Comparative profile of refractory status epilepticus models following exposure of cholinergic agents pilocarpine, DFP, and soman

Reddy, Doodipala Samba; Zaayman, Marcus; Kuruba, Ramkumar; Wu, Xin

doi:10.1016/j.neuropharm.2021.108571

Cited by 26 publications

(57 citation statements)

References 101 publications

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“…Since these agents are highly regulated and permitted to use by defense or authorized high-security laboratories, diisopropylfluorophosphate (DFP) has been used as a surrogate for soman/sarin in academic laboratories (Reddy and Kuruba, 2013;Bruun et al, 2019;Gage et al, 2020;Putra et al, 2020). 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).…”

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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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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“…However, a repeated-low-dose approach is not suitable for DFP, soman, or other OPNA models as it does not mimic the real-world exposure of OPNAs to the general public. We and others have demonstrated that both DFP and soman models demonstrated the classical features of epilepsy, such as the onset of spontaneously recurring CS, gliosis, and neurodegeneration ( Apland et al, 2014 ; Apland et al, 2018 ; Lumley et al, 2019 ; Putra et al, 2020a , 2020b ; Rojas et al, 2020 ; Gage et al, 2021a , 2022a , 2022b ; González et al, 2021 ; Reddy et al, 2021 ). Off note, some of these studies used pyridostigmine bromide (PB) or other medical countermeasures such as HI-6 or 2-PAM as a pretreatment to minimize mortality ( Anderson et al, 1992 ; Apland et al, 2014 ; de Araujo Furtado et al, 2010 ; Reddy et al, 2020 , 2021 ).…”

Section: Discussionmentioning

confidence: 92%

“…We and others have demonstrated that both DFP and soman models demonstrated the classical features of epilepsy, such as the onset of spontaneously recurring CS, gliosis, and neurodegeneration ( Apland et al, 2014 ; Apland et al, 2018 ; Lumley et al, 2019 ; Putra et al, 2020a , 2020b ; Rojas et al, 2020 ; Gage et al, 2021a , 2022a , 2022b ; González et al, 2021 ; Reddy et al, 2021 ). Off note, some of these studies used pyridostigmine bromide (PB) or other medical countermeasures such as HI-6 or 2-PAM as a pretreatment to minimize mortality ( Anderson et al, 1992 ; Apland et al, 2014 ; de Araujo Furtado et al, 2010 ; Reddy et al, 2020 , 2021 ). Although some studies show that pretreatment has no impact on SE severity induced by DFP or soman, PB usage in a mixed-sex cohort can be a problem since females are less responsive to PB and confound SE severity and sex differences ( Hernandez et al, 2020 ).…”

Section: Discussionmentioning

confidence: 92%

DFP-Induced Status Epilepticus Severity in Mixed-Sex Cohorts of Adult Rats Housed in the Same Room: Behavioral and EEG Comparisons

Gage

Thippeswamy

2022

Front. Cell Dev. Biol.

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Sex is a biological variable in experimental models. In our previous diisopropylfluorophosphate (DFP) studies, female rats required a higher dose of DFP to achieve a somewhat similar severity of status epilepticus (SE) as males. In those studies, male and female rats were bought separately from the same vendor, housed in different rooms, and the DFP used was from different batches. We had also shown that surgery for epidural electrodes implantation reduces the threshold for SE. Our recent study in the soman (GD) model using a mixed-sex cohort of rats housed individually but in the same room showed that females achieved significantly higher SE severity than males for the same dose of GD. In this study, we demonstrate that housing the mixed-sex cohorts in the same room and treating them with DFP (4 mg/kg, s.c.) from the same pool, though from different batches, yielded reproducible SE severity in both sexes and both telemetry (surgery) and non-telemetry (non-surgery) groups. We conducted experiments in four mixed-sex cohorts of adult Sprague-Dawley rats. In females, the surgery for implanting the telemetry devices reduced the latency to convulsive seizure (CS) and increased SE severity compared to non-telemetry females. However, there were no sex differences in latency or SE severity within telemetry or non-telemetry groups. Once animals reached CS stage ≥3, they remained in CS stage in both sexes until midazolam was administered. Midazolam (3 mg/kg, i.m.) treatment 1-one-hour post-DFP significantly reduced epileptiform spikes in both sexes. The mortality was only 2% in 24 h. Irrespective of sex or stage of estrous cycle or surgery, the animals had continuous convulsive SE for ∼40 min. In telemetry rats, electrographic changes correlated with behavioral seizures. However, there was a significant difference in SE severity and the latency between directly-observed behavioral CS and EEG-based CS quantification in both sexes. Overall, these results suggest that housing both sexes in the same room and treating with DFP in a mixed-sex cohort from the same pool of reagents will minimize variability in SE severity. Such rigorous experiments will yield better outcomes while testing disease-modifying agents in epilepsy models.

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“…For the remaining KERs, response-response data were sparse, and a feedback loop in the AOP (KERs 5, 6, 7, 10) precludes the use of response-response modeling and necessitates the development of a biologically based model. Of the papers reviewed for qAOP model development, approximately 10 studies in the primary literature resulted in useable quantitative data for model development ( Michaels and Rothman, 1990 ; Kosasa et al, 1999 ; Kim et al, 2003 ; Falkenburger et al, 2010 ; Mergenthal et al, 2020 ), and model evaluation ( Lallement et al, 1992 ; Marks et al, 1996 ; McDonough and Shih, 1997 ; Miller et al, 2015 ; Reddy et al, 2021 ).…”

Section: Case Study: Ache Inhibition Leading To Neurodegenerationmentioning

confidence: 99%

From Qualitative to Quantitative AOP: A Case Study of Neurodegeneration

2022

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Adverse outcome pathways (AOPs) include a sequence of events that connect a molecular-level initiating event with an adverse outcome at the cellular level for human health endpoints, or at the population level for ecological endpoints. When there is enough quantitative understanding of the relationships between key events in an AOP, a mathematical model may be developed to connect key events in a quantitative AOP (qAOP). Ideally, a qAOP will reduce the time and resources spent for chemical toxicity testing and risk assessment and enable the extrapolation of data collected at the molecular-level by in vitro assays, for example, to predict whether an adverse outcome may occur. Here, we review AOPs in the AOPWiki, an AOP repository, to determine best practices that would facilitate conversion from AOP to qAOP. Then, focusing on a particular case study, acetylcholinesterase inhibition leading to neurodegeneration, we describe specific methods and challenges. Examples of challenges include the availability and collection of quantitative data amenable to model development, the lack of studies that measure multiple key events, and model accessibility or transferability across platforms. We conclude with recommendations for improving key event and key event relationship descriptions in the AOPWiki that facilitate the transition of qualitative AOPs to qAOPs.

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Comparative profile of refractory status epilepticus models following exposure of cholinergic agents pilocarpine, DFP, and soman

Cited by 26 publications

References 101 publications

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

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

DFP-Induced Status Epilepticus Severity in Mixed-Sex Cohorts of Adult Rats Housed in the Same Room: Behavioral and EEG Comparisons

From Qualitative to Quantitative AOP: A Case Study of Neurodegeneration

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