Novel brain-penetrating oximes for reactivation of cholinesterase inhibited by sarin and VX surrogates
Corresponding Author
Janice E. Chambers
Center for Environmental Health Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi
Address for correspondence: Janice E. Chambers, Center for Environmental Health Sciences, College of Veterinary Medicine, PO Box 6100, Mississippi State University, Mississippi State, MS 39762-6100. [email protected]Search for more papers by this authorEdward C. Meek
Center for Environmental Health Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi
Search for more papers by this authorHoward W. Chambers
Department of Biochemistry, Molecular Biology, Entomology and Plant Pathology, Mississippi State University, Mississippi State, Mississippi
Search for more papers by this authorCorresponding Author
Janice E. Chambers
Center for Environmental Health Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi
Address for correspondence: Janice E. Chambers, Center for Environmental Health Sciences, College of Veterinary Medicine, PO Box 6100, Mississippi State University, Mississippi State, MS 39762-6100. [email protected]Search for more papers by this authorEdward C. Meek
Center for Environmental Health Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi
Search for more papers by this authorHoward W. Chambers
Department of Biochemistry, Molecular Biology, Entomology and Plant Pathology, Mississippi State University, Mississippi State, Mississippi
Search for more papers by this authorAbstract
Current oxime reactivators for organophosphate-inhibited cholinesterase (ChE) do not effectively cross the blood–brain barrier and therefore cannot restore brain ChE activity in vivo. Our laboratories have studied highly relevant sarin and VX surrogates, which differ from their respective nerve agents only in the leaving group and thereby leave ChE phosphylated with the same chemical moiety as sarin and VX. Our laboratories have developed novel substituted phenoxyalkyl pyridinium oximes that lead to reduced ChE inhibition in the brains of rats challenged with a high sublethal dosage of the sarin surrogate, whereas 2-PAM did not, using a paradigm designed to demonstrate brain penetration. In addition, treatment of rats with these novel oximes is associated with attenuation of seizure-like behavior compared to rats treated with 2-PAM, providing additional evidence that the oximes penetrate the blood–brain barrier. Further, some of the oximes provided 24-h survival superior to 2-PAM, and shortened the duration of seizure-like behavior when rats were challenged with lethal dosages of the sarin and VX surrogates, providing additional support for the conclusion that these oximes penetrate the brain.
References
- 1Ecobichon, D.J. 2001. “ Toxic effects of pesticides.” In Casarett and Doull's Toxicology. C.D. Klaassen, Ed.: 763–810. New York: McGraw-Hill.
- 2Taylor, P., Z. Radic, N.A. Hosca, et al. 1995. Structural basis for the specificity of cholinesterase catalysis and inhibition. Toxicol. Lett. 82–83: 453–458.
- 3Tucker, J.B. 2007. War of Nerves: Chemical Warfare from World War I to Al-Qaeda. New York: Pantheon Books.
- 4Johnson, N.H., J.C. Larson & E.C. Meek. 2015. “ Historical perspectives of chemical warfare agents.” In Handbook of Toxicology of Chemical Warfare Agents. R.C. Gupta, Ed.: 7–16. London: Elsevier.
10.1016/B978-0-12-800159-2.00002-6 Google Scholar
- 5Smart, J.K. 1997. “ History of chemical and biological warfare: an American perspective.” In Medical Aspects of Chemical and Biological Warfare, Textbook of Military Medicine. F.R. Sidell, E.T. Takafuji & D.R. Franz, Eds.: 9–86. Washington, DC: Office of the Surgeon General, Bordon Institute.
- 6Aldridge, W.N. & E. Reiner. 1972. Enzyme Inhibitors as Substrates—Interactions of Esterases with Esters of Organophosphorus and Carbamic Acids. Amsterdam, London: North-Holland Publishing Company.
- 7Worek, F., C. Diepold & P. Eyer. 1999. Dimethylphosphoryl-inhibited human cholinesterases: inhibition, reactivation, and aging kinetics. Arch. Toxicol. 73: 7–14.
- 8Shafferman, A., A. Ordentlich, D. Barak, et al. 1996. Aging of phosphylated human acetylcholinesterase: catalytic processes mediated by aromatic and polar residues of the active centre. Biochem. J. 318: 833–840.
- 9Worek, F., H. Thiermann, L. Szinicz, et al. 2004. Kinetic analysis of interactions between human acetylcholinesterase, structurally different organophosphorus compounds and oximes. Biochem. Pharmacol. 68: 2237–2248.
- 10Marrs, T.C., R.L. Maynard & F.R. Sidell. 2007. Chemical Warfare Agents: Toxicology and Treatment. T.C. Marrs, Ed. 191–222. Wiltshire: John Wiley & Sons.
10.1002/9780470060032 Google Scholar
- 11Brown, J.H. & P. Taylor. 2001. “ Muscarinic receptor agonists and antagonists.” In Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. J.G. Hardman, L.E. Limbird & A.G. Gilman, Eds.: 155–173. New York: McGraw-Hill.
- 12Gerald, D.R., Sr. 2002. Organophosphate poisoning. Emerg. Med. Serv. 31: 64–69, 91.
- 13Balali-Mood, M. & M. Shariat. 1998. Treatment of organophosphate poisoning. Experience of nerve agents and acute pesticide poisoning on the effects of oximes. J. Physiol. Paris 92: 375–378.
- 14Mercey, G., T. Verdelet, J. Renou, et al. 2012. Reactivators of acetylcholinesterase inhibited by organophosphorus nerve agents. Acc. Chem. Res. 45: 756–766.
- 15Worek, F. & H. Thiermann. 2013. The value of novel oximes for treatment of poisoning by organophosphorus compounds. Pharmacol. Ther. 139: 249–259.
- 16Kassa, J. 2002. Review of oximes in the antidotal treatment of poisoning by organophosphorus nerve agents. J. Toxicol. Clin. Toxicol. 40: 803–816.
- 17Worek, F., L. Szinicz, P. Eyer, et al. 2005. Evaluation of oxime efficacy in nerve agent poisoning: development of a kinetic-based dynamic model. Toxicol. Appl. Pharmacol. 209: 193–202.
- 18Shih, T.M., J.W. Skovira, J.C. O'Donnell, et al. 2010. In vivo reactivation by oximes of inhibited blood, brain and peripheral tissue cholinesterase activity following exposure to nerve agents in guinea pigs. Chem. Biol. Interact. 187: 207–214.
- 19Herkenhoff, S., L. Szinicz, V.K. Rastogi, et al. 2004. Effect of organophosphorus hydrolyzing enzymes on obidoxime induced reactivation of organophosphate-inhibited human acetylcholinesterase. Arch. Toxicol. 78: 338–343.
- 20McDonough, J.H., Jr. & T.M. Shih. 1997. Neuropharmacological mechanisms of nerve agent-induced seizure and neuropathology. Neurosci. Biobehav. Rev. 21: 559–579.
- 21Wilson, I.B. & B. Ginsburg. 1955. A powerful reactivator of alkylphosphate-inhibited acetylcholinesterase. Biochim. Biophys. Acta 18: 168–170.
- 22Clement, J.G. 1979. Efficacy of pro-PAM (N-methyl-1,6-dihydropyridine-2-carbaldoxime hydrochloride) as a prophylaxis against organophosphate poisoning. Toxicol. Appl. Pharmacol. 47: 305–311.
- 23Sakurada, K., K. Matsubara, K. Shimizu, et al. 2003. Pralidoxime iodide (2-PAM) penetrates across the blood–brain barrier. Neurochem. Res. 28: 1401–1407.
- 24Kenley, R.A., R.A. Howd & E.T. Uyeno. 1982. Effects of PAM, proPAM, and DFP on behavior, thermoregulation, and brain AChE in rats. Pharmacol. Biochem. Behav. 17: 1001–1008.
- 25Shih, T.M., S.M. Duniho & J.H. McDonough. 2003. Control of nerve agent-induced seizures is critical for neuroprotection and survival. Toxicol. Appl. Pharmacol. 188: 69–80.
- 26McDonough, J.H., Jr., N.K. Jaax, R.A. Crowley, et al. 1989. Atropine and/or diazepam therapy protects against soman-induced neural and cardiac pathology. Fundam. Appl. Toxicol. 13: 256–276.
- 27McDonough, J.H., Jr., L.D. Zoeffel, J. McMonagle, et al. 2000. Anticonvulsant treatment of nerve agent seizures: anticholinergics versus diazepam in soman-intoxicated guinea pigs. Epilepsy Res. 38: 1–14.
- 28Gilat, E., T. Kadar, A. Levy, et al. 2005. Anticonvulsant treatment of sarin-induced seizures with nasal midazolam: an electrographic, behavioral, and histological study in freely moving rats. Toxicol. Appl. Pharmacol. 209: 74–85.
- 29Chambers, J.E., H.W. Chambers & E.C. Meek, et al. 2013. Testing of novel brain-penetrating oxime reactivators of acetylcholinesterase inhibited by nerve agent surrogates. Chem. Biol. Interact. 203: 135–138.
- 30Skovira, J.W., J.C. O'Donnell, I. Koplovitz, et al. 2010. Reactivation of brain acetylcholinesterase by monoisonitrosoacetone increases the therapeutic efficacy against nerve agents in guinea pigs. Chem. Biol. Interact. 187: 318–324.
- 31Shih, T.M., J.W. Skovira, J.C. O'Donnell, et al. 2010. Treatment with tertiary oximes prevents seizures and improves survival following sarin intoxication. J. Mol. Neurosci. 40: 63–69.
- 32Kalisiak, J., E.C. Ralph & J.R. Cashman. 2012. Nonquaternary reactivators for organophosphate-inhibited cholinesterases. J. Med. Chem. 55: 465–474.
- 33Radic, Z., R.K. Sit, Z. Kovarik, et al. 2012. Refinement of structural leads for centrally acting oxime reactivators of phosphylated cholinesterases. J. Biol. Chem. 287: 11798–11809.
- 34Meek, E., H. Chambers, A. Coban, et al. 2012. Synthesis and in vitro and in vivo inhibition potencies of highly relevant nerve agent surrogates. Toxicol. Sci. 126: 525–533.
- 35Chambers, J.E., E.C. Meek, J.P. Bennett, et al. 2016. Novel substituted phenoxyalkyl pyridinium oximes enhance survival and attenuate seizure-like behavior of rats receiving lethal levels of nerve agent surrogates. Toxicology 339: 51–57.
- 36Meek, E.C., H.W. Chambers, R.B. Pringle, et al. 2015. The effect of PON1 enhancers on reducing acetylcholinesterase inhibition following organophosphate anticholinesterase exposure in rats. Toxicology 336: 79–83.