Age and sex effects on nerve agent damage to the brain and antidotal therapies

Summary

Principal Investigator: Edson X Albuquerque
Abstract: 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.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi Acetylcholinesterase inhibition reveals endogenous nicotinic modulation of glutamate inputs to CA1 stratum radiatum interneurons in hippocampal slices
    Manickavasagom Alkondon
    Division of Translational Toxicology, Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, United States
    Neurotoxicology 36:72-81. 2013
  2. ncbi Galantamine counteracts development of learning impairment in guinea pigs exposed to the organophosphorus poison soman: clinical significance
    Jacek Mamczarz
    Division of Translational Toxicology, Department Epidemiology and Public Health, University of Maryland School of Medicine, 10 S Pine St Suite 900, Baltimore, MD 21210, USA
    Neurotoxicology 32:785-98. 2011
  3. pmc Pretreatment of Guinea pigs with galantamine prevents immediate and delayed effects of soman on inhibitory synaptic transmission in the hippocampus
    Elena A Alexandrova
    Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, 655 W Baltimore St, Baltimore, MD 21201, USA
    J Pharmacol Exp Ther 334:1051-8. 2010
  4. ncbi An acute exposure to a sub-lethal dose of soman triggers anxiety-related behavior in guinea pigs: interactions with acute restraint
    Jacek Mamczarz
    Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    Neurotoxicology 31:77-84. 2010
  5. ncbi Magnetic resonance imaging reveals that galantamine prevents structural brain damage induced by an acute exposure of guinea pigs to soman
    Rao P Gullapalli
    Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
    Neurotoxicology 31:67-76. 2010
  6. pmc Effectiveness of donepezil, rivastigmine, and (+/-)huperzine A in counteracting the acute toxicity of organophosphorus nerve agents: comparison with galantamine
    Yasco Aracava
    Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland, USA
    J Pharmacol Exp Ther 331:1014-24. 2009
  7. ncbi Molecular and cellular actions of galantamine: clinical implications for treatment of organophosphorus poisoning
    Edna F R Pereira
    Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    J Mol Neurosci 40:196-203. 2010
  8. pmc Mammalian nicotinic acetylcholine receptors: from structure to function
    Edson X Albuquerque
    Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD, USA
    Physiol Rev 89:73-120. 2009
  9. pmc Acute toxicity of organophosphorus compounds in guinea pigs is sex- and age-dependent and cannot be solely accounted for by acetylcholinesterase inhibition
    William P Fawcett
    Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    J Pharmacol Exp Ther 328:516-24. 2009
  10. pmc A single in vivo application of cholinesterase inhibitors has neuron type-specific effects on nicotinic receptor activity in guinea pig hippocampus
    Manickavasagom Alkondon
    Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, 655 W Baltimore St, Baltimore, MD 21201, USA
    J Pharmacol Exp Ther 328:69-82. 2009

Scientific Experts

  • Jacek Mamczarz
  • Edna F R Pereira
  • Edson X Albuquerque
  • Yasco Aracava
  • Manickavasagom Alkondon
  • Istvan Merchenthaler
  • Rao P Gullapalli
  • Elena A Alexandrova
  • Miriam Akkerman
  • William P Fawcett
  • Michael Adler
  • Edward Helal Neto
  • Jiachen Zhuo
  • Jiazheng Wang
  • George Makris
  • Scott W Rogers

Detail Information

Publications10

  1. ncbi Acetylcholinesterase inhibition reveals endogenous nicotinic modulation of glutamate inputs to CA1 stratum radiatum interneurons in hippocampal slices
    Manickavasagom Alkondon
    Division of Translational Toxicology, Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, United States
    Neurotoxicology 36:72-81. 2013
    ..These results support the concept that AChE inhibition is able to recruit nAChR-dependent glutamate transmission in the hippocampus and such a mechanism can contribute to the acute neurotoxicological actions of soman...
  2. ncbi Galantamine counteracts development of learning impairment in guinea pigs exposed to the organophosphorus poison soman: clinical significance
    Jacek Mamczarz
    Division of Translational Toxicology, Department Epidemiology and Public Health, University of Maryland School of Medicine, 10 S Pine St Suite 900, Baltimore, MD 21210, USA
    Neurotoxicology 32:785-98. 2011
    ..In conclusion, learning impairment develops months after a single exposure to 1xLD50 soman, and galantamine prevents both the acute toxicity and the delayed cognitive deficits triggered by this OP poison...
  3. pmc Pretreatment of Guinea pigs with galantamine prevents immediate and delayed effects of soman on inhibitory synaptic transmission in the hippocampus
    Elena A Alexandrova
    Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, 655 W Baltimore St, Baltimore, MD 21201, USA
    J Pharmacol Exp Ther 334:1051-8. 2010
    ..Pretreatment with galantamine prevented soman-induced changes in IPSCs. Counteracting the effects of soman on inhibitory transmission can be an important determinant of the antidotal effectiveness of galantamine...
  4. ncbi An acute exposure to a sub-lethal dose of soman triggers anxiety-related behavior in guinea pigs: interactions with acute restraint
    Jacek Mamczarz
    Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    Neurotoxicology 31:77-84. 2010
    ..It is concluded that a single exposure to sub-lethal doses of soman triggers long-lasting anxiogenesis and decreased locomotor activity and that acute restraint stress modifies the magnitude of these effects...
  5. ncbi Magnetic resonance imaging reveals that galantamine prevents structural brain damage induced by an acute exposure of guinea pigs to soman
    Rao P Gullapalli
    Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
    Neurotoxicology 31:67-76. 2010
    ..It is, therefore, concluded that galantamine can effectively prevent the structural brain damage induced by an acute exposure to soman...
  6. pmc Effectiveness of donepezil, rivastigmine, and (+/-)huperzine A in counteracting the acute toxicity of organophosphorus nerve agents: comparison with galantamine
    Yasco Aracava
    Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland, USA
    J Pharmacol Exp Ther 331:1014-24. 2009
    ..6 or 0.7 x LD(50) soman. Thus, galantamine emerges as a superior antidotal therapy against the toxicity of soman...
  7. ncbi Molecular and cellular actions of galantamine: clinical implications for treatment of organophosphorus poisoning
    Edna F R Pereira
    Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    J Mol Neurosci 40:196-203. 2010
    ..The results presented herein corroborate that galantamine is an effective antidote against OP poisoning...
  8. pmc Mammalian nicotinic acetylcholine receptors: from structure to function
    Edson X Albuquerque
    Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD, USA
    Physiol Rev 89:73-120. 2009
    ..Despite these numerous developments, our understanding of the contributions of specific neuronal nAChR subtypes to the many facets of physiology throughout the body remains in its infancy...
  9. pmc Acute toxicity of organophosphorus compounds in guinea pigs is sex- and age-dependent and cannot be solely accounted for by acetylcholinesterase inhibition
    William P Fawcett
    Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    J Pharmacol Exp Ther 328:516-24. 2009
    ..They also support the contention that mechanisms other than AChE inhibition contribute to the lethality of nerve agents...
  10. pmc A single in vivo application of cholinesterase inhibitors has neuron type-specific effects on nicotinic receptor activity in guinea pig hippocampus
    Manickavasagom Alkondon
    Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, 655 W Baltimore St, Baltimore, MD 21201, USA
    J Pharmacol Exp Ther 328:69-82. 2009
    ..The neuron type-specific changes in nAChR activity induced by soman, some of which could be prevented by galantamine, may contribute to the maintenance of pathological rhythms in the hippocampal neuronal network...