A Decade after the Tokyo Sarin Attack: A Review of Neurological Follow-Up of the Victims

Hoffman, Azik; Eisenkraft, Arik; Finkelstein, Arseny; Schein, Ophir; Rotman, Eran; Dushnitsky, Tsvika

doi:10.7205/milmed.172.6.607

Cited by 56 publications

(38 citation statements)

References 14 publications

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“…Increased anxiety is observed in animals that have been exposed to nerve agents (Coubard et al, 2008;Langston et al, 2012;Prager et al, 2014). Similarly, the human victims of the sarin terrorist attack in Japan report enduring symptoms of anxiety disorders, long after the exposure (Ohtani et al, 2004;Hoffman et al, 2007). The amygdala plays a central role in emotional behavior, and dysfunction with increased excitability of the BLA is associated with anxiety (Gonzalez et al, 1996;Shekhar et al, 2003;Zhou et al, 2010;Pidoplichko et al, 2014).…”

Section: Efficacy Of Diazepam and Ubp302 Against Somanmentioning

confidence: 99%

“…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%

“…In this study, we used a rat model of nerve agent exposure in which the anticonvulsant treatment was delayed to at least 1 hour, and compared the efficacy of DZP with that of another GluK1R antagonist UBP302 [(S)-3-(2-carboxybenzyl)willardiine], which selectively antagonizes the GluK1Rs (More et al, 2004), against soman-induced seizures, as well as acute and long-term neuropathology. We also examined the efficacy of DZP and UBP302 in preventing the development of anxiety, which is a prevalent behavioral deficit resulting from nerve agent-induced brain damage, in both animals (Coubard et al, 2008;Langston et al, 2012;Prager et al, 2014) and humans (Ohtani et al, 2004;Hoffman et al, 2007 Jimmerson et al, 1989) to rats that were 7 to 8 weeks old. To increase the survival rate, rats were administered HI-6 [1-(2-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium)-2-oxapropane dichloride; 125 mg/kg i.p.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Efficacy Of Diazepam and Ubp302 Against Somanmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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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“…Similarly, exposure to sarin from the demolition of depositories containing sarin during the bombing phase of the 1991 Gulf War and after the ground war is a suggested cause of the neuropsychological disabilities suffered by 30 % or more of the veterans [3]. It should be noted that, despite this apparent link between sarin exposure and cognitive impairment, a second school of thought purports that these deficits may be linked to the emotional response to the trauma of exposure or warfare and are more consistent with the symptoms of post-traumatic stress disorder [see [4] for review].…”

Section: Introductionmentioning

confidence: 99%

Chronic Treatment with Naltrexone Prevents Memory Retention Deficits in Rats Poisoned with the Sarin Analog Diisopropylfluorophosphate (DFP) and Treated with Atropine and Pralidoxime

2015

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Humans and rats poisoned with sarin develop chronic neurological disabilities that are not prevented with standardized antidotal therapy. We hypothesized that rats poisoned with the sarin analogue diisopropylfluorophosphate (DFP) and resuscitated with atropine and pralidoxime would have long-term memory deficits that were preventable with naltrexone treatment. Long Evans rats (250-275 g) were randomized to: DFP (N=8): single subcutaneous (SC) injection of DFP (5 mg/kg). Treatment (N=9): DFP (5 mg/kg) followed by chronic naltrexone (5 mg/kg/day × 12 weeks). Control (N= 12): single SC injection of isopropyl alcohol, (DFP vehicle) followed by chronic naltrexone (5 mg/kg/day). If toxicity developed after injection, antidotal therapy was initiated with atropine (2 mg/kg) and pralidoxime (25 mg/kg) and repeated as needed. After 12 weeks, rats underwent testing for place learning (acquisition) across 5 days of training using the Morris Water Maze. On day 6 a memory retention test was performed. Statistical analysis was performed using IBM SPSS Statistics. Rats receiving DFP rapidly developed toxicity requiring antidotal rescue. No differences in acquisition were seen between the DFP vs. DFP+naltrexone rats. During memory testing, DFP-poisoned rats spent significantly less time (29.4±2.11 versus 38.5±2.5 s, p<0.05) and traveled less distance (267±24.6 versus 370±27.5 cm, p<0.05) in the target quadrant compared to the treatment group. Treatment rats performed as well as control rats (p>0.05) on the test for memory retention. Poisoning with DFP induced impaired memory retention. Deficits were not prevented by acute rescue with atropine and pralidoxime. Chronic naltrexone treatment led to preserved memory after DFP poisoning.

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“…If seizures are not controlled, 98% of surviving animals suffer moderate to severe neuropathology, evident within 24 hours after nerve agent exposure (Figueiredo et al, 2011; McDonough et al, 1995; Prager et al, 2013, 2014), and go on to develop long-term neurological and behavioral impairments. Victims of the Tokyo and Matsumoto sarin attacks, for example, reported symptoms associated with anxiety disorders over a decade after the attacks (Hoffman et al, 2007; Ohtani et al, 2004). Similarly, animals display enduring anxiety and fear-like behaviors after exposure to soman (Coubard et al, 2008; Filliat et al, 2007; Langston et al, 2012; Moffett et al, 2011; Prager et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Pathophysiological mechanisms underlying increased anxiety after soman exposure: Reduced GABAergic inhibition in the basolateral amygdala

et al. 2014

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The recent sarin attack in Syria killed 1,429 people, including 426 children, and left countless more to deal with the health consequences of the exposure. Prior to the Syrian chemical assault, nerve agent attacks in Japan left many victims suffering from neuropsychiatric illnesses, particularly anxiety disorders, more than a decade later. Uncovering the neuro-pathophysiological mechanisms underlying the development of anxiety after nerve agent exposure is necessary for successful treatment. Anxiety is associated with hyperexcitability of the basolateral amygdala (BLA). The present study sought to determine the nature of the nerve agent-induced alterations in the BLA, which could explain the development of anxiety. Rats were exposed to soman, at a dose that induced prolonged status epilepticus. Twenty-four hours and 14-days after exposure, neurons from the BLA were recorded using whole-cell patch-clamp techniques. At both the 24 h and 14-day post-exposure time-points, the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) in the BLA were reduced, along with reduction in the frequency but not amplitude of miniature IPSCs. In addition, activation of α7-nicotinic acetylcholine receptors, a cholinergic receptor that participates in the regulation of BLA excitability and is involved in anxiety, increased spontaneous excitatory postsynaptic currents (sEPSCs) in both soman-exposed rats and controls, but was less effective in increasing sIPSCs in soman-exposed rats. Despite the loss of both interneurons and principal cells after soman-induced status epilepticus, the frequency of sEPSCs was increased in the soman-exposed rats. Impaired function and cholinergic modulation of GABAergic inhibition in the BLA may underlie anxiety disorders that develop after nerve agent exposure.

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A Decade after the Tokyo Sarin Attack: A Review of Neurological Follow-Up of the Victims

Abstract: The results emphasize the need for a national preparedness program for such mass casualty events, led by national health systems. This should include long-term, neurological, follow-up monitoring with performance tests and a post-traumatic stress disorder screening test.

Cited by 56 publications

References 14 publications

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

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

Chronic Treatment with Naltrexone Prevents Memory Retention Deficits in Rats Poisoned with the Sarin Analog Diisopropylfluorophosphate (DFP) and Treated with Atropine and Pralidoxime

Pathophysiological mechanisms underlying increased anxiety after soman exposure: Reduced GABAergic inhibition in the basolateral amygdala

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