Neuroinflammation in organophosphate-induced neurotoxicity

Guignet, Michelle; Lein, Pamela J.

doi:10.1016/bs.ant.2018.10.003

Cited by 29 publications

(27 citation statements)

References 191 publications

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“…The dual combinations of MDZ + ALLO, MDZ + PPL, and ALLO + PPL were significantly more effective than MDZ alone at 3 days but not 28 days following DFP exposure. Overall, the present results are consistent with previous studies of OP-induced SE, in which it was concluded that neurodegeneration and neuroinflammation are mediated by independent mechanisms, 92 and that seizure severity and duration are not the only variables driving neuronal cell loss. 90 In conclusion, our results confirm that MDZ at a dose equivalent to that recommended for the treatment of OP nerve agent seizures does not terminate DFP-induced SE in a rat model when administered 40 min after seizure onset.…”

Section: Discussionsupporting

confidence: 93%

Allopregnanolone and perampanel as adjuncts to midazolam for treating diisopropylfluorophosphate‐induced status epilepticus in rats

Dhir

Bruun

Guignet

et al. 2020

Annals of the New York Academy of Sciences

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Combinations of midazolam, allopregnanolone, and perampanel were assessed for antiseizure activity in a rat diisopropylfluorophosphate (DFP) status epilepticus model. Animals receiving DFP followed by atropine and pralidoxime exhibited continuous high-amplitude rhythmical electroencephalography (EEG) spike activity and behavioral seizures for more than 5 hours. Treatments were administered intramuscularly 40 min after DFP. Seizures persisted following midazolam (1.8 mg/kg). The combination of midazolam with either allopregnanolone (6 mg/kg) or perampanel (2 mg/kg) terminated EEG and behavioral status epilepticus, but the onset of the perampanel effect was slow. The combination of midazolam, allopregnanolone, and perampanel caused rapid and complete suppression of EEG and behavioral seizures. In the absence of DFP, animals treated with the three-drug combination were sedated but not anesthetized. Animals that received midazolam alone exhibited spontaneous recurrent EEG seizures, whereas those that received the three-drug combination did not, demonstrating antiepileptogenic activity. All combination treatments reduced neurodegeneration as assessed with Fluoro-Jade C staining to a greater extent than midazolam alone, and most reduced astrogliosis as assessed by GFAP immunoreactivity but had mixed effects on markers of microglial activation. We conclude that allopregnanolone, a positive modulator of the GABA A receptor, and perampanel, an AMPA receptor antagonist, are potential adjuncts to midazolam in the treatment of benzodiazepine-refractory organophosphate nerve agent-induced status epilepticus.

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Section: Discussionsupporting

confidence: 93%

Allopregnanolone and perampanel as adjuncts to midazolam for treating diisopropylfluorophosphate‐induced status epilepticus in rats

Dhir

Bruun

Guignet

et al. 2020

Annals of the New York Academy of Sciences

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“…Neuroinflammation, apoptosis of neurons and glial cells, neurotransmission disruption, and axonal damage cause impairment to the nervous system as a result of chemical exposure, through processes such as oxidative stress, calcium overload, and cytoskeleton disruption (Donkin and Williams 2000;Costa 2017;Guignet and Lein 2019). However, these mechanisms have been described mainly for humans; information on transmissibility to fish is limited, and the mechanisms behind molecular uptake of pollutants into neurons, interaction with target molecules, and activation of cellular pathways are largely unknown for many neurotoxic pollutants.…”

Section: Assessing Molecular Changesmentioning

confidence: 99%

Approaches to Test the Neurotoxicity of Environmental Contaminants in the Zebrafish Model: From Behavior to Molecular Mechanisms

Fitzgerald

Könemann

Krümpelmann

et al. 2021

Enviro Toxic and Chemistry

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The occurrence of neuroactive chemicals in the aquatic environment is on the rise and poses a potential threat to aquatic biota of currently unpredictable outcome. In particular, subtle changes caused by these chemicals to an organism's sensation or behavior are difficult to tackle with current test systems that focus on rodents or with in vitro test systems that omit whole-animal responses. In recent years, the zebrafish (Danio rerio) has become a popular model organism for toxicological studies and testing strategies, such as the standardized use of zebrafish early life stages in the Organisation for Economic Cooperation and Development's guideline 236. In terms of neurotoxicity, the zebrafish provides a powerful model to investigate changes to the nervous system from several different angles, offering the ability to tackle the mechanisms of action of chemicals in detail. The mechanistic understanding gained through the analysis of this model species provides a good basic knowledge of how neuroactive chemicals might interact with a teleost nervous system. Such information can help infer potential effects occurring to other species exposed to neuroactive chemicals in their aquatic environment and predicting potential risks of a chemical for the aquatic ecosystem. In the present article, we highlight approaches ranging from behavioral to structural, functional, and molecular analysis of the larval zebrafish nervous system, providing a holistic view of potential neurotoxic outcomes.

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“…It is believed that the overstimulation of cholinergic pathways and hypoxia are the main causes of seizure onset (127). Seizures activate neuronal inflammation and induce signalling in astrocytes, which leads to higher expression of the glial fibrillary acidic protein (GFAP) (128). High levels of GFAP, in turn, cause astrogliosis and glial scarring (129).…”

Section: Anticonvulsant Drugsmentioning

confidence: 99%

“…High levels of GFAP, in turn, cause astrogliosis and glial scarring (129). Seizures also activate microglia, which results in the release of both pro-inflammatory (IL-1β, IL-1α, IL-6, IFN-γ) and anti-inflammatory (IL-10, IL-4, TGF-β, arginase) cytokines and reactive oxygen species (ROS) causing oxidative stress (128,(130)(131)(132). Therefore, OP-induced seizures require effective treatment to minimise brain damage such as treatment with benzodiazepine anticonvulsants diazepam, lorazepam, and midazolam (133,134).…”

Section: Anticonvulsant Drugsmentioning

confidence: 99%

Counteracting poisoning with chemical warfare nerve agents

Hrvat

Kovarik

2020

Archives of Industrial Hygiene and Toxicology

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Phosphylation of the pivotal enzyme acetylcholinesterase (AChE) by nerve agents (NAs) leads to irreversible inhibition of the enzyme and accumulation of neurotransmitter acetylcholine, which induces cholinergic crisis, that is, overstimulation of muscarinic and nicotinic membrane receptors in the central and peripheral nervous system. In severe cases, subsequent desensitisation of the receptors results in hypoxia, vasodepression, and respiratory arrest, followed by death. Prompt action is therefore critical to improve the chances of victim’s survival and recovery. Standard therapy of NA poisoning generally involves administration of anticholinergic atropine and an oxime reactivator of phosphylated AChE. Anticholinesterase compounds or NA bioscavengers can also be applied to preserve native AChE from inhibition. With this review of 70 years of research we aim to present current and potential approaches to counteracting NA poisoning.

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Neuroinflammation in organophosphate-induced neurotoxicity

Cited by 29 publications

References 191 publications

Allopregnanolone and perampanel as adjuncts to midazolam for treating diisopropylfluorophosphate‐induced status epilepticus in rats

Allopregnanolone and perampanel as adjuncts to midazolam for treating diisopropylfluorophosphate‐induced status epilepticus in rats

Approaches to Test the Neurotoxicity of Environmental Contaminants in the Zebrafish Model: From Behavior to Molecular Mechanisms

Counteracting poisoning with chemical warfare nerve agents

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