Professor of Pharmacology and Cancer Biology
Professor of Neurobiology
Duke University School of Medicine
Durham, NC 27710
Organophosphorus compounds (Ops) induce neurodegenerative disorders. This action is related to their ability to phosphorylate target proteins. Ops have three distinct actions: 1) Cholinergic neurotoxicity resulting from inhibition of acetylcholinesterase (AChE), 2) Organophosphorus ester-Induced Delayed Neurotoxicity (OPIDN), and 3) Organophosphorus ester-Induced Chronic Neurotoxicity (OPICN). Our recent studies using gene expression of rat brain, 15 min and 3 months after exposure to sarin, elucidated the sarin-induced neurotoxicity. A lethal dose of sarin caused up-regulation of nicotinic, muscarinic, GABAnergic and glutamergic receptors, consistent with the activation of glutamate receptors leading to the release of l-glutamate amino acid and activation of NMDA receptor resulting in massive Ca2+ influx and neuronal cell death. Calcium calmodulin kinase II was up-regulated in brain regions that are sensitive to OPIDN. This enzyme that is involved with glutamate receptors in the process of learning and memory is activated by Ca2+ influx through NMDA receptors resulting in mitochondrial dysfunction and free radical formation, followed by caspase activation and apoptotic cell death.
Abdel-Rahman, A.A., Shetty, A.K. , and Abou-Donia, M.B. (2002) Acute exposure to sarin increases blood brain barrier permeability and induces neuropathological changes in the rat brain: dose-responsed relationship. Neuroscience 113: 721-741.
Abdel-Rahman, A.A. Shetty, A.K. and Abou-Donia, M.B. (2002) Disruption of blood brain barrier and neuronal cell death in cingulated cortex, dentate gyrus, thalamus, and hypothalamus in a rat model of Gulf-War syndrome. Neurobiol. Disease 10: 306-326.
Abou-Donia, M. B. (2003). Organophosphorus ester-induced chronic neurotoxicity. Arch. Environ. Health. 58: 484-497.
Damodaran T.V., Patel, A.G., Greenfield, S.T., Dressman, H.K., Lin, S.A., and Abou-Donia, M.B. (2006) Gene expression profiles in the rat brain both immediately and three months following acute sarin exposure. Biochem. Pharmacol. 71:497-520.
Damadaran, TV, Gupta, RP, Attia, MKM, and Abou-Donia, MB (2009) Involvement of Protein Kinase A (PKA)/Phosphorylated CREP (p-CREP) Pathway in the Development of Delayed Neurotoxicit (OPIDN) Induced by O,O-diisopropylphosphoro-fluoridate (DFP) in hens. Toxicol Appl Pharmacol 240:132-142.
Damadaran, TV, Attia, MKM, and Abou-Donia, MB (2011) Early differential cell death and survival mechanisms initiate and contribute to the development of OPIDN: A study of molecular, cellular, and anatomical parameters. Toxicol Appl Pharmacol 256(3):348-359.