Age-Related Susceptibility to Epileptogenesis and Neuronal Loss in Male Fischer Rats Exposed to Soman and Treated With Medical Countermeasures

Overview

Journal Toxicol Sci

Publisher Oxford University Press

Specialty Toxicology

Date 2018 Mar 30

PMID 29596688

Citations 8

Authors

Brenda Marrero-Rosado

Franco Rossetti

Matthew W Rice

Mark C Moffett

Robyn B Lee

Michael F Stone

Lucille A Lumley

Affiliations

Soon will be listed here.

Abstract

Elderly individuals compose a large percentage of the world population; however, few studies have addressed the efficacy of current medical countermeasures (MCMs) against the effects of chemical warfare nerve agent exposure in aged populations. We evaluated the efficacy of the anticonvulsant diazepam in an old adult rat model of soman (GD) poisoning and compared the toxic effects to those observed in young adult rats when anticonvulsant treatment is delayed. After determining their respective median lethal dose (LD50) of GD, we exposed young adult and old adult rats to an equitoxic 1.2 LD50 dose of GD followed by treatment with atropine sulfate and the oxime HI-6 at 1 min after exposure, and diazepam at 30 min after seizure onset. Old adult rats that presented with status epilepticus were more susceptible to developing spontaneous recurrent seizures (SRSs). Neuropathological analysis revealed that in rats of both age groups that developed SRS, there was a significant reduction in the density of mature neurons in the piriform cortex, thalamus, and amygdala, with more pronounced neuronal loss in the thalamus of old adult rats compared with young adult rats. Furthermore, old adult rats displayed a reduced density of cells expressing glutamic acid decarboxylase 67, a marker of GABAergic interneurons, in the basolateral amygdala and piriform cortex, and a reduction of astrocyte activation in the piriform cortex. Our observations demonstrate the reduced effectiveness of current MCM in an old adult animal model of GD exposure and strongly suggest the need for countermeasures that are more tailored to the vulnerabilities of an aging population.

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References

Nissinen J, Lukasiuk K, Pitkanen A . Is mossy fiber sprouting present at the time of the first spontaneous seizures in rat experimental temporal lobe epilepsy?. Hippocampus. 2002; 11(3):299-310. DOI: 10.1002/hipo.1044. View

Schultz M, Wright L, Stone M, Schwartz J, Kelley N, Moffett M . The anticholinergic and antiglutamatergic drug caramiphen reduces seizure duration in soman-exposed rats: synergism with the benzodiazepine diazepam. Toxicol Appl Pharmacol. 2012; 259(3):376-86. DOI: 10.1016/j.taap.2012.01.017. View

Almeida-Suhett C, Prager E, Pidoplichko V, Figueiredo T, Marini A, Li Z . GABAergic interneuronal loss and reduced inhibitory synaptic transmission in the hippocampal CA1 region after mild traumatic brain injury. Exp Neurol. 2015; 273:11-23. DOI: 10.1016/j.expneurol.2015.07.028. View

Zimmer L, Ennis M, Shipley M . Soman-induced seizures rapidly activate astrocytes and microglia in discrete brain regions. J Comp Neurol. 1997; 378(4):482-92. DOI: 10.1002/(sici)1096-9861(19970224)378:4<482::aid-cne4>3.0.co;2-z. View

Aroniadou-Anderjaska V, Figueiredo T, Apland J, Prager E, Pidoplichko V, Miller S . Long-term neuropathological and behavioral impairments after exposure to nerve agents. Ann N Y Acad Sci. 2016; 1374(1):17-28. PMC: 4940270. DOI: 10.1111/nyas.13028. View

Asada H, Kawamura Y, Maruyama K, Kume H, Ding R, Kanbara N . Cleft palate and decreased brain gamma-aminobutyric acid in mice lacking the 67-kDa isoform of glutamic acid decarboxylase. Proc Natl Acad Sci U S A. 1997; 94(12):6496-9. PMC: 21078. DOI: 10.1073/pnas.94.12.6496. View

Li Q, Guo M, Xu X, Xiao X, Xu W, Sun X . Rapid decrease of GAD 67 content before the convulsion induced by hyperbaric oxygen exposure. Neurochem Res. 2007; 33(1):185-93. DOI: 10.1007/s11064-007-9436-4. View

Hsu S, RAINE L, FANGER H . Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem. 1981; 29(4):577-80. DOI: 10.1177/29.4.6166661. View

Goh C, Aw C, Lee J, Chen C, Browne E . Pharmacokinetic and pharmacodynamic properties of cholinesterase inhibitors donepezil, tacrine, and galantamine in aged and young Lister hooded rats. Drug Metab Dispos. 2010; 39(3):402-11. DOI: 10.1124/dmd.110.035964. View

10.

Kumamoto E . Action of an irreversible acetylcholine esterase inhibitor, soman, on muscarinic hyperpolarization in cat bladder parasympathetic ganglia. Br J Pharmacol. 1990; 99(1):157-63. PMC: 1917518. DOI: 10.1111/j.1476-5381.1990.tb14670.x. View

11.

Zilker T . Medical management of incidents with chemical warfare agents. Toxicology. 2005; 214(3):221-31. DOI: 10.1016/j.tox.2005.06.028. View

12.

Petras J . Neurology and neuropathology of Soman-induced brain injury: an overview. J Exp Anal Behav. 1994; 61(2):319-29. PMC: 1334419. DOI: 10.1901/jeab.1994.61-319. View

13.

Vela J, Gutierrez A, Vitorica J, Ruano D . Rat hippocampal GABAergic molecular markers are differentially affected by ageing. J Neurochem. 2003; 85(2):368-77. DOI: 10.1046/j.1471-4159.2003.01681.x. View

14.

Shetty A, Upadhya D . GABA-ergic cell therapy for epilepsy: Advances, limitations and challenges. Neurosci Biobehav Rev. 2016; 62:35-47. PMC: 4869704. DOI: 10.1016/j.neubiorev.2015.12.014. View

15.

Towne A . Epidemiology and outcomes of status epilepticus in the elderly. Int Rev Neurobiol. 2007; 81:111-27. DOI: 10.1016/S0074-7742(06)81007-X. View

16.

Gallagher M, Stocker A, Koh M . Mindspan: lessons from rat models of neurocognitive aging. ILAR J. 2011; 52(1):32-40. PMC: 3199952. DOI: 10.1093/ilar.52.1.32. View

17.

Karanth S, Liu J, Ray A, Pope C . Comparative in vivo effects of parathion on striatal acetylcholine accumulation in adult and aged rats. Toxicology. 2007; 239(3):167-79. DOI: 10.1016/j.tox.2007.07.004. View

18.

Di Maio R, Cannon J, Greenamyre J . Post-status epilepticus treatment with the cannabinoid agonist WIN 55,212-2 prevents chronic epileptic hippocampal damage in rats. Neurobiol Dis. 2014; 73:356-65. DOI: 10.1016/j.nbd.2014.10.018. View

19.

Towne A, Pellock J, Ko D, DeLorenzo R . Determinants of mortality in status epilepticus. Epilepsia. 1994; 35(1):27-34. DOI: 10.1111/j.1528-1157.1994.tb02908.x. View

20.

Niquet J, Baldwin R, Suchomelova L, Lumley L, Naylor D, Eavey R . Benzodiazepine-refractory status epilepticus: pathophysiology and principles of treatment. Ann N Y Acad Sci. 2016; 1378(1):166-173. PMC: 5063678. DOI: 10.1111/nyas.13147. View