE), the enzyme that inactivates the endogenous neurotransmitter acetylcholine. The limitations of available therapies against OP poisoning are well recognized, and more effective antidotes have to be developed. In this project, we will test the central hypothesis that an antidotal therapy composed of galantamine, a drug presently approved for treatment of Alzheimer's disease (AD), with or without the muscarinic antagonist atropine can counteract the immediate and delayed toxicity of nerve agents in guinea pigs of both sexes at different ages. We have evidence that the combination of galantamine and atropine, administered before or after an acute exposure to lethal doses of nerve agents or insecticides, effectively and safely counteracts their toxicity in peripubertal male guinea pigs. Although little is known regarding their neurophysiology, guinea pigs are considered the best non-primate model to predict the effectiveness of antidotes against OP intoxication in humans.
In aim 1, we will determine the age and sex dependencies of the acute toxicity of soman, sarin, and VX, and optimize the antidotal therapy consisting of galantamine, with or without atropine, for male and female guinea pigs at three ages, i.e.neonatal, peripubertal, and adult. The effectiveness of the optimized therapy to prevent immediate and/or delayed toxic effects of the nerve agents will then be examined in neuronal function and brain integrity.
In aim 2, we will investigate the effects of the therapy on the temporal relationship between changes in synaptic function (electrophysiological studies) and alterations in morphometry (non-invasive MRI studies) and neuronal viability (histopathological analysis) in the brains of guinea pigs acutely exposed to nerve agents. In collaboration with USAMRICD researchers, we will further examine the effectiveness of the antidotal therapy to maintain normal diaphragm and cognitive behavior in guinea pigs of both sexes exposed to nerve agents at different ages.
In aim 3, we will derive pharmacokinetic parameters needed for subsequent clinical studies of the safety of the proposed therapy for human use. Still within this aim, we will determine the relevance of galantamine-induced reversible inhibition of AChE in distinct compartments to the effectiveness of the therapy. Particular emphasis will be given to the notion that galantamine, acting as a selective inhibitor of blood AChE, will facilitate the clearance of the nerve agents.
In aim 4, we will determine, at whole animal level, how novel molecular mechanisms contribute to the toxicity of nerve agents and the effectiveness of galantamine/atropine. The results of these studies will be far reaching as they will provide the foundation to expedite the development of safe antidotes to be used by the first responders and the general population in the event of an exposure to nerve agents.
|Pereira, Edna F R; Aracava, Yasco; DeTolla Jr, Louis J et al. (2014) Animal models that best reproduce the clinical manifestations of human intoxication with organophosphorus compounds. J Pharmacol Exp Ther 350:313-21|
|Alexandrova, Elena A; Aracava, Yasco; Pereira, Edna F R et al. (2010) Pretreatment of Guinea pigs with galantamine prevents immediate and delayed effects of soman on inhibitory synaptic transmission in the hippocampus. J Pharmacol Exp Ther 334:1051-8|
|Mamczarz, Jacek; Pereira, Edna F R; Aracava, Yasco et al. (2010) An acute exposure to a sub-lethal dose of soman triggers anxiety-related behavior in guinea pigs: interactions with acute restraint. Neurotoxicology 31:77-84|
|Gullapalli, Rao P; Aracava, Yasco; Zhuo, Jiachen et al. (2010) Magnetic resonance imaging reveals that galantamine prevents structural brain damage induced by an acute exposure of guinea pigs to soman. Neurotoxicology 31:67-76|
|Aracava, Yasco; Pereira, Edna F R; Akkerman, Miriam et al. (2009) Effectiveness of donepezil, rivastigmine, and (+/-)huperzine A in counteracting the acute toxicity of organophosphorus nerve agents: comparison with galantamine. J Pharmacol Exp Ther 331:1014-24|
|Alkondon, Manickavasagom; Aracava, Yasco; Pereira, Edna F R et al. (2009) A single in vivo application of cholinesterase inhibitors has neuron type-specific effects on nicotinic receptor activity in guinea pig hippocampus. J Pharmacol Exp Ther 328:69-82|
|Fawcett, William P; Aracava, Yasco; Adler, Michael et al. (2009) Acute toxicity of organophosphorus compounds in guinea pigs is sex- and age-dependent and cannot be solely accounted for by acetylcholinesterase inhibition. J Pharmacol Exp Ther 328:516-24|
|Albuquerque, Edson X; Pereira, Edna F R; Alkondon, Manickavasagom et al. (2009) Mammalian nicotinic acetylcholine receptors: from structure to function. Physiol Rev 89:73-120|