ArticleThe Journal of pharmacology and experimental therapeutics2018
Midazolam-Resistant Seizures and Brain Injury after Acute Intoxication of Diisopropylfluorophosphate, an Organophosphate Pesticide and Surrogate for Nerve Agents.
Article in The Journal of pharmacology and experimental therapeutics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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Who cites it
60 citing papers in PubMed, 92 citations in OpenAlex.
- Article
- Article
- Assessment of Intramuscular Verapamil as Pharmacological Countermeasure in a Rat Model of Organophosphate DFP-induced Status Epilepticus.Neurotoxicity research · 2025Article
- Organophosphate Chemical Nerve Agents, Oxidative Stress, and NADPH Oxidase Inhibitors: An Overview.International journal of molecular sciences · 2025Review
- Diet-incorporated saracatinib, a Src tyrosine kinase inhibitor, counteracts diisopropylfluorophosphate (DFP)-induced chronic neurotoxicity in the rat model.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2025Article
- Neurosteroid mitigation of developmental neurological dysfunction, long-term epileptic biomarkers, chronic neuroinflammation, and neurodegeneration in a pediatric rat model of organophosphate exposure.The Journal of pharmacology and experimental therapeutics · 2025Article
- Development of a Colorimetric Polydiacetylene Nanocomposite Fiber Sensor for Selective Detection of Organophosphate Pesticides.ACS omega · 2025Article
- Spatiotemporal perturbations of the plasminogen activation system in a rat model of acute organophosphate intoxication.Acta neuropathologica communications · 2025Article
- Allopregnanolone as an Adjunct Therapy to Midazolam is More Effective Than Midazolam Alone in Suppressing Soman-Induced Status Epilepticus in Male Rats.CNS neuroscience & therapeutics · 2025Article
- The Role of Intravenous Anesthetics for Neuro: Protection or Toxicity?Neuroscience bulletin · 2025Review
- A Comprehensive Stereology Method for Quantitative Evaluation of Neuronal Injury, Neurodegeneration, and Neurogenesis in Brain Disorders.Current protocols · 2024Article
- Shifts in the spatiotemporal profile of inflammatory phenotypes of innate immune cells in the rat brain following acute intoxication with the organophosphate diisopropylfluorophosphate.Journal of neuroinflammation · 2024Article
- A longitudinal MRI and TSPO PET-based investigation of brain region-specific neuroprotection by diazepam versus midazolam following organophosphate-induced seizures.Neuropharmacology · 2024Article
- Quantitative TNeuropharmacology · 2024Article
- Cardiovascular responses of adult male Sprague-Dawley rats following acute organophosphate intoxication and post-exposure treatment with midazolam with or without allopregnanolone.Archives of toxicology · 2024Article
- Neurosteroids as Novel Anticonvulsants for Refractory Status Epilepticus and Medical Countermeasures for Nerve Agents: A 15-Year Journey to Bring Ganaxolone from Bench to Clinic.The Journal of pharmacology and experimental therapeutics · 2024Review
- Long-Term Neuropsychiatric Developmental Defects after Neonatal Organophosphate Exposure: Mitigation by Synthetic Neurosteroids.The Journal of pharmacology and experimental therapeutics · 2024Article
- Sex Differences in Organophosphate Model of Benzodiazepine-Refractory Status Epilepticus and Neuronal Damage.The Journal of pharmacology and experimental therapeutics · 2024Article
- Chronic Epilepsy and Mossy Fiber Sprouting Following Organophosphate-Induced Status Epilepticus in Rats.The Journal of pharmacology and experimental therapeutics · 2024Article
- Neuroprotectant Activity of Novel Water-Soluble Synthetic Neurosteroids on Organophosphate Intoxication and Status Epilepticus-Induced Long-Term Neurological Dysfunction, Neurodegeneration, and Neuroinflammation.The Journal of pharmacology and experimental therapeutics · 2024Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Organophosphates (OP) such as the pesticide diisopropylfluorophosphate (DFP) and the nerve agent sarin are lethal chemicals that induce seizures, status epilepticus (SE), and brain damage. Midazolam, a benzodiazepine modulator of synaptic GABA-A receptors, is currently considered as a new anticonvulsant for nerve agents. Here, we characterized the time course of protective efficacy of midazolam (0.2-5 mg/kg, i.m.) in rats exposed to DFP, a chemical threat agent and surrogate for nerve agents. Behavioral and electroencephalogram (EEG) seizures were monitored for 24 hours after DFP exposure. The extent of brain injury was determined 3 days after DFP exposure by unbiased stereologic analyses of valid markers of neurodegeneration and neuroinflammation. Seizures were elicited within ∼8 minutes after DFP exposure that progressively developed into persistent SE lasting for hours. DFP exposure resulted in massive neuronal injury or necrosis, neurodegeneration of principal cells and interneurons, and neuroinflammation as evident by extensive activation of microglia and astrocytes in the hippocampus, amygdala, and other brain regions. Midazolam controlled seizures, neurodegeneration, and neuroinflammation when given early (10 minutes) after DFP exposure, but it was less effective when given at 40 minutes or later. Delayed therapy (≥40 minutes), a simulation of the practical therapeutic window for first responders or hospital admission, was associated with reduced seizure protection and neuroprotection. These results strongly reaffirm that the DFP-induced seizures and brain damage are progressively resistant to delayed treatment with midazolam, confirming the benzodiazepine refractory SE after OP intoxication. Thus, novel anticonvulsants superior to midazolam or adjunct therapies that enhance its efficacy are needed for effective treatment of refractory SE.
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