Control of Nerve Agent-Induced Seizures is Critical for Neuroprotection and Survival

Shih, Tsung‐Ming; Duniho, Steven; McDonough, John H.

doi:10.21236/ada417799

Cited by 103 publications

(221 citation statements)

References 37 publications

Supporting

Mentioning

200

Contrasting

Unclassified

Order By: Relevance

“…This finding confirmed the report of Atchison et al (2004) that in guinea pigs dosed once daily for 2 weeks (using the same exposure protocol as the current study) the MTD was 0.4 x LD 50 for sarin. The fact that we found no pathological evidence in any of the animals that received all 10 sarin (0.3, 0.4 or 0.5 x LD 50 ) injections (cumulative doses of 3, 4 and 5 x LD 50 , respectively) indirectly supports prior studies showing that nerve agent-induced brain pathology is due to seizures (McDonough et al, 1989(McDonough et al, , 1995Shih et al, 2003) and not total dose of nerve agent.…”

Section: Discussionsupporting

confidence: 85%

“…The buildup of ACh in response to a large exposure to nerve agents can lead, unless promptly treated, to muscle weakness, increased secretions (i.e., lacrimation, rhinorrhea, salivation), convulsions and seizures, respiratory depression, coma and death (Taylor, 1996). The progression of signs, their neuropharmacological basis, and toxic consequence elicited from acute high-dose exposures has been well characterized Shih, 1993, 1997;Shih et al, 2003). However, much less is known about the long-term effects of repeated low-dose CWNA exposure.…”

Section: Introductionmentioning

confidence: 99%

“…Ongoing medical research and development of antidotes against the toxic effects of CWNAs in our laboratory has been focused on the guinea pig animal model (Atchison et al, 2004;Shih et al, 2003). Guinea pigs are considered a more valid rodent model for studying the toxicological effects of nerve agents and for predicting the efficacy of treatment for CWNA poisoning in primate species than are mice or rats (Inns and Leadbeater, 1983).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The effects of repeated low-dose sarin exposure☆

Shih¹,

Hulet²,

McDonough³

2006

Toxicology and Applied Pharmacology

View full text Add to dashboard Cite

Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The effects of repeated low-dose sarin exposure☆

Shih¹,

Hulet²,

McDonough³

2006

Toxicology and Applied Pharmacology

View full text Add to dashboard Cite

“…Seizure control was strongly associated with protection against acute lethality and brain pathology, after exposure of guinea pigs to soman and other nerve agents [41]. It is likely that persistent oxidative stress induced by excessive excitotoxic injury induced by glutamate in seizures could have overwhelmed the antioxidant defenses in the neurons, resulting in cell death.…”

Section: Discussionmentioning

confidence: 99%

Injury and recovery of pyramidal neurons in the rat hippocampus after a single episode of oxidative stress induced by intracerebroventricular injection of ferrous ammonium citrate

et al. 2005

View full text Add to dashboard Cite

-The present study was carried out to elucidate the effect of a single episode of oxidative stress on pyramidal neurons of the rat hippocampus. A significant increase in the number of neurons that were immunolabeled for the toxic lipid peroxidation product, 4-hydroxynonenal (HNE) was observed in field CA3 of the hippocampus, at 1 day, 7 days and 14 days after intracerebroventricular injection of 1 µL of 5mM ferrous ammonium citrate, compared to ammonium citrate injected controls at these time points. The number of HNE positive cells was fewer at 14 days, compared to 1 day, after ferrous ammonium citrate injection. The changes in HNE imunoreactivity were paralleled by changes in cytoplasmic phospholipase A 2 (cPLA 2 ) labeling in the pyramidal neurons in adjacent sections, suggesting that some of the HNE could have arisen as a result of peroxidation of arachidonic acid that was released by cPLA 2 . Interestingly, despite the HNE and cPLA 2 labeling, no loss of neurons was observed in adjacent Nissl and Fluoro-Jade stained sections. Electron microscopy also showed that the HNE or cPLA 2 labeled cells had features of injured neurons, rather than necrotic neurons. The reduction of HNE immunoreactivity in neurons at 14 days after oxidative injury, and the absence of cell loss at any of the time intervals, shows that hippocampal pyramidal neurons have remarkable ability to recover from a single episode of oxidative stress, if repeated injury such as seizures / excitotoxicity could be avoided.iron / neurodegeneration / 4-hydroxynonenal / cytosolic phospholipase A 2 / lipid peroxidation / antioxidant defenses Abbreviations: AP-1: activator protein-1; CA: cornu ammonis; cPLA 2 : cytosolic phospholipase A 2;

show abstract

“…Briefly, galantamine (i) is a reversible AChE inhibitor that crosses the blood-brain barrier (14); (ii) has anticonvulsant properties (15,16); and (iii) prevents neurodegeneration (17)(18)(19), a hallmark of OP poisoning (20). Thus, we used guinea pigs, the best nonprimate model to predict the effectiveness of antidotal therapies for OP poisoning in humans (21), to test the hypothesis that galantamine may be an effective and safe countermeasure against OP intoxication.…”

mentioning

confidence: 99%

Effective countermeasure against poisoning by organophosphorus insecticides and nerve agents

Albuquerque

Pereira

Aracava

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

145

129

View full text Add to dashboard Cite

The nerve agents soman, sarin, VX, and tabun are deadly organophosphorus (OP) compounds chemically related to OP insecticides. Most of their acute toxicity results from the irreversible inhibition of acetylcholinesterase (AChE), the enzyme that inactivates the neurotransmitter acetylcholine. The limitations of available therapies against OP poisoning are well recognized, and more effective antidotes are needed. Here, we demonstrate that galantamine, a reversible and centrally acting AChE inhibitor approved for treatment of mild to moderate Alzheimer's disease, protects guinea pigs from the acute toxicity of lethal doses of the nerve agents soman and sarin, and of paraoxon, the active metabolite of the insecticide parathion. In combination with atropine, a single dose of galantamine administered before or soon after acute exposure to lethal doses of soman, sarin, or paraoxon effectively and safely counteracted their toxicity. Doses of galantamine needed to protect guinea pigs fully against the lethality of OPs were well tolerated. In preventing the lethality of nerve agents, galantamine was far more effective than pyridostigmine, a peripherally acting AChE inhibitor, and it was less toxic than huperzine, a centrally acting AChE inhibitor. Thus, a galantamine-based therapy emerges as an effective and safe countermeasure against OP poisoning.galantamine ͉ guinea pig ͉ pyridostigmine ͉ soman ͉ sarin T he organophosphorus (OP) compounds soman, sarin, VX, and tabun, referred to as nerve agents, are among the most lethal chemical weapons ever developed (1). Some of them were used with catastrophic results in wars and also in terrorist attacks in Japan in the 1990s (2). The majority of insecticides are also OPs, and intoxication with these compounds represents a major public-health concern worldwide (3, 4). The possibility of further terrorist attacks with nerve agents and the escalating use of OP insecticides underscore the urgent need to develop effective and safe antidotes against OP poisoning.The acute toxicity of OPs results primarily from their action as irreversible inhibitors of acetylcholinesterase (AChE) (5). In the periphery, acetylcholine accumulation leads to persistent muscarinic receptor stimulation that triggers a syndrome whose symptoms include miosis, profuse secretions, bradycardia, bronchoconstriction, hypotension, and diarrhea. It also leads to overstimulation followed by desensitization of nicotinic receptors, causing severe skeletal muscle fasciculations and subsequent weakness. Central nervous system-related effects include anxiety, restlessness, confusion, ataxia, tremors, seizures, cardiorespiratory paralysis, and coma.Current therapeutic strategies to decrease OP toxicity include atropine to reduce the muscarinic syndrome, oximes to reactivate OP-inhibited AChE, and benzodiazepines to control OPtriggered seizures (5). The limitations of these treatments are well recognized (4), and alternative therapies have been sought. Among these therapies are phosphotriesterases and butyrylcholinesterase (...

show abstract

Control of Nerve Agent-Induced Seizures is Critical for Neuroprotection and Survival

Cited by 103 publications

References 37 publications

The effects of repeated low-dose sarin exposure☆

The effects of repeated low-dose sarin exposure☆

Injury and recovery of pyramidal neurons in the rat hippocampus after a single episode of oxidative stress induced by intracerebroventricular injection of ferrous ammonium citrate

Effective countermeasure against poisoning by organophosphorus insecticides and nerve agents

Contact Info

Product

Resources

About