Long-term behavioral consequences of soman poisoning in mice

Filliat, Pierre; Coubard, Stéphanie; Piérard, Christophe; Liscia, Pierrette; Béracochéa, Daniel; Four, Elise; Baubichon, Dominique; Masqueliez, Catherine; Lallement, G.; Collombet, Jean-Marc

doi:10.1016/j.neuro.2006.11.004

Cited by 57 publications

(50 citation statements)

References 27 publications

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“…Other studies reported that rats and mice that developed severe signs of acute toxicity, including convulsions, following a single subcutaneous exposure to 1.0-1.2Â LD 50 soman, showed immediate and delayed cognitive impairments in the Morris water maze (Filliat et al, 1999;Raveh et al, 2002). Of particular interest is a report that in asymptomatic, soman-challenged mice cognitive deficits could be detected at 3 months, but not 1 month following the challenge (Filliat et al, 2007). Guinea pigs, too, develop cognitive deficits long after their exposure to soman (Mamczarz et al, 2011;Pereira et al, 2012).…”

Section: Animal Models Of Op Intoxicationmentioning

confidence: 99%

Animal Models That Best Reproduce the Clinical Manifestations of Human Intoxication with Organophosphorus Compounds

Pereira

Aracava

DeTolla

et al. 2014

J Pharmacol Exp Ther

104

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The translational capacity of data generated in preclinical toxicological studies is contingent upon several factors, including the appropriateness of the animal model. The primary objectives of this article are: 1) to analyze the natural history of acute and delayed signs and symptoms that develop following an acute exposure of humans to organophosphorus (OP) compounds, with an emphasis on nerve agents; 2) to identify animal models of the clinical manifestations of human exposure to OPs; and 3) to review the mechanisms that contribute to the immediate and delayed OP neurotoxicity. As discussed in this study, clinical manifestations of an acute exposure of humans to OP compounds can be faithfully reproduced in rodents and nonhuman primates. These manifestations include an acute cholinergic crisis in addition to signs of neurotoxicity that develop long after the OP exposure, particularly chronic neurologic deficits consisting of anxiety-related behavior and cognitive deficits, structural brain damage, and increased slow electroencephalographic frequencies. Because guinea pigs and nonhuman primates, like humans, have low levels of circulating carboxylesterases-the enzymes that metabolize and inactivate OP compounds-they stand out as appropriate animal models for studies of OP intoxication. These are critical points for the development of safe and effective therapeutic interventions against OP poisoning because approval of such therapies by the Food and Drug Administration is likely to rely on the Animal Efficacy Rule, which allows exclusive use of animal data as evidence of the effectiveness of a drug against pathologic conditions that cannot be ethically or feasibly tested in humans.

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Section: Animal Models Of Op Intoxicationmentioning

confidence: 99%

Animal Models That Best Reproduce the Clinical Manifestations of Human Intoxication with Organophosphorus Compounds

Pereira

Aracava

DeTolla

et al. 2014

J Pharmacol Exp Ther

104

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“…If immediate death is prevented by adequate control of the peripheral symptoms, but SE is not controlled effectively, lives may still be lost from the prolonged SE, or severe brain damage can ensue with long-term behavioral consequences. The lasting behavioral deficits that follow nerve agent exposure are well known from experimental studies in animals (Filliat et al, 2007;Coubard et al, 2008;Langston et al, 2012;Prager et al, 2014) as well as from studies in the victims of the sarin attacks in Japan, who present neurologic and neuropsychiatric disturbances years after the exposure (Ohtani et al, 2004;Yanagisawa et al, 2006;Hoffman et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

The Limitations of Diazepam as a Treatment for Nerve Agent–Induced Seizures and Neuropathology in Rats: Comparison with UBP302

Apland

Aroniadou‐Anderjaska

Figueiredo

et al. 2014

J Pharmacol Exp Ther

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Exposure to nerve agents induces prolonged status epilepticus (SE), causing brain damage or death. Diazepam (DZP) is the current US Food and Drug Administration-approved drug for the cessation of nerve agent-induced SE. Here, we compared the efficacy of DZP with that of UBP302 [(S)-3-(2-carboxybenzyl) willardiine; an antagonist of the kainate receptors that contain the GluK1 subunit] against seizures, neuropathology, and behavioral deficits induced by soman in rats. DZP, administered 1 hour or 2 hours postexposure, terminated the SE, but seizures returned; thus, the total duration of SE within 24 hours after soman exposure was similar to (DZP at 1 hour) or longer than (DZP at 2 hours) that in the soman-exposed rats that did not receive the anticonvulsant. Compared with DZP, UBP302 stopped SE with a slower time course, but dramatically reduced the total duration of SE within 24 hours. Neuropathology and behavior were assessed in the groups that received anticonvulsant treatment 1 hour after exposure. UBP302, but not DZP, reduced neuronal degeneration in a number of brain regions, as well as neuronal loss in the basolateral amygdala and the CA1 hippocampal area, and prevented interneuronal loss in the basolateral amygdala. Anxiety-like behavior was assessed in the open field and by the acoustic startle response 30 days after soman exposure. The results showed that anxiety-like behavior was increased in the DZP-treated group and in the group that did not receive anticonvulsant treatment, but not in the UBP302-treated group. The results argue against the use of DZP for the treatment of nerve agent-induced seizures and brain damage and suggest that targeting GluK1-containing receptors is a more effective approach.

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“…The underlying mechanism of OP-induced toxicity is accumulation of synaptic acetylcholine due to the irreversible inhibition of acetylcholinesterase (AChE), leading to excitotoxic neuronal cell death Lallement et al 1991Lallement et al , 1998McDonough and Shih 1997;Raveh et al 1999;Solberg and Belkin 1997). Some data indicate that the neurodegenerative process in the piriform cortex, amygdala and hippocampus underlie the pathophysiology of the cognitive deficits (Filliat et al 1999(Filliat et al , 2007. However, increasing evidence suggests that neurogenesis may also be a contributory factor to nerve agent-induced long-term cognitive and behavioral disorders as impaired adult neurogenesis in rodents has been shown to be associated with defective spatial and contextual memory (Collombet et al 2005;Gheusi et al 2000;Joosen et al 2009;Pan et al 2012b;Saxe et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Alpha-Linolenic Acid-Induced Increase in Neurogenesis is a Key Factor in the Improvement in the Passive Avoidance Task After Soman Exposure

Piermartiri

Pan

McDonough³

et al. 2015

Neuromol Med

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Exposure to organophosphorous (OP) nerve agents such as soman inhibits the critical enzyme acetylcholinesterase (AChE) leading to excessive acetylcholine accumulation in synapses, resulting in cholinergic crisis, status epilepticus and brain damage in survivors. The hippocampus is profoundly damaged after soman exposure leading to long-term memory deficits. We have previously shown that treatment with three sequential doses of alpha-linolenic acid, an essential omega-3 polyunsaturated fatty acid, increases brain plasticity in naïve animals. However, the effects of this dosing schedule administered after a brain insult and the underlying molecular mechanisms in the hippocampus are unknown. We now show that injection of three sequential doses of alpha-linolenic acid after soman exposure increases the endogenous expression of mature BDNF, activates Akt and the mammalian target of rapamycin complex 1 (mTORC1), increases neurogenesis in the subgranular zone of the dentate gyrus, increases retention latency in the passive avoidance task and increases animal survival. In sharp contrast, while soman exposure also increases mature BDNF, this increase did not activate downstream signaling pathways or neurogenesis. Administration of the inhibitor of mTORC1, rapamycin, blocked the alpha-linolenic acid-induced neurogenesis and the enhanced retention latency but did not affect animal survival. Our results suggest that alpha-linolenic acid induces a long-lasting neurorestorative effect that involves activation of mTORC1 possibly via a BDNF-TrkB-mediated mechanism.

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Long-term behavioral consequences of soman poisoning in mice

Cited by 57 publications

References 27 publications

Animal Models That Best Reproduce the Clinical Manifestations of Human Intoxication with Organophosphorus Compounds

Animal Models That Best Reproduce the Clinical Manifestations of Human Intoxication with Organophosphorus Compounds

The Limitations of Diazepam as a Treatment for Nerve Agent–Induced Seizures and Neuropathology in Rats: Comparison with UBP302

Alpha-Linolenic Acid-Induced Increase in Neurogenesis is a Key Factor in the Improvement in the Passive Avoidance Task After Soman Exposure

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