NIH Countermeasures Against Chemical Threats (CounterACT) Research Network

Individual Research Project: Age and Sex Effects on Nerve Agent Damage to the Brain and Antidotal Therapies [U01 NS059344-01]

P.I. Edson X. Albuquerque, M.D., Ph.D.

Background

Intoxication with organophosphorus compounds (OPs), which are largely used as insecticides and chemical warfare agents, is a major health concern worldwide. Based on the concept that OP toxicity results primarily from heightened cholinergic activity due to the irreversible cholinesterase (ChE) inhibition, prophylaxis consists of the use of pyridostigmine, a reversible ChE inhibitor, and atropine, a muscarinic receptor antagonist. Because pyridostigmine crosses the blood-brain barrier very poorly, additional treatment with benzodiazepines is necessary to halt the convulsions that arise from the OPs' actions in the brain.

Approach

We have shown that galantamine, a drug used to treat patients with mild-to-moderate Alzheimer's disease and that acts as both a ChE inhibitor and a nicotinic allosteric potentiating ligand (APL), is an effective prophylactic treatment for OP intoxication. Peripubertal male guinea pigs pre-treated with galantamine and subsequently challenged with sarin or soman survive indefinitely without any signs of toxicity. In this study we are using a multidisciplinary approach to determine whether galantamine, with or without the muscarinic antagonist atropine, can counteract the immediate (up to 24 h) and delayed (7 to 30 days) toxicity of nerve agents in guinea pigs of both sexes at different ages.

Nicotinic Ligands in Ancient History 

Nicotine was detected in hair, soft tissue, and bone tissue samples from Egyptian mummies dated between 1070 BC and 395 AD at quantities similar to those found in modern addicts (Balabanova et al., 1992). In Homer's epic poem, the Odyssey, Hermes counseled Odysseus to use "moly" to save his crew from Circe's poison. Circe's poison could have been scopolamine, which is found in the extracts from the plant Datura stramonium. The antidote may well have been an extract of the common snowdrop (Galanthus nivalis, right), which contains galantamine.

Significance

Galantamine has the potential to afford complete protection of U.S. forces and the general population against the toxic effects of OPs. In the battlefield, timely provision of efficient countermeasures to prevent and/or treat intoxication with nerve agents is essential to preserve and sustain combat effectiveness of the soldiers.

Investigators

• Dr. Edson X. Albuquerque, P.I., Research Coordinator, Electrophysiology, Animal treatments and followup

• Dr. Yasco Aracava, Animal treatments and followup, Electrophysiology

• Dr. Michael Adler, Muscle studies

• Dr. Sergei Karnup, Electrophysiology

• Dr. Istvan Merchenthaler, Histological studies

• Dr. Edna Pereira, Data management and analysis, western blots, 2-D gels, Electrophysiology

• Dr. Rao Gullapalli, MRI studies

• Dr. William Fawcett, Biochemical studies

Research Results

• Galantamine is an effective medical countermeasure against nerve agent and OP insecticide poisoning in peripubertal male guinea pigs.

• Continuing research in this area is revealing that female guinea pigs are more sensitive than male guinea pigs to the toxicity of nerve agents and that the treatment with galantamine is as efficacious in female as it is in male guinea pigs.

• Treatment with galantamine counteracts the neuronal damage and the impairment in synaptic transmission and plasticity induced by OPs.

• The effectiveness of galantamine has been attributed in part to its differential inhibitory effect in brain and blood AChE, its selectivity to AChE compared to BuChE, its competitive antagonism of KYNA (whose levels in the brain are increased by OPs), and its ability to activate cell survival pathways.

• The use of galantamine as an antidote against OP poisoning is protected under the International Patent Application PCT/US05/33789 filed on 9/23/05, and the patent is currently being licensed by UMB.

Publications

• Albuquerque EX, Pereira EF, Aracava Y, Fawcett WP, Oliveira M, Randall WR, Hamilton TA, Kan RK, Romano JA Jr, Adler M.  Effective countermeasure against poisoning by organophosphorus insecticides and nerve agents. Proc Natl Acad Sci U S A. 2006 Aug 29;103(35):13220-5.

• See Also -- Comment on above article by Kenneth Kellar, Department of Pharmacology, Georgetown University School of Medicine, Washington, DC 20057, USA. Proc Natl Acad Sci U S A. 2006 Sep 5;103(36):13263-4.

 Abstracts

• Aracava Y, Pereira EFR, Fawcett WP, Oliveira M, Randall WR, Hamilton T, Kan RK, Adler M, Romano Jr. JA, Albuquerque EX An effective countermeasure against poisoning by organophosphorus insecticides and nerve agents. 2006 Annual Meeting of the Society for Neuroscience, Atlanta, GA.

• Merchenthaler I, Aracava Y, Puskar A, Pereira EFR, Albuquerque EX Galantamine prevents organophosphorus-induced cell death in the guinea pig telencephalon. 2007 Annual Meeting of the Society for Neuroscience, San Diego, CA.

• Alkondon M, Pereira EFR, Albuquerque EX Functional alpha7 nicotinic acetylcholine receptors are present in CA1 stratum radiatum interneurons in the hippocampus of guinea pigs. 2007 Annual Meeting of the Society for Neuroscience, San Diego, CA.

• Gullapalli R, Aracava Y, Helal-Neto E, Makris G, Zhuo J, Pereira EF, Albuquerque, EX Magnetic resonance imaging (MRI) reveals that galantamine effectively prevents morphological changes in the brain of guinea pigs challenged with lethal doses of soman. 2007 Annual Meeting of the Society for Neuroscience, San Diego, CA.

• Alexandrova E, Randall WR, Aracava Y, Pereira EFR, Albuquerque EX Effects of galantamine on spontaneous inhibitory and excitatory postsynaptic currents in hippocampal CA1 pyramidal cells of guinea pigs challenged with soman. 2007 Annual Meeting of the Society for Neuroscience, San Diego, CA.

• Karnup SV, Nagode EA, Aracava Y, Pereira EFR, Albuquerque EX Effects of antidotal galantamine dose on synaptic transmission in hippocampus and basolateral amygdala. 2007 Annual Meeting of the Society for Neuroscience, San Diego, CA.