Characterization and treatment of spontaneous recurrent seizures following nerve agent-induced status epilepticus in mice

McCarren, Hilary S.; Eisen, Margaret R.; Nguyen, Dominique L.; Dubée, Parker B.; Ardinger, Cherish E.; Dunn, Emily N.; Haines, Kari M.; Santoro, Antonia N.; Bodner, P; Ondeck, Celinia A.; Honnold, Cary L.; McDonough, John H.; Beske, Phillip; McNutt, Patrick

doi:10.1016/j.eplepsyres.2020.106320

Cited by 9 publications

(9 citation statements)

References 42 publications

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“…In mice exposed to a seizure‐inducing dose of soman, a low dose of phenobarbital monotherapy (20 mg/kg) resulted in a delay in onset to SRS but did not reduce neuropathology. 41 Higher doses of phenobarbital as evaluated against DFP in rats 17 , 18 or combination of lower doses of phenobarbital with other antiseizure medications as used in the current study may be needed to improve neuroprotection. These findings demonstrate the efficacy of combining subanesthetic doses of antiseizure medications in reducing cholinergic‐induced SE and epileptogenesis.…”

Section: Discussionmentioning

confidence: 97%

Combination of antiseizure medications phenobarbital, ketamine, and midazolam reduces soman‐induced epileptogenesis and brain pathology in rats

et al. 2021

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Section: Discussionmentioning

confidence: 97%

Combination of antiseizure medications phenobarbital, ketamine, and midazolam reduces soman‐induced epileptogenesis and brain pathology in rats

et al. 2021

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“…However, a mouse model of OP-induced SE would be desirable because of the availability of transgenic strains that could be leveraged to investigate pathogenic mechanisms underlying the acute and chronic neurotoxicity of acute OP intoxication. OP-induced SE has been studied in mice (see Table 1 ), but these studies ( Baccus et al, 2018 ; Collombet et al, 2008 ; Coubard et al, 2008 ; Dhote et al, 2012 , 2007 ; Enderlin et al, 2020 ; Golderman et al, 2019 ; Maupu et al, 2021 ; McCarren et al, 2020 ) have not rigorously measured the spatiotemporal progression of neuropathology at delayed times post-exposure or evaluated long-term behavioral effects. The main objective of this study was to develop a mouse model of OP-induced SE that did not require antiseizure treatment to survive with the goal of generating a model for characterizing acute and chronic neurotoxic effects with the long-term goal of using this model to investigate pathogenic mechanisms and evaluate novel therapeutics for both acute and chronic effects of acute OP intoxication.…”

Section: Introductionmentioning

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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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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“…Experimental models of OP-SE outcomes report of neuronal injury, neuroinflammation, SRS, and behavioral morbidities ( de Araujo Furtado et al, 2010 ; Deshpande et al, 2010 , 2014a ; Shrot et al, 2014 ; Bar-Klein et al, 2016 ; Gage et al, 2020 ; Guignet et al, 2020 ; McCarren et al, 2020 ; Reddy et al, 2021 ; Rojas et al, 2021 ). However, a chronic long-term assessment of the effect of OP-induced SE on epilepsy and neuro-histologic outcomes is not fully available.…”

Section: Discussionmentioning

confidence: 99%

“…These levels were applied to remove the background, binarized corrected images, and underwent auto-thresholding. H&E has been used previously to evaluate neuronal pathology following chemo-convulsant-induced SE ( Fujikawa, 1996 ; Sankar et al, 1998a ; Gao and Geng, 2013 ; McCarren et al, 2020 ). H&E staining of viable neurons presents with pronounced basophilic cytoplasmic staining of large pyramidal cell bodies allowing for the exclusion of non-neuronal/glial cells, which show as dense nuclei with little to no cytoplasmic staining.…”

Section: Methodsmentioning

confidence: 99%

Chronic Epilepsy and Mossy Fiber Sprouting Following Organophosphate-Induced Status Epilepticus in Rats

Blair,

Hawkins,

Pinchbeck

et al. 2023

J Pharmacol Exp Ther

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Organophosphate (OP) compounds are highly toxic and include pesticides and chemical warfare nerve agents. OP exposure inhibits the acetylcholinesterase enzyme, causing cholinergic overstimulation that can evolve into status epilepticus (SE) and produce lethality. Furthermore, OP-induced SE survival is associated with mood and memory dysfunction and spontaneous recurrent seizures (SRS). In male Sprague–Dawley rats, we assessed hippocampal pathology and chronic SRS following SE induced by administration of OP agents paraoxon (2 mg/kg, s.c.), diisopropyl fluorophosphate (4 mg/kg, s.c.), or O-isopropyl methylphosphonofluoridate (GB; sarin) (2 mg/kg, s.c.), immediately followed by atropine and 2-PAM. At 1-hour post-OP–induced SE onset, midazolam was administered to control SE. Approximately 6 months after OP-induced SE, SRS were evaluated using video and electroencephalography monitoring. Histopathology was conducted using hematoxylin and eosin (H&E), while silver sulfide (Timm) staining was used to assess mossy fiber sprouting (MFS). Across all the OP agents, over 60% of rats that survived OP-induced SE developed chronic SRS. H&E staining revealed a significant hippocampal neuronal loss, while Timm staining revealed extensive MFS within the inner molecular region of the dentate gyrus. This study demonstrates that OP-induced SE is associated with hippocampal neuronal loss, extensive MFS, and the development of SRS, all hallmarks of chronic epilepsy. SIGNIFICANCE STATEMENT Models of organophosphate (OP)-induced SE offer a unique resource to identify molecular mechanisms contributing to neuropathology and the development of chronic OP morbidities. These models could allow the screening of targeted therapeutics for efficacious treatment strategies for OP toxicities.

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Characterization and treatment of spontaneous recurrent seizures following nerve agent-induced status epilepticus in mice

Cited by 9 publications

References 42 publications

Combination of antiseizure medications phenobarbital, ketamine, and midazolam reduces soman‐induced epileptogenesis and brain pathology in rats

Combination of antiseizure medications phenobarbital, ketamine, and midazolam reduces soman‐induced epileptogenesis and brain pathology in rats

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

Chronic Epilepsy and Mossy Fiber Sprouting Following Organophosphate-Induced Status Epilepticus in Rats

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