Comparison of neuropathology in rats following status epilepticus induced by diisopropylfluorophosphate and soman

Rojas, Asheebo; McCarren, Hilary S.; Wang, Jennifer; Wang, Wenyi; Abreu-Melon, JuanMartin; Wang, Sarah; McDonough, John H.; Dingledine, Raymond

doi:10.1016/j.neuro.2020.12.010

Cited by 14 publications

(7 citation statements)

References 39 publications

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“…Wireless EEG recordings confirmed electrographic seizures within minutes following DFP injection and these are similar to EEG recordings of DFP-intoxicated rats ( Deshpande et al, 2010 ; Pouliot et al, 2016 ). The loss of body weight in DFP mice during the first days after SE is also consistent with published observations of preclinical rat models of OP intoxication ( Pessah et al, 2016 ; Rojas et al, 2021 ). Additionally, the AChE inhibition observed in the brains of DFP mice was consistent with observations in rat models of acute DFP intoxication with respect to both the percent inhibition of AChE, and the persistence of decreased AChE activity to 14 DPE ( Ferchmin et al, 2014 ; González et al, 2020 ).…”

Section: Discussionsupporting

confidence: 90%

“…Increased astrocytic expression of S100β has been associated with compromised blood brain barrier (BBB) integrity ( Krishnan et al, 2020 ), suggesting that acute DFP intoxication adversely impacts the BBB. Indeed, BBB breakdown has been reported in the cortex of rats 4 days after soman-induced SE ( Rojas et al, 2021 ), suggesting another mechanism of neuropathology in DFP mice. Future studies should investigate the potential disruption of the BBB during DFP intoxication in mice as a potential therapeutic target for OP poisoning.…”

Section: Discussionmentioning

confidence: 99%

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Persistent neuropathology and behavioral deficits in a mouse model of status epilepticus induced by acute intoxication with diisopropylfluorophosphate

et al. 2021

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Organophosphate (OP) nerve agents and pesticides are a class of neurotoxic compounds that can cause status epilepticus (SE), and death following acute high-dose exposures. While the standard of care for acute OP intoxication (atropine, oxime, and high-dose benzodiazepine) can prevent mortality, survivors of OP poisoning often experience long-term brain damage and cognitive deficits. Preclinical studies of acute OP intoxication have primarily used rat models to identify candidate medical countermeasures. However, the mouse offers the advantage of readily available knockout strains for mechanistic studies of acute and chronic consequences of OP-induced SE. Therefore, the main objective of this study was to determine whether a mouse model of acute diisopropylfluorophosphate (DFP) intoxication would produce acute and chronic neurotoxicity similar to that observed in rat models and humans following acute OP intoxication. Adult male C57BL/6J mice injected with DFP (9.5 mg/kg, s.c.) followed 1 min later with atropine sulfate (0.1 mg/kg, i.m.) and 2-pralidoxime (25 mg/kg, i.m.) developed behavioral and electrographic signs of SE within minutes that continued for at least 4 h. Acetylcholinesterase inhibition persisted for at least 3 d in the blood and 14 d in the brain of DFP mice relative to vehicle (VEH) controls. Immunohistochemical analyses revealed significant neurodegeneration and neuroinflammation in multiple brain regions at 1, 7, and 28 d post-exposure in the brains of DFP mice relative to VEH controls. Deficits in locomotor and home-cage behavior were observed in DFP mice at 28 d post-exposure. These findings demonstrate that this mouse model replicates many of the outcomes observed in rats and humans acutely intoxicated with OPs, suggesting the feasibility of using this model for mechanistic studies and therapeutic screening.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Persistent neuropathology and behavioral deficits in a mouse model of status epilepticus induced by acute intoxication with diisopropylfluorophosphate

et al. 2021

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“…In this rat soman study without PB pretreatment in a mixed sex cohort, we demonstrated no morality during SE despite severe convulsive seizures. The initial SE severity [i.e., the duration of convulsive seizures (stage ≥ 3) between OP exposure and midazolam treatment] determines epileptogenesis and brain pathology (Wu et al, 2018;Gage et al, 2021;Rojas et al, 2021). This is an important factor for testing disease-modifying agents for their long-term effects on the brain in animal models.…”

Section: Discussionmentioning

confidence: 99%

“…DFP is structurally similar to soman (Gotor et al, 2011;Reddy et al, 2021). The brain pathology caused by both DFP and OPNA induced SE are also similar (de Araujo Furtado et al, 2010;Deshpande et al, 2010;Todorovic et al, 2012;Guignet et al, 2020;Putra et al, 2020;Rojas et al, 2021). Both DFP and OPNAs irreversibly inhibit acetylcholinesterase (AChE) and cause neurological, respiratory and cardiac symptoms (Lemercier et al, 1983;Kerenyi et al, 1990;Miller et al, 1993;Grunwald et al, 1994;Auta et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Soman (GD) Rat Model to Mimic Civilian Exposure to Nerve Agent: Mortality, Video-EEG Based Status Epilepticus Severity, Sex Differences, Spontaneously Recurring Seizures, and Brain Pathology

Gage

Rao

Samidurai

et al. 2022

Front. Cell. Neurosci.

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Modeling a real-world scenario of organophosphate nerve agent (OPNA) exposure is challenging. Military personnel are premedicated with pyridostigmine, which led to the development of OPNA models with pyridostigmine/oxime pretreatment to investigate novel therapeutics for acute and chronic effects. However, civilians are not premedicated with pyridostigmine/oxime. Therefore, experimental models without pyridostigmine were developed by other laboratories though often only in males. Following OPNA exposure, prolonged convulsive seizures (CS) or status epilepticus (SE) are concerning. The duration and severity of CS/SE determine the extent of brain injury in survivors even after treating with medical countermeasures (MCM)/antidotes such as atropine, an oxime, and an anticonvulsant such as diazepam/midazolam. In this study, using a large mixed sex cohort of adult male and female rats, without pretreatment, we demonstrate severe SE lasting for >20 min in 82% of the animals in response to soman (GD,132 μg/kg, s.c.). Atropine sulfate (2 mg/kg, i.m.) and HI-6 (125 mg/kg, i.m.) were administered immediately following soman, and midazolam (3 mg/kg, i.m.) 1 h post-exposure. Immediate MCM treatment is impractical in civilian exposure to civilians, but this approach reduces mortality in experimental models. Interestingly, female rats, irrespective of estrous stages, had an average of 44 min CS (stage ≥ 3), while males had an average of 32 min CS during SE, starting from soman exposure to midazolam treatment. However, in telemetry device implanted groups, there were no significant sex differences in SE severity; males had 40 min and females 43 min of continuous CS until midazolam was administered. No animals died prior to midazolam administration and less than 5% died in the first week after soman intoxication. In telemetered animals, there was a direct correlation between EEG changes and behavioral seizures in real-time. In the long-term, convulsive spontaneously recurring seizures (SRS) were observed in 85% of randomly chosen animals. At 4-months post-soman, the brain histology confirmed reactive gliosis and neurodegeneration. The novel findings of this study are that, in non-telemetered animals, the SE severity following soman intoxication was significantly greater in females compared to males and that the estrous cycle did not influence the response.

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“…A DFP exposure in rats leads to early consequences of cholinesterase inhibition such as whole-body motor convulsions, muscle weakness, and SE, followed days later by neuronal death, neuroinflammation, gliosis, BBB breakdown, weight loss, muscle weakness, and gastrointestinal dysfunction. The long-term consequences of DFP exposure include anxiety behaviors, cognitive deficits, and unprovoked seizures. , Treatment with compound 4 after a DFP-induced SE in rats with six doses beginning 80–150 min after the SE onset substantially decreased the weight loss, acute neuronal death in the hippocampus, inflammatory cytokine burst, reactive microgliosis, and the BBB breakdown in the days after the SE (Table ). , A selective inhibition of the EP2 receptor by compound 4 in rats did not prevent the anxiety-like behavior assessed by open-field and light-dark box tests four weeks following the DFP exposure; however, it did alleviate the DFP SE-induced memory impairment measured by a novel object recognition test 6–12 weeks after the SE. , …”

Section: Epileptic Seizuresmentioning

confidence: 99%

EP2 Antagonists (2011–2021): A Decade’s Journey from Discovery to Therapeutics

Sluter

et al. 2021

J. Med. Chem.

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In the wake of health disasters associated with the chronic use of cyclooxygenase-2 (COX-2) inhibitor drugs, it has been widely proposed that modulation of downstream prostanoid synthases or receptors might provide more specificity than simply shutting down the entire COX cascade for anti-inflammatory benefits. The pathogenic actions of COX-2 have long been thought attributable to the prostaglandin E2 (PGE 2 ) signaling through its Gα s -coupled EP2 receptor subtype; however, the truly selective EP2 antagonists did not emerge until 2011. These small molecules provide game-changing tools to better understand the EP2 receptor in inflammation-associated conditions. Their applications in preclinical models also reshape our knowledge of PGE 2 /EP2 signaling as a node of inflammation in health and disease. As we celebrate the 10-year anniversary of this breakthrough, the exploration of their potential as drug candidates for next-generation anti-inflammatory therapies has just begun. The first decade of EP2 antagonists passes, while their future looks brighter than ever.

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Comparison of neuropathology in rats following status epilepticus induced by diisopropylfluorophosphate and soman

Cited by 14 publications

References 39 publications

Persistent neuropathology and behavioral deficits in a mouse model of status epilepticus induced by acute intoxication with diisopropylfluorophosphate

Persistent neuropathology and behavioral deficits in a mouse model of status epilepticus induced by acute intoxication with diisopropylfluorophosphate

Soman (GD) Rat Model to Mimic Civilian Exposure to Nerve Agent: Mortality, Video-EEG Based Status Epilepticus Severity, Sex Differences, Spontaneously Recurring Seizures, and Brain Pathology

EP2 Antagonists (2011–2021): A Decade’s Journey from Discovery to Therapeutics

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