Complex View on Poisoning with Nerve Agents and Organophosphates

Bajgar, Jiří

doi:10.14712/18059694.2018.23

Cited by 59 publications

(50 citation statements)

References 100 publications

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“…)], an acetylcholinesterase reactivator that restores activity in molecules that have not undergone aging (Bajgar 2005;Shih et al 2010) followed by soman [180 lg/ kg, subcutaneously (s.c.), 1.6 9 LD 50 ] 30 min later. This dose of soman was chosen because it reproducibly elicits seizures in 100 % of the animals tested (Pan et al 2012a).…”

Section: Drug Treatmentsmentioning

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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Section: Drug Treatmentsmentioning

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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“…Nerve agents act by irreversibly inhibiting acetylcholinesterase (AChE) activity (Bajgar, 2005; Collombet et al, 2011; Prager et al, 2013). Without pharmacological intervention after nerve agent exposure, death may ensue due to the peripheral cholinergic crisis, and/or to intense seizure activity (status epilepticus, SE).…”

Section: 0 Introductionmentioning

confidence: 99%

LY293558 prevents soman-induced pathophysiological alterations in the basolateral amygdala and the development of anxiety

et al. 2015

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Without timely pharmacological treatment, nerve agent exposure can cause a large number of casualties, as occurred in the recent sarin attack in Syria. Nerve agent-induced seizures are initiated due to inhibition of acetylcholinesterase, but they become quickly refractory to muscarinic antagonists, and their suppression by benzodiazepines can be only temporary. Therefore, novel treatments are necessary to stop seizures and prevent brain damage and the resulting long-term behavioral deficits. We have previously shown that LY293558, a GluK1/AMPA receptor antagonist, is a very effective anticonvulsant and neuroprotectant against nerve agent exposure. In the present study, we examined whether the protection against nerve agent-induced seizures and neuropathology conferred by LY293558 translates into protection against pathophysiological alterations in the basolateral amygdala (BLA) and the development of anxiety, which is the most prevalent behavioral deficit resulting from exposure. LY293558 (15 mg/kg) was administered to rats along with atropine and the oxime HI-6, at 20 min after exposure to soman (1.2 x LD50). At 24 h, 7 days, and 30 days after exposure, soman-exposed rats that did not receive LY293558 had reduced but prolonged evoked field potentials in the BLA, as well as increased paired-pulse ratio, suggesting neuronal damage and impaired synaptic inhibition. In contrast, soman-exposed rats that received LY293558 did not differ from controls in these parameters. Similarly, long-term potentiation of synaptic transmission was impaired at 7 days after exposure in the soman-exposed rats that did not receive anticonvulsant treatment, while this impairment was not present in the LY293558-treated rats. Anxiety-like behavior assessed by the open field and acoustic startle response tests was increased in the soman-exposed rats at 30 and 90 days after exposure, while soman-exposed rats treated with LY293558 did not differ from controls. Along with our previous findings, the present data demonstrate the remarkable efficacy of LY293558 in counteracting nerve agent-induced seizures, neuropathology, pathophysiological alterations in the BLA, and anxiety-related behavioral deficits.

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“…In today’s global political climate, nerve agents are a major threat, both in military operations and against civilians, because they are relatively simple to produce, transport, and deploy. The most well known nerve agents are soman, sarin, cyclosarin, tabun, and VX (Bajgar, 2005; Barthold and Schier, 2005; Layish et al, 2005). They are organophosphorus compounds, and their primary action is the irreversible inhibition of acetylcholinesterase (AChE), which results in accumulation of acetylcholine at cholinergic synapses; a cholinergic crisis follows due to overstimulation of muscarinic and nicotinic receptors in the central and peripheral nervous system, including the neuromuscular junction (Bajgar, 2005; Barthold and Schier, 2005; Layish et al, 2005, Schecter, 2004).…”

mentioning

confidence: 99%

Primary brain targets of nerve agents: The role of the amygdala in comparison to the hippocampus

et al. 2009

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Exposure to nerve agents and other organophosphorus acetylcholinesterases used in industry and agriculture can cause death, or brain damage, producing long-term cognitive and behavioral deficits. Brain damage is primarily caused by the intense seizure activity induced by these agents. Identifying the brain regions that respond most intensely to nerve agents, in terms of generating and spreading seizure activity, along with knowledge of the physiology and biochemistry of these regions, can facilitate the development of pharmacological treatments that will effectively control seizures even if administered when seizures are well underway. Here, we contrast the pathological (neuronal damage) and pathophysiological (neuronal activity) findings of responses to nerve agents in the amygdala and the hippocampus, the two brain structures that play a central role in the generation and spread of seizures. The evidence so far suggests that the amygdala suffers the most extensive damage by nerve agent exposure, which appears consistent with the tendency of the amygdala to generate prolonged, seizure-like neuronal discharges in vitro in response to the nerve agent soman, at a time when the hippocampus generates only interictal-like activity. In vivo experiments are now required to confirm the primary role that the amygdala seems to play in nerve agent-induced seizure generation.

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Complex View on Poisoning with Nerve Agents and Organophosphates

Cited by 59 publications

References 100 publications

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

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

LY293558 prevents soman-induced pathophysiological alterations in the basolateral amygdala and the development of anxiety

Primary brain targets of nerve agents: The role of the amygdala in comparison to the hippocampus

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