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MacMahon JA, Andrew PM, Izadi A, Bruun DA, Saito NH, Tancredi DJ, Brooks‐Kayal A, Lein PJ, Gurkoff GG. Acute and persistent changes in neural oscillatory activity predict development of epilepsy following acute organophosphate intoxication in adult rats. Epilepsia 2025; 66:1329-1342. [PMID: 39931903 PMCID: PMC11997943 DOI: 10.1111/epi.18212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 11/19/2024] [Accepted: 11/20/2024] [Indexed: 04/16/2025]
Abstract
OBJECTIVE Acute organophosphate (OP) intoxication affects a significant number of individuals worldwide. Those who survive OP-induced cholinergic crisis, which includes status epilepticus, often develop neurological morbidities. Here, we provide a rigorous characterization of the acute and delayed electrophysiological responses to OP intoxication with the goal of identifying early electrophysiological changes that predict later brain changes, including spontaneous recurrent seizures (SRS). METHODS Male and female rats were implanted with electroencephalographic (EEG) and intracranial EEG electrodes prior to acute intoxication with diisopropylfluorophosphate (DFP). All animals received standard of care therapeutics and were recorded continuously for 70 min post-DFP, then again for 5 min at 180 min post-DFP, 1 day postexposure (DPE), 3 DPE, and 7 DPE. Between 7 and 14 DPE, animals were recorded continuously. RESULTS In both sexes, acute DFP intoxication produced rapid and robust elevations in broadband power that were reduced but not terminated by midazolam (MDZ). Theta-delta ratio (TDR) was reduced immediately following DFP exposure and was further depressed by MDZ intervention. In the days that followed, broadband power and TDR recovered toward baseline. From 7 to 14 DPE, electrographic spiking was observed in all animals, and 80% developed SRS. Increased broadband power during status epilepticus was positively correlated with spike rate and SRS frequency. Slower recovery of broadband power to baseline in the days following exposure also correlated with increased SRS burden. Finally, a higher acute TDR correlated with increased spike rates at 3 and 7 DPE. SIGNIFICANCE The data presented in this study provide a rigorous characterization of post-DFP electrographic sequelae that significantly extends the field's current understanding of electrophysiological shifts caused by acute OP intoxication. Critically, we identified potential EEG-based biomarkers that may identify at-risk patients in a clinical setting.
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Affiliation(s)
- Jeremy A. MacMahon
- Department of Molecular Biosciences, School of Veterinary MedicineUniversity of California, DavisDavisCaliforniaUSA
| | - Peter M. Andrew
- Department of Molecular Biosciences, School of Veterinary MedicineUniversity of California, DavisDavisCaliforniaUSA
| | - Ali Izadi
- Department of Neurological Surgery, School of MedicineUniversity of California, DavisSacramentoCaliforniaUSA
| | - Donald A. Bruun
- Department of Molecular Biosciences, School of Veterinary MedicineUniversity of California, DavisDavisCaliforniaUSA
| | - Naomi H. Saito
- Department of Public Health Sciences, School of MedicineUniversity of California, DavisDavisCaliforniaUSA
| | - Daniel J. Tancredi
- Department of Pediatrics, School of MedicineUniversity of California, DavisSacramentoCaliforniaUSA
| | - Amy Brooks‐Kayal
- Department of Neurology, School of MedicineUniversity of California, DavisSacramentoCaliforniaUSA
| | - Pamela J. Lein
- Department of Molecular Biosciences, School of Veterinary MedicineUniversity of California, DavisDavisCaliforniaUSA
| | - Gene G. Gurkoff
- Department of Neurological Surgery, School of MedicineUniversity of California, DavisSacramentoCaliforniaUSA
- Veterans Association of Northern California Health Care SystemSacramentoCaliforniaUSA
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Ramakrishnan S, Singh T, Chen A, Wu X, Reddy DS. Neurosteroid mitigation of developmental neurological dysfunction, long-term epileptic biomarkers, chronic neuroinflammation, and neurodegeneration in a pediatric rat model of organophosphate exposure. J Pharmacol Exp Ther 2025; 392:103555. [PMID: 40273512 DOI: 10.1016/j.jpet.2025.103555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 02/22/2025] [Accepted: 03/10/2025] [Indexed: 04/26/2025] Open
Abstract
Children are particularly susceptible to the neurotoxic effects of organophosphates, which can lead to developmental neuronal deficits and associated dysfunction, including cognitive disabilities, epilepsy, and associated comorbidities. Anticonvulsants like benzodiazepines fail to prevent the lasting neurobehavioral and neuropathological effects of organophosphate exposure, emphasizing the need for new anticonvulsants to address these effects. This study evaluated the efficacy of the synthetic neurosteroid ganaxolone (GX) in combating persistent behavioral deficits, electrographic abnormalities, and neuropathological damage induced by diisopropylfluorophosphate (DFP) intoxication in pediatric rats. Postnatal day 21 rats were exposed to DFP acutely and were treated with GX (5-10 mg/kg). Behavior deficits were systematically monitored up to 3 months after exposure. Video electroencephalography at 3 months assessed spontaneous recurrent seizures, nonconvulsive epileptiform discharges, high-frequency oscillations, and interictal spike activity. GX treatment significantly mitigated anxiety, aggression, memory deficits, and depression-like phenotypes in DFP-exposed pediatric animals. It also reduced DFP-induced occurrence of epileptic biomarkers such as spontaneous recurrent seizures, epileptiform discharges, interictal spikes, and high-frequency oscillations demonstrating potential disease-modifying effects. Histological analysis showed that GX decreased the loss of parvalbumin (+) inhibitory neurons, neuronal nuclei antigen (+) principal neurons, and aberrant mossy fiber sprouting. GX also reduced neuroinflammation, indicated by decreased ionized calcium binding adaptor molecule 1 (+) microgliosis. Together, these results demonstrate the neuroprotective activity of GX in mitigating chronic neurologic dysfunction, neuroinflammation, and neurodegeneration and confirm GX as a promising treatment option for DFP exposure. SIGNIFICANCE STATEMENT: Acute organophosphate (OP) intoxication poses a severe risk, particularly to children, leading to life-threatening seizures and long-term neurological deficits. Current treatments, including benzodiazepines, are less effective against persistent seizures and neurological sequel after acute exposure. This study explores the potential of ganaxolone, a synthetic neurosteroid, to mitigate the neurodevelopmental consequences of OP exposure. Our findings reveal that ganaxolone provides significant neuroprotection in a pediatric model of OP intoxication, reducing long-term seizures, ictal biomarkers, neurodegeneration, neuroinflammation, and associated neurological dysfunctions, offering a promising therapeutic avenue for pediatric victims of OP exposure.
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Affiliation(s)
- Sreevidhya Ramakrishnan
- Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas
| | - Tanveer Singh
- Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas
| | - Albert Chen
- Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas
| | - Xin Wu
- Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas
| | - Doodipala Samba Reddy
- Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas.
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Massey N, Vasanthi SS, Gimenez-Lirola LG, Tyler H, Thippeswamy T. Proinflammatory cytokines, oxidative stress, and organ function as biomarkers of soman (GD) chronic neurotoxicity. Sci Rep 2025; 15:9021. [PMID: 40089647 PMCID: PMC11910520 DOI: 10.1038/s41598-025-94190-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 03/12/2025] [Indexed: 03/17/2025] Open
Abstract
Organophosphate (OP) nerve agents, such as soman (GD), pose great risk to neurological health by inhibiting acetylcholinesterase, leading to seizures, epilepsy, and behavioral deficits. While acute treatment may alleviate immediate symptoms, the long-term consequences, particularly those involving neuroinflammation and systemic toxicity, remain poorly understood. This study used adult male and female Sprague Dawley rats to investigate the chronic effects of a single acute exposure to soman (132 µg/kg, s.c., 1.2 × LD50) on neuroinflammation, behavioral comorbidity, and systemic toxicity. Following exposure, animals were treated with atropine sulfate (2 mg/kg, i.m.) and oxime HI-6 (125 mg/kg, i.m.) to mitigate peripheral cholinergic effects, and with midazolam (3 mg/kg, i.m., 1 h post-exposure) to control seizures. Spontaneously recurring seizures were monitored during handling and with video electroencephalogram (vEEG). Neurobehavioral deficits were assessed 4-8 weeks post-exposure. At 18 weeks post-exposure, brain, serum, and cerebrospinal fluid (CSF) were analyzed for inflammatory and nitro-oxidative stress markers, and the liver and kidney function biomarkers were evaluated. Soman-exposed animals developed epilepsy, confirmed by handling-induced seizures and/or continuous vEEG monitoring. Behavioral assessments revealed significant memory deficits following soman exposure. Proinflammatory cytokines (TNF-α, IL-6, IL-1α, IL-18, IL-17A, and MCP-1) were significantly elevated in both serum and CSF, alongside corresponding increases in their gene expression in the brain. Elevated reactive oxygen/nitrogen species were detected in the serum. Although hematological parameters remained unchanged, a significant increase in total bilirubin and an upward trend in serum blood urea nitrogen (BUN) levels and BUN: Creatinine ratio indicated potential liver and kidney dysfunction. However, no significant structural changes in these organs at the cellular level were observed in histological analyses. This study identifies critical chronic biomarkers of soman exposure affecting the brain, serum, CSF, liver, and kidney. The findings highlight the critical need to monitor systemic and neurological impacts, as well as organ function, to develop effective diagnostic and therapeutic strategies for survivors of nerve agent exposure or OP pesticide poisoning. Behavioral deficits and EEG changes in soman-exposed animals further emphasize the long-term neurological consequences of exposure.
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Affiliation(s)
- Nyzil Massey
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, USA
| | - Suraj S Vasanthi
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, USA
| | - Luis G Gimenez-Lirola
- Vet Diagnostic and Production Animal Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA, USA
| | - Harm Tyler
- Department of Veterinary Pathology, College of Veterinary Medicine, Iowa State University, Ames, IA, USA
| | - Thimmasettappa Thippeswamy
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, USA.
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Liu X, Jiang T, Xu L, Zhang W, Gao F. Efficacy of propofol and midazolam combination in managing refractory epileptic encephalopathy with spike-wave activation in sleep. Epilepsy Behav Rep 2025; 29:100732. [PMID: 39722895 PMCID: PMC11667020 DOI: 10.1016/j.ebr.2024.100732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Revised: 12/02/2024] [Accepted: 12/02/2024] [Indexed: 12/28/2024] Open
Abstract
We presented a 7-year-old boy with refractory Epileptic Encephalopathy with Spike-and-Wave Activation in Sleep (EE-SWAS) successfully managed with a combination of propofol and midazolam. His seizures began at age 2, initially controlled by multiple antiseizure medications (ASMs) for almost three years. At age 5, seizures recurred with electroencephalography (EEG) showing electrical status epilepticus in sleep (ESES) and a spike-wave index (SWI) of 85 %. High-dose methylprednisolone pulse therapy initially reduced the SWI to 50 %, but it relapsed to 80 % within six months. Despite further treatments, including methylprednisolone, midazolam infusion, and four combined ASMs, the SWI persisted between 75 % and 85 %, leading to progressively worsening cognitive impairment and subsequently a somnolent state with nearly continuous discharges. During hospitalization, a combination of propofol and midazolam significantly improved the condition, reducing the SWI to 50 % upon completion of the treatment period. Over a three-year follow-up, no ESES or seizures were reported, and cognitive function notably improved. Currently, there is no consensus on the treatment of ESES, which is sometimes refractory to medication and can result in partially irreversible cognitive impairment. Propofol in combination with midazolam has demonstrated effective suppression of ESES phenomena, presenting a promising treatment strategy for refractory ESES.
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Affiliation(s)
- Xiaorui Liu
- Department of Neurology, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China
- Epilepsy Center, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China
- Children’s Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou 310052, China
| | - Tiejia Jiang
- Department of Neurology, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China
- Epilepsy Center, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China
- Children’s Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou 310052, China
| | - Lu Xu
- Department of Neurology, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China
- Epilepsy Center, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China
- Children’s Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou 310052, China
| | - Weiran Zhang
- Department of Neurology, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China
- Epilepsy Center, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China
- Children’s Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou 310052, China
| | - Feng Gao
- Department of Neurology, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China
- Epilepsy Center, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou 310052, China
- Children’s Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou 310052, China
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Gorecki L, Pejchal J, Torruellas C, Korabecny J, Soukup O. Midazolam - A diazepam replacement for the management of nerve agent-induced seizures. Neuropharmacology 2024; 261:110171. [PMID: 39362626 DOI: 10.1016/j.neuropharm.2024.110171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 08/27/2024] [Accepted: 09/26/2024] [Indexed: 10/05/2024]
Abstract
A benzodiazepine, diazepam, has been the leading antidote for seizures caused by nerve agents, the most toxic chemical weapons of mass destruction, since the 1960s. However, its limitations have often brought questions about its usefulness. Extensive effort has been devoted into exploring alternatives, such as other benzodiazepines, anticholinergics, or glutamate antagonists. However, only few showed clear clinical benefit. The only two options to ultimately reach clinical milestones are Avizafone, a water-soluble prodrug of diazepam adopted by the French and UK armed forces, and intramuscular midazolam, adopted by the US Army. The recently FDA-approved new intramuscular application of midazolam brought several advantages, such as rapid onset of action, short duration with predictable pharmacokinetics, increased water solubility for aqueous injectable solutions, and prolonged storage stability. Herein, we discuss the pitfalls and prospects of using midazolam as a substitute in anticonvulsant therapy with a particular focus on military purposes in combat casualty care. We have also considered and discussed several other alternatives that are currently at the experimental level. Recent studies have shown the superiority of midazolam over other benzodiazepines in the medical management of poisoned casualties. While its use in emergency care is straightforward, the proper dose for soldiers under battlefield conditions is questionable due to its sedative effects.
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Affiliation(s)
- Lukas Gorecki
- University of Defence, Military Faculty of Medicine, Department of Toxicology and Military Pharmacy, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic; University Hospital Hradec Kralove, Biomedical Research Centre, Sokolska 581, 500 05, Hradec Kralove, Czech Republic.
| | - Jaroslav Pejchal
- University of Defence, Military Faculty of Medicine, Department of Toxicology and Military Pharmacy, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic
| | - Carilyn Torruellas
- U. S. Army CCDC Chemical Biological Center, Aberdeen Proving Ground, MD, 21010-5424, USA
| | - Jan Korabecny
- University of Defence, Military Faculty of Medicine, Department of Toxicology and Military Pharmacy, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic; University Hospital Hradec Kralove, Biomedical Research Centre, Sokolska 581, 500 05, Hradec Kralove, Czech Republic
| | - Ondrej Soukup
- University of Defence, Military Faculty of Medicine, Department of Toxicology and Military Pharmacy, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic; University Hospital Hradec Kralove, Biomedical Research Centre, Sokolska 581, 500 05, Hradec Kralove, Czech Republic
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6
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Cornelissen AS, van den Berg RM, Klaassen SD, de Koning JC, Langenberg JP, de Lange ECM, Joosen MJA. Synergistic polytherapy for the broad-spectrum treatment of chemically-induced seizures in rats. Toxicol Appl Pharmacol 2024; 493:117137. [PMID: 39476875 DOI: 10.1016/j.taap.2024.117137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 10/12/2024] [Accepted: 10/27/2024] [Indexed: 11/11/2024]
Abstract
Chemically-induced seizures, as a result of exposure to a neurotoxic compound, present a serious health concern. Compounds can elicit seizure activity through disruption of neuronal signaling by neurotransmitters, either by mimicking, modulating or antagonizing their action at the receptor or interfering with their metabolism. Benzodiazepines, such as diazepam and midazolam, and barbiturates are the mainstay of treatment of seizures. However, chemically-induced seizures are often persistent, requiring repeated treatment and increased doses of anticonvulsants, which in turn may lead to severe adverse effects such as respiratory depression. Here, we investigated the potential of rational polytherapy consisting of the benzodiazepine midazolam and the selective α2-adrenergic agonist dexmedetomidine as an improved, generically applicable anticonvulsant treatment regimen. Therapeutic efficacy was evaluated against two experimental paradigm compounds that induce persistent seizures in rats, the rodenticide TETS and the nerve agent soman. Following exposure, both TETS and soman elicited profound seizure activity and convulsions, associated with substantial mortality. Treatment with midazolam or dexmedetomidine alone provided no or limited suppression of seizure activity and improvement of survival at 4 h. Polytherapy consisting of midazolam and dexmedetomidine showed excellent anticonvulsant efficacy. Even at low doses, polytherapy showed a profound effect that lasted for the duration of the experiment. Analysis of the dose-response relationships confirmed presence of synergy. Administration of polytherapy in non-exposed animals did not indicate aggravation of adverse effects on respiration or heart rate. Even though more research is needed for the translation to clinical use, polytherapy consisting of midazolam and dexmedetomidine shows promise for the broad-spectrum treatment of (chemically-induced) seizures in emergency situations.
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Affiliation(s)
- Alex S Cornelissen
- Department of CBRN Protection, TNO Defence, Safety and Security, Lange Kleiweg 137, 2288 GJ Rijswijk, the Netherlands; Predictive Pharmacology group, Division of Systems Pharmacology and Pharmacy, Leiden Academic Center for Drug Research, Leiden University, Gorlaeus Laboratory, Einsteinweg 55, 2333 CC Leiden, the Netherlands.
| | - Roland M van den Berg
- Department of CBRN Protection, TNO Defence, Safety and Security, Lange Kleiweg 137, 2288 GJ Rijswijk, the Netherlands
| | - Steven D Klaassen
- Department of CBRN Protection, TNO Defence, Safety and Security, Lange Kleiweg 137, 2288 GJ Rijswijk, the Netherlands
| | - Jelle C de Koning
- Department of CBRN Protection, TNO Defence, Safety and Security, Lange Kleiweg 137, 2288 GJ Rijswijk, the Netherlands
| | - Jan P Langenberg
- Department of CBRN Protection, TNO Defence, Safety and Security, Lange Kleiweg 137, 2288 GJ Rijswijk, the Netherlands
| | - Elizabeth C M de Lange
- Predictive Pharmacology group, Division of Systems Pharmacology and Pharmacy, Leiden Academic Center for Drug Research, Leiden University, Gorlaeus Laboratory, Einsteinweg 55, 2333 CC Leiden, the Netherlands
| | - Marloes J A Joosen
- Department of CBRN Protection, TNO Defence, Safety and Security, Lange Kleiweg 137, 2288 GJ Rijswijk, the Netherlands
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Zhao BS, Deng B, Chen QB, Li X, Yang Y, Min S. Effect of quantitative consciousness index on seizure parameters during electroconvulsive therapy in patients with major depressive disorder. World J Psychiatry 2024; 14:1375-1385. [PMID: 39319236 PMCID: PMC11417648 DOI: 10.5498/wjp.v14.i9.1375] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 08/18/2024] [Accepted: 08/28/2024] [Indexed: 09/11/2024] Open
Abstract
BACKGROUND Electroconvulsive therapy (ECT) is both an effective treatment for patients with major depressive disorder (MDD) and a noxious stimulus. Although some studies have explored the effect of sedation depth on seizure parameters in ECT, there is little research on the noxious stimulation response to ECT. In this study, we used two electroencephalography (EEG)-derived indices, the quantitative consciousness (qCON) index and quantitative nociceptive (qNOX) index, to monitor sedation, hypnosis, and noxious stimulation response in patients with MDD undergoing acute ECT. AIM To evaluate the effect of anesthesia depth based on the qCON and qNOX indices on seizure parameters. METHODS Patients with MDD (n = 24) underwent acute bilateral temporal ECT under propofol anesthesia. Before ECT, the patients were randomly divided into three groups according to qCON scores (qCON60-70, qCON50-60, and qCON40-50). Continuous qCON monitoring was performed 3 minutes before and during ECT, and the qCON, qNOX, vital signs, EEG seizure parameters, and complications during the recovery period were recorded. The 24-item Hamilton Rating Scale for Depression, Zung's Self-rating Depression Scale, and Montreal Cognitive Assessment scores were evaluated before the first ECT session, after the fourth ECT session, and after the full course of ECT. RESULTS A total of 193 ECT sessions were performed on 24 participants. The qCON index significantly affected the EEG seizure duration, peak mid-ictal amplitude, and maximum heart rate during ECT (P < 0.05). The qNOX index significantly affected the post-ictal suppression index (P < 0.05). Age, number of ECT sessions, and anesthetic-ECT time intervals also had a significant effect on EEG seizure parameters (P < 0.05). However, there were no significant differences in complications, 24-item Hamilton Rating Scale for Depression scores, Zung's Self-rating Depression Scale scores, or Montreal Cognitive Assessment scores among the three groups (P > 0.05). CONCLUSION Electrical stimulation at a qCON index of 60-70 resulted in better EEG seizure parameters without increasing complications in patients with MDD undergoing bilateral temporal ECT under propofol anesthesia.
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Affiliation(s)
- Bang-Shu Zhao
- Department of Anesthesiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Bi Deng
- Department of Anesthesiology, The First Clinical College of Chongqing Medical University, Chongqing 400016, China
| | - Qi-Bin Chen
- Department of Anesthesiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Xiao Li
- Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - You Yang
- Department of Anesthesiology, The First Clinical College of Chongqing Medical University, Chongqing 400016, China
| | - Su Min
- Department of Anesthesiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
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Hobson BA, Rowland DJ, Dou Y, Saito N, Harmany ZT, Bruun DA, Harvey DJ, Chaudhari AJ, Garbow JR, Lein PJ. A longitudinal MRI and TSPO PET-based investigation of brain region-specific neuroprotection by diazepam versus midazolam following organophosphate-induced seizures. Neuropharmacology 2024; 251:109918. [PMID: 38527652 PMCID: PMC11250911 DOI: 10.1016/j.neuropharm.2024.109918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 03/01/2024] [Accepted: 03/13/2024] [Indexed: 03/27/2024]
Abstract
Acute poisoning with organophosphorus cholinesterase inhibitors (OPs), such as OP nerve agents and pesticides, can cause life threatening cholinergic crisis and status epilepticus (SE). Survivors often experience significant morbidity, including brain injury, acquired epilepsy, and cognitive deficits. Current medical countermeasures for acute OP poisoning include a benzodiazepine to mitigate seizures. Diazepam was long the benzodiazepine included in autoinjectors used to treat OP-induced seizures, but it is now being replaced in many guidelines by midazolam, which terminates seizures more quickly, particularly when administered intramuscularly. While a direct correlation between seizure duration and the extent of brain injury has been widely reported, there are limited data comparing the neuroprotective efficacy of diazepam versus midazolam following acute OP intoxication. To address this data gap, we used non-invasive imaging techniques to longitudinally quantify neuropathology in a rat model of acute intoxication with the OP diisopropylfluorophosphate (DFP) with and without post-exposure intervention with diazepam or midazolam. Magnetic resonance imaging (MRI) was used to monitor neuropathology and brain atrophy, while positron emission tomography (PET) with a radiotracer targeting translocator protein (TSPO) was utilized to assess neuroinflammation. Animals were scanned at 3, 7, 28, 65, 91, and 168 days post-DFP and imaging metrics were quantitated for the hippocampus, amygdala, piriform cortex, thalamus, cerebral cortex and lateral ventricles. In the DFP-intoxicated rat, neuroinflammation persisted for the duration of the study coincident with progressive atrophy and ongoing tissue remodeling. Benzodiazepines attenuated neuropathology in a region-dependent manner, but neither benzodiazepine was effective in attenuating long-term neuroinflammation as detected by TSPO PET. Diffusion MRI and TSPO PET metrics were highly correlated with seizure severity, and early MRI and PET metrics were positively correlated with long-term brain atrophy. Collectively, these results suggest that anti-seizure therapy alone is insufficient to prevent long-lasting neuroinflammation and tissue remodeling.
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Affiliation(s)
- Brad A Hobson
- Department of Molecular Biosciences, University of California, Davis, School of Veterinary Medicine, Davis, CA 95616, USA; Center for Molecular and Genomic Imaging, University of California, Davis, College of Engineering, Davis, CA 95616, USA.
| | - Douglas J Rowland
- Center for Molecular and Genomic Imaging, University of California, Davis, College of Engineering, Davis, CA 95616, USA.
| | - Yimeng Dou
- Department of Molecular Biosciences, University of California, Davis, School of Veterinary Medicine, Davis, CA 95616, USA.
| | - Naomi Saito
- Department of Public Health Sciences, University of California, Davis, School of Medicine, California 95616, USA.
| | - Zachary T Harmany
- Center for Molecular and Genomic Imaging, University of California, Davis, College of Engineering, Davis, CA 95616, USA.
| | - Donald A Bruun
- Department of Molecular Biosciences, University of California, Davis, School of Veterinary Medicine, Davis, CA 95616, USA.
| | - Danielle J Harvey
- Department of Public Health Sciences, University of California, Davis, School of Medicine, California 95616, USA.
| | - Abhijit J Chaudhari
- Center for Molecular and Genomic Imaging, University of California, Davis, College of Engineering, Davis, CA 95616, USA; Department of Radiology, University of California, Davis, School of Medicine, California 95817, USA.
| | - Joel R Garbow
- Biomedical Magnetic Resonance Center, Mallinckrodt Institute of Radiology, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, 63110, USA.
| | - Pamela J Lein
- Department of Molecular Biosciences, University of California, Davis, School of Veterinary Medicine, Davis, CA 95616, USA.
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Almeida AJD, Hobson BA, Saito N, Bruun DA, Porter VA, Harvey DJ, Garbow JR, Chaudhari AJ, Lein PJ. Quantitative T 2 mapping-based longitudinal assessment of brain injury and therapeutic rescue in the rat following acute organophosphate intoxication. Neuropharmacology 2024; 249:109895. [PMID: 38437913 PMCID: PMC11227117 DOI: 10.1016/j.neuropharm.2024.109895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 02/07/2024] [Accepted: 02/29/2024] [Indexed: 03/06/2024]
Abstract
Acute intoxication with organophosphate (OP) cholinesterase inhibitors poses a significant public health risk. While currently approved medical countermeasures can improve survival rates, they often fail to prevent chronic neurological damage. Therefore, there is need to develop effective therapies and quantitative metrics for assessing OP-induced brain injury and its rescue by these therapies. In this study we used a rat model of acute intoxication with the OP, diisopropylfluorophosphate (DFP), to test the hypothesis that T2 measures obtained from brain magnetic resonance imaging (MRI) scans provide quantitative metrics of brain injury and therapeutic efficacy. Adult male Sprague Dawley rats were imaged on a 7T MRI scanner at 3, 7 and 28 days post-exposure to DFP or vehicle (VEH) with or without treatment with the standard of care antiseizure drug, midazolam (MDZ); a novel antiseizure medication, allopregnanolone (ALLO); or combination therapy with MDZ and ALLO (DUO). Our results show that mean T2 values in DFP-exposed animals were: (1) higher than VEH in all volumes of interest (VOIs) at day 3; (2) decreased with time; and (3) decreased in the thalamus at day 28. Treatment with ALLO or DUO, but not MDZ alone, significantly decreased mean T2 values relative to untreated DFP animals in the piriform cortex at day 3. On day 28, the DUO group showed the most favorable T2 characteristics. This study supports the utility of T2 mapping for longitudinally monitoring brain injury and highlights the therapeutic potential of ALLO as an adjunct therapy to mitigate chronic morbidity associated with acute OP intoxication.
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Affiliation(s)
- Alita Jesal D Almeida
- Department of Biomedical Engineering, University of California-Davis College of Engineering, Davis, CA, 95616, USA; Department of Radiology, University of California-Davis School of Medicine, Sacramento, CA, 95817, USA.
| | - Brad A Hobson
- Center for Molecular and Genomic Imaging, Department of Biomedical Engineering, University of California-Davis College of Engineering, Davis, CA, 95616, USA.
| | - Naomi Saito
- Department of Public Health Sciences, University of California-Davis School of Medicine, Davis, CA, 95616, USA
| | - Donald A Bruun
- Department of Molecular Biosciences, University of California-Davis School of Veterinary Medicine, Davis, CA, 95616, USA.
| | - Valerie A Porter
- Department of Biomedical Engineering, University of California-Davis College of Engineering, Davis, CA, 95616, USA; Department of Radiology, University of California-Davis School of Medicine, Sacramento, CA, 95817, USA.
| | - Danielle J Harvey
- Department of Public Health Sciences, University of California-Davis School of Medicine, Davis, CA, 95616, USA.
| | - Joel R Garbow
- Department of Radiology, Washington University School of Medicine, St Louis, MO, 63110, USA.
| | - Abhijit J Chaudhari
- Department of Radiology, University of California-Davis School of Medicine, Sacramento, CA, 95817, USA; Center for Molecular and Genomic Imaging, Department of Biomedical Engineering, University of California-Davis College of Engineering, Davis, CA, 95616, USA.
| | - Pamela J Lein
- Department of Molecular Biosciences, University of California-Davis School of Veterinary Medicine, Davis, CA, 95616, USA.
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10
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Pan S, Bruun DA, Lein PJ, Chen CY. Cardiovascular responses of adult male Sprague-Dawley rats following acute organophosphate intoxication and post-exposure treatment with midazolam with or without allopregnanolone. Arch Toxicol 2024; 98:1177-1189. [PMID: 38305864 PMCID: PMC10944447 DOI: 10.1007/s00204-023-03679-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 12/20/2023] [Indexed: 02/03/2024]
Abstract
Recent experimental evidence suggests combined treatment with midazolam and allopregnanolone is more effective than midazolam alone in terminating seizures triggered by acute organophosphate (OP) intoxication. However, there are concerns that combined midazolam and allopregnanolone increases risk of adverse cardiovascular events. To address this, we used telemetry devices to record cardiovascular responses in adult male Sprague-Dawley rats acutely intoxicated with diisopropylfluorophosphate (DFP). Animals were administered DFP (4 mg/kg, sc), followed immediately by atropine (2 mg/kg, i.m.) and 2-PAM (25 mg/kg, i.m.). At 40 min post-exposure, a subset of animals received midazolam (0.65 mg/kg, im); at 50 min, these rats received a second dose of midazolam or allopregnanolone (12 mg/kg, im). DFP significantly increased blood pressure by ~ 80 mmHg and pulse pressure by ~ 34 mmHg that peaked within 12 min. DFP also increased core temperature by ~ 3.5 °C and heart rate by ~ 250 bpm that peaked at ~ 2 h. Heart rate variability (HRV), an index of autonomic function, was reduced by ~ 80%. All acute (within 15 min of exposure) and two-thirds of delayed (hours after exposure) mortalities were associated with non-ventricular cardiac events within 10 min of cardiovascular collapse, suggesting that non-ventricular events should be closely monitored in OP-poisoned patients. Compared to rats that survived DFP intoxication without treatment, midazolam significantly improved recovery of cardiovascular parameters and HRV, an effect enhanced by allopregnanolone. These data demonstrate that midazolam improved recovery of cardiovascular and autonomic function and that the combination of midazolam and allopregnanolone may be a better therapeutic strategy than midazolam alone.
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Affiliation(s)
- Shiyue Pan
- Department of Pharmacology, Davis, School of Medicine, University of California, Davis, CA, USA
| | - Donald A Bruun
- Department of Molecular Biosciences, Davis, School of Veterinary Medicine, University of California, Davis, CA, USA
| | - Pamela J Lein
- Department of Molecular Biosciences, Davis, School of Veterinary Medicine, University of California, Davis, CA, USA
- Davis, School of Medicine, MIND Institute, University of California, Sacramento, CA, USA
| | - Chao-Yin Chen
- Department of Pharmacology, Davis, School of Medicine, University of California, Davis, CA, USA.
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11
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Reddy DS. 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. J Pharmacol Exp Ther 2024; 388:273-300. [PMID: 37977814 PMCID: PMC10801762 DOI: 10.1124/jpet.123.001816] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 10/05/2023] [Accepted: 10/23/2023] [Indexed: 11/19/2023] Open
Abstract
This article describes recent advances in the use of neurosteroids as novel anticonvulsants for refractory status epilepticus (RSE) and as medical countermeasures (MCs) for organophosphates and chemical nerve agents (OPNAs). We highlight a comprehensive 15-year journey to bring the synthetic neurosteroid ganaxolone (GX) from bench to clinic. RSE, including when caused by nerve agents, is associated with devastating morbidity and permanent long-term neurologic dysfunction. Although recent approval of benzodiazepines such as intranasal midazolam and intranasal midazolam offers improved control of acute seizures, novel anticonvulsants are needed to suppress RSE and improve neurologic function outcomes. Currently, few anticonvulsant MCs exist for victims of OPNA exposure and RSE. Standard-of-care MCs for postexposure treatment include benzodiazepines, which do not effectively prevent or mitigate seizures resulting from nerve agent intoxication, leaving an urgent unmet medical need for new anticonvulsants for RSE. Recently, we pioneered neurosteroids as next-generation anticonvulsants that are superior to benzodiazepines for treatment of OPNA intoxication and RSE. Because GX and related neurosteroids that activate extrasynaptic GABA-A receptors rapidly control seizures and offer robust neuroprotection by reducing neuronal damage and neuroinflammation, they effectively improve neurologic outcomes after acute OPNA exposure and RSE. GX has been selected for advanced, Biomedical Advanced Research and Development Authority-supported phase 3 trials of RSE and nerve agent seizures. In addition, in mechanistic studies of neurosteroids at extrasynaptic receptors, we identified novel synthetic analogs with features that are superior to GX for current medical needs. Development of new MCs for RSE is complex, tedious, and uncertain due to scientific and regulatory challenges. Thus, further research will be critical to fill key gaps in evaluating RSE and anticonvulsants in vulnerable (pediatric and geriatric) populations and military persons. SIGNIFICANCE STATEMENT: Following organophosphate and nerve agent intoxication, refractory status epilepticus (RSE) occurs despite benzodiazepine treatment. RSE occurs in 40% of status epilepticus patients, with a 35% mortality rate and significant neurological morbidity in survivors. To treat RSE, neurosteroids are better anticonvulsants than benzodiazepines. Our pioneering use of neurosteroids for RSE and nerve agents led us to develop ganaxolone as a novel anticonvulsant and neuroprotectant with significantly improved neurological outcomes. This article describes the bench-to-bedside journey of bringing neurosteroid therapy to patients, with ganaxolone leading the way.
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Affiliation(s)
- Doodipala Samba Reddy
- Department of Neuroscience and Experimental Therapeutics, Texas A&M University School of Medicine, Bryan, Texas and Institute of Pharmacology and Neurotherapeutics, Texas A&M University Health Science Center, Bryan, Texas
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12
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Reddy DS, Singh T, Ramakrishnan S, Huber M, Wu X. Neuroprotectant Activity of Novel Water-Soluble Synthetic Neurosteroids on Organophosphate Intoxication and Status Epilepticus-Induced Long-Term Neurological Dysfunction, Neurodegeneration, and Neuroinflammation. J Pharmacol Exp Ther 2024; 388:399-415. [PMID: 38071567 PMCID: PMC10801736 DOI: 10.1124/jpet.123.001819] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 09/18/2023] [Indexed: 01/19/2024] Open
Abstract
Organophosphates (OPs) and nerve agents are potent neurotoxic compounds that cause seizures, status epilepticus (SE), brain injury, or death. There are persistent long-term neurologic and neurodegenerative effects that manifest months to years after the initial exposure. Current antidotes are ineffective in preventing these long-term neurobehavioral and neuropathological changes. Additionally, there are few effective neuroprotectants for mitigating the long-term effects of acute OP intoxication. We have pioneered neurosteroids as novel anticonvulsants and neuroprotectants for OP intoxication and seizures. In this study, we evaluated the efficacy of two novel synthetic, water-soluble neurosteroids, valaxanolone (VX) and lysaxanolone (LX), in combating the long-term behavioral and neuropathological impairments caused by acute OP intoxication and SE. Animals were exposed to the OP nerve agent surrogate diisopropylfluorophosphate (DFP) and were treated with VX or LX in addition to midazolam at 40 minutes postexposure. The extent of neurodegeneration, along with various behavioral and memory deficits, were assessed at 3 months postexposure. VX significantly reduced deficits of aggressive behavior, anxiety, memory, and depressive-like traits in control (DFP-exposed, midazolam-treated) animals; VX also significantly prevented the DFP-induced chronic loss of NeuN(+) principal neurons and PV(+) inhibitory neurons in the hippocampus and other regions. Additionally, VX-treated animals exhibited a reduced inflammatory response with decreased GFAP(+) astrogliosis and IBA1(+) microgliosis in the hippocampus, amygdala, and other regions. Similarly, LX showed significant improvement in behavioral and memory deficits, and reduced neurodegeneration and cellular neuroinflammation. Together, these results demonstrate the neuroprotectant effects of the novel synthetic neurosteroids in mitigating the long-term neurologic dysfunction and neurodegeneration associated with OP exposure. SIGNIFICANCE STATEMENT: Survivors of nerve agents and organophosphate (OP) exposures suffer from long-term neurological deficits. Currently, there is no specific drug therapy for mitigating the impact of OP exposure. However, novel synthetic neurosteroids that activate tonic inhibition provide a viable option for treating OP intoxication. The data from this study indicates the neuroprotective effects of synthetic, water-soluble neurosteroids for attenuation of long-term neurological deficits after OP intoxication. These findings establish valaxanolone and lysaxanolone as potent and efficacious neuroprotectants suitable for injectable dosing.
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Affiliation(s)
- Doodipala Samba Reddy
- Department of Neuroscience and Experimental Therapeutics, Texas A&M University School of Medicine, Bryan, Texas (D.S.R., T.S., S.R., M.H., X.W.) and Institute of Pharmacology and Neurotherapeutics, Texas A&M University Health Science Center, Bryan, Texas (D.S.R., S.R., X.W.)
| | - Tanveer Singh
- Department of Neuroscience and Experimental Therapeutics, Texas A&M University School of Medicine, Bryan, Texas (D.S.R., T.S., S.R., M.H., X.W.) and Institute of Pharmacology and Neurotherapeutics, Texas A&M University Health Science Center, Bryan, Texas (D.S.R., S.R., X.W.)
| | - Sreevidhya Ramakrishnan
- Department of Neuroscience and Experimental Therapeutics, Texas A&M University School of Medicine, Bryan, Texas (D.S.R., T.S., S.R., M.H., X.W.) and Institute of Pharmacology and Neurotherapeutics, Texas A&M University Health Science Center, Bryan, Texas (D.S.R., S.R., X.W.)
| | - Madeline Huber
- Department of Neuroscience and Experimental Therapeutics, Texas A&M University School of Medicine, Bryan, Texas (D.S.R., T.S., S.R., M.H., X.W.) and Institute of Pharmacology and Neurotherapeutics, Texas A&M University Health Science Center, Bryan, Texas (D.S.R., S.R., X.W.)
| | - Xin Wu
- Department of Neuroscience and Experimental Therapeutics, Texas A&M University School of Medicine, Bryan, Texas (D.S.R., T.S., S.R., M.H., X.W.) and Institute of Pharmacology and Neurotherapeutics, Texas A&M University Health Science Center, Bryan, Texas (D.S.R., S.R., X.W.)
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13
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Singh T, Ramakrishnan S, Wu X, Reddy DS. Sex Differences in Organophosphate Model of Benzodiazepine-Refractory Status Epilepticus and Neuronal Damage. J Pharmacol Exp Ther 2024; 388:313-324. [PMID: 37770202 PMCID: PMC10801723 DOI: 10.1124/jpet.123.001747] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 08/15/2023] [Accepted: 08/17/2023] [Indexed: 10/03/2023] Open
Abstract
Sex differences are common in human epilepsy. Although men are more susceptible to seizure than women, the mechanisms underlying sex-specific vulnerabilities to seizure are unclear. The organophosphate (OP) diisopropylfluorophosphate (DFP) is known to cause neurotoxicity and status epilepticus (SE), a serious neurologic condition that causes prolonged seizures and brain damage. Current therapies for OP poisoning and SE do not consider neuronal variations between male and female brains. Therefore, we investigated sex-dependent differences in electrographic seizure activity and neuronal injury using the DFP model of refractory SE in rats. Electroencephalogram recordings were used to monitor DFP-induced SE, and the extent of brain injury was determined using fluoro-jade-B staining to detect cellular necrosis. After DFP exposure, we observed striking sex-dependent differences in SE and seizure activity patterns as well as protective responses to midazolam treatment. Following acute DFP exposure, male animals displayed more severe SE with intense epileptiform spiking and greater mortality than females. In contrast, we observed significantly more injured cells and cellular necrosis in the hippocampus and other brain regions in females than in males. We also observed extensive neuronal injury in the somatosensory cortex of males. The anticonvulsant effect of midazolam against SE was limited in this model and found to be similar in males and females. However, unlike males, females exhibited substantially more protection against neuronal damage after midazolam treatment. Overall, these results demonstrate significant sex-dependent differences in DFP-induced refractory SE and neuronal damage patterns, suggesting that it may be possible to develop sex-specific neuroprotective strategies for OP intoxication and refractory SE. SIGNIFICANCE STATEMENT: Sex-dependent differences in neurotoxicity and status epilepticus (SE) are key biological variables after organophosphate (OP) exposure. Here, we investigated sex-dependent differences in SE and brain injury after acute diisopropylfluorophosphate exposure. Male rats had more severe SE and less survival than females, while females had more neuronal damage. Females had more neuroprotection to midazolam than males, while both sexes had similar but partial anticonvulsant effects. These findings suggest that a sex-specific therapeutic approach may prevent neurological complications of OP-induced SE.
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Affiliation(s)
- Tanveer Singh
- Department of Neuroscience and Experimental Therapeutics and Institute of Pharmacology and Neurotherapeutics, Texas A&M University School of Medicine, Bryan, Texas
| | - Sreevidhya Ramakrishnan
- Department of Neuroscience and Experimental Therapeutics and Institute of Pharmacology and Neurotherapeutics, Texas A&M University School of Medicine, Bryan, Texas
| | - Xin Wu
- Department of Neuroscience and Experimental Therapeutics and Institute of Pharmacology and Neurotherapeutics, Texas A&M University School of Medicine, Bryan, Texas
| | - Doodipala Samba Reddy
- Department of Neuroscience and Experimental Therapeutics and Institute of Pharmacology and Neurotherapeutics, Texas A&M University School of Medicine, Bryan, Texas
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14
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Shah EJ, Grunwald WC, Garrett TL, Brown TL, Cool DR. Sarin-Induced Neuroinflammation in Mouse Brain Is Attenuated by the Caspase Inhibitor Q-VD-OPh. J Pharmacol Exp Ther 2024; 388:367-375. [PMID: 37918856 PMCID: PMC10801781 DOI: 10.1124/jpet.123.001820] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 10/02/2023] [Accepted: 10/04/2023] [Indexed: 11/04/2023] Open
Abstract
Organophosphates cause hyperstimulation of the central nervous system, leading to extended seizures, convulsions, and brain damage. Sarin is a highly toxic organophosphate nerve agent that has been employed in several terrorist attacks. The prolonged toxicity of sarin may be enhanced by the neuroinflammatory response initiated by the inflammasome, caspase involvement, and generation/release of proinflammatory cytokines. Since neurodegeneration and neuroinflammation are prevalent in sarin-exposed animals, we were interested in evaluating the capacity of quinolyl-valyl-O-methylaspartyl-[-2,6-difluorophenoxy]-methyl ketone (Q-VD-OPh), a pan caspase inhibitor to attenuate neuroinflammation following sarin exposure. To test this hypothesis, sarin-exposed C57BL/6 mice were treated with Q-VD-OPh or negative control quinolyl-valyl-O-methylglutamyl-[-2,6-difluorophenoxy]-methyl ketone, sacrificed at 2- and 14-day time points, followed by removal of the amygdala and hippocampus. A Bio-Rad 23-Plex cytokine analysis was completed on each tissue. The results suggest that exposure to sarin induced a dramatic increase in interleukin-1β and 6 other cytokines and a decrease in 2 of the 23 cytokines at 2 days in the amygdala compared with controls. Q-VD-OPh attenuated these changes at the 2-day time point. At 14 days, six of these cytokines were still significantly different from controls. Hippocampus was less affected at both time points. Diazepam, a neuroprotective drug against nerve agents, caused an increase in several cytokines but did not have a synergistic effect with Q-VD-OPh. Treatment of sarin exposure with apoptosis inhibitors appears to be a worthwhile approach for further testing as a comprehensive counteragent against organophosphate exposure. SIGNIFICANCE STATEMENT: A pan inhibitor of caspases (Q-VD-OPh) was proposed as a potential antidote for sarin-induced neuroinflammation by reducing the level of inflammation via inflammasome caspase inhibition. Q-VD-OPh added at 30 minutes post-sarin exposure attenuated the inflammatory response of a number of cytokines and chemokines in the amygdala and hippocampus, two brain regions sensitive to organophosphate exposure. Apoptotic marker reduction at 2 and 14 days further supports further testing of inhibitors of apoptosis as a means to lessen extended organophosphate toxicity in the brain.
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Affiliation(s)
- Ekta J Shah
- Departments of Pharmacology and Toxicology (E.J.S., W.C.G, T.L.G., D.R.C) and Neuroscience, Cell Biology and Physiology (T.L.G., T.L.B.), Wright State University, Dayton, Ohio
| | - William C Grunwald
- Departments of Pharmacology and Toxicology (E.J.S., W.C.G, T.L.G., D.R.C) and Neuroscience, Cell Biology and Physiology (T.L.G., T.L.B.), Wright State University, Dayton, Ohio
| | - Teresa L Garrett
- Departments of Pharmacology and Toxicology (E.J.S., W.C.G, T.L.G., D.R.C) and Neuroscience, Cell Biology and Physiology (T.L.G., T.L.B.), Wright State University, Dayton, Ohio
| | - Thomas L Brown
- Departments of Pharmacology and Toxicology (E.J.S., W.C.G, T.L.G., D.R.C) and Neuroscience, Cell Biology and Physiology (T.L.G., T.L.B.), Wright State University, Dayton, Ohio
| | - David R Cool
- Departments of Pharmacology and Toxicology (E.J.S., W.C.G, T.L.G., D.R.C) and Neuroscience, Cell Biology and Physiology (T.L.G., T.L.B.), Wright State University, Dayton, Ohio
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15
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Ramakrishnan S, Singh T, Reddy DS. Protective Activity of Novel Hydrophilic Synthetic Neurosteroids on Organophosphate Status Epilepticus-induced Chronic Epileptic Seizures, Non-Convulsive Discharges, High-Frequency Oscillations, and Electrographic Ictal Biomarkers. J Pharmacol Exp Ther 2024; 388:386-398. [PMID: 38050069 PMCID: PMC10801763 DOI: 10.1124/jpet.123.001817] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 11/07/2023] [Accepted: 11/08/2023] [Indexed: 12/06/2023] Open
Abstract
Nerve agents and organophosphates (OP) are neurotoxic chemicals that induce acute seizures, status epilepticus (SE), and mortality. Long-term neurologic and neurodegenerative effects manifest months to years after OP exposure. Current benzodiazepine anticonvulsants are ineffective in preventing such long-term neurobehavioral and neuropathological changes. New and effective anticonvulsants are needed for OP intoxication, especially for mitigating the long-term sequelae after acute exposure. We developed neurosteroids as novel anticonvulsants and neuroprotectants in OP exposure models. In this study, we evaluated the long-term efficacy of novel synthetic neurosteroids in preventing the development of chronic epilepsy and hyperexcitable ictal events in a rat OP model of SE. Rats were exposed to the OP nerve agent surrogate diisopropylfluorophosphate (DFP), and the experimental groups were treated with the synthetic neurosteroid valaxanolone (VX) or lysaxanolone (LX) 40 minutes post-exposure in conjunction with midazolam. Video-electroencephalography was monitored for two months to assess spontaneous recurrent seizures (SRS), epileptiform discharges, interictal spikes, and high-frequency oscillations (HFOs). Within 60 days of DFP exposure, rats developed chronic epilepsy characterized by frequent SRS, epileptiform discharges, and HFOs. LX treatment was associated with a dose-dependent reduction of epilepsy occurrence and overall seizure burden with a significant decrease in SRS and epileptiform discharges. It also significantly reduced the occurrence of epileptic biomarkers of HFOs and interictal spikes, indicating potential disease-modifying activity. Similarly, the neurosteroid analog VX also significantly attenuated SRS, discharges, HFOs, and ictal events. These results demonstrate the long-term protective effects of synthetic neurosteroids in the OP-exposed post-SE model, indicating their disease-modifying potential to prevent epilepsy and ictal abnormalities. SIGNIFICANCE STATEMENT: The effects of nerve agents and organophosphate (OP) exposure are persistent, and survivors suffer from a number of devastating, chronic neurological dysfunctions. Currently, there is no specific therapy for preventing this disastrous impact of OP exposure. We propose synthetic neurosteroids that activate tonic inhibition provide viable options for preventing the long-term neurological effects of OP intoxication. The results from this study reveal the disease-modifying potential of two novel synthetic neurosteroids in preventing epileptogenesis and chronic epileptic seizures after OP-induced SE.
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Affiliation(s)
- Sreevidhya Ramakrishnan
- Department of Neuroscience and Experimental Therapeutics (S.R., T.S., D.S.R.) and Institute of Pharmacology and Neurotherapeutics (D.S.R.), School of Medicine, Texas A&M University Health Science Center, Bryan, Texas
| | - Tanveer Singh
- Department of Neuroscience and Experimental Therapeutics (S.R., T.S., D.S.R.) and Institute of Pharmacology and Neurotherapeutics (D.S.R.), School of Medicine, Texas A&M University Health Science Center, Bryan, Texas
| | - Doodipala Samba Reddy
- Department of Neuroscience and Experimental Therapeutics (S.R., T.S., D.S.R.) and Institute of Pharmacology and Neurotherapeutics (D.S.R.), School of Medicine, Texas A&M University Health Science Center, Bryan, Texas
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16
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Neff MJ, Reddy DS. Long-Term Neuropsychiatric Developmental Defects after Neonatal Organophosphate Exposure: Mitigation by Synthetic Neurosteroids. J Pharmacol Exp Ther 2024; 388:451-468. [PMID: 37863488 PMCID: PMC10806574 DOI: 10.1124/jpet.123.001763] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 07/25/2023] [Accepted: 07/31/2023] [Indexed: 10/22/2023] Open
Abstract
Children are much more susceptible to the neurotoxic effects of organophosphate (OP) pesticides and nerve agents than adults. OP poisoning in children leads to acute seizures and neuropsychiatric sequela, including the development of long-term disabilities and cognitive impairments. Despite these risks, there are few chronic rodent models that use pediatric OP exposure for studying neurodevelopmental consequences and interventions. Here, we investigated the protective effect of the neurosteroid ganaxolone (GX) on the long-term developmental impact of neonatal exposure to the OP compound, diisopropyl-fluorophosphate (DFP). Pediatric postnatal day-28 rats were acutely exposed to DFP, and at 3 and 10 months after exposure, they were evaluated using a series of cognitive and behavioral tests with or without the postexposure treatment of GX. Analysis of the neuropathology was performed after 10 months. DFP-exposed animals displayed significant long-term deficits in mood, anxiety, depression, and aggressive traits. In spatial and nonspatial cognitive tests, they displayed striking impairments in learning and memory. Analysis of brain sections showed significant loss of neuronal nuclei antigen(+) principal neurons, parvalbumin(+) inhibitory interneurons, and neurogenesis, along with increased astrogliosis, microglial neuroinflammation, and mossy fiber sprouting. These detrimental neuropathological changes are consistent with behavioral dysfunctions. In the neurosteroid GX-treated cohort, behavioral and cognitive deficits were significantly reduced and were associated with strong protection against long-term neuroinflammation and neurodegeneration. In conclusion, this pediatric model replicates the salient features of children exposed to OPs, and the protective outcomes from neurosteroid intervention support the viability of developing this strategy for mitigating the long-term effects of acute OP exposure in children. SIGNIFICANCE STATEMENT: An estimated 3 million organophosphate exposures occur annually worldwide, with children comprising over 30% of all victims. Our understanding of the neurodevelopmental consequences in children exposed to organophosphates is limited. Here, we investigated the long-term impact of neonatal exposure to diisopropyl-fluorophosphate in pediatric rats. Neurosteroid treatment protected against major deficits in behavior and memory and was well correlated with neuropathological changes. Overall, this pediatric model is helpful to screen novel therapies to mitigate long-term developmental deficits of organophosphate exposure.
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Affiliation(s)
- Michael James Neff
- Department of Neuroscience and Experimental Therapeutics (M.J.N., D.S.R.) and Institute of Pharmacology and Neurotherapeutics (M.J.N., D.S.R.), School of Medicine, Texas A&M University Health Science Center, Bryan, Texas
| | - Doodipala Samba Reddy
- Department of Neuroscience and Experimental Therapeutics (M.J.N., D.S.R.) and Institute of Pharmacology and Neurotherapeutics (M.J.N., D.S.R.), School of Medicine, Texas A&M University Health Science Center, Bryan, Texas
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17
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Reddy DS. Progress and Challenges in Developing Medical Countermeasures for Chemical, Biological, Radiological, and Nuclear Threat Agents. J Pharmacol Exp Ther 2024; 388:260-267. [PMID: 38233227 PMCID: PMC10801730 DOI: 10.1124/jpet.123.002040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 12/06/2023] [Accepted: 12/06/2023] [Indexed: 01/10/2024] Open
Abstract
This Commentary delves into the current progress and challenges on ongoing research on medical countermeasures (MCs) for chemical, biologic, radiologic, and nuclear (CBRN) threats. CBRN agents pose a serious risk to human health and safety, with the potential for mass casualties in both military and civilian settings. Chemical threats are toxic compounds that could be used in a terrorist attack, an accidental release, or chemical warfare. They include nerve agents, organophosphates, pulmonary agents, metabolic/cellular agents, vesicants, ocular toxicants, and opioid agents. Developing effective MCs is crucial for mitigating the acute and chronic effects of exposure to CBRN agents. The papers in this special issue of JPET highlights the latest advancements in MC research, showcasing insightful outcomes on experimental models, mechanisms, and translational research on MCs for CBRN threats. They portray several notable contributions, including the development of neurosteroid and combination anticonvulsant therapies for nerve agent poisoning, the exploration of chronic impacts and diagnostic tracers for OP neurotoxicity, the establishment of innovative pediatric OP models, the identification of novel molecules for ocular, pulmonary and vesicant injuries, and the repurposing of existing drugs for the treatment of botulism, cyanide, and OP poisoning. These crucial outcomes underscore the breadth of current research covering a variety of chemical threats. Overall, this collection of articles highlights the importance of ongoing research and development in the field of MCs, emphasizing the potential of these countermeasures to effectively treat and mitigate the effects of toxicant exposures and thereby enhance our preparedness for mass casualty incidents. SIGNIFICANCE STATEMENT: CBRN agents pose a significant threat to public health. Effective MCs exist for certain chemical threats, but there is a need for new and improved MCs for many others. The research presented in this special issue of JPET highlights the latest advancements in MCs for CBRN threats. This research has the potential to lead to the development of new and repurposed MCs that are more effective, broad-spectrum, and easier to administer to mitigate acute and long-term consequences of chemical exposures.
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Affiliation(s)
- Doodipala Samba Reddy
- Department of Neuroscience and Experimental Therapeutics, Texas A&M University School of Medicine and Institute of Pharmacology and Neurotherapeutics, Texas A&M University Health Science Center, Bryan, Texas
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Singh T, Ramakrishnan S, Wu X, Reddy DS. A Pediatric Rat Model of Organophosphate-Induced Refractory Status Epilepticus: Characterization of Long-Term Epileptic Seizure Activity, Neurologic Dysfunction and Neurodegeneration. J Pharmacol Exp Ther 2024; 388:416-431. [PMID: 37977810 PMCID: PMC10801778 DOI: 10.1124/jpet.123.001794] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 09/09/2023] [Accepted: 09/26/2023] [Indexed: 11/19/2023] Open
Abstract
Children are highly vulnerable to the neurotoxic effects of organophosphates (OPs), which can cause neuronal developmental defects, including intellectual disability, autism, epilepsy, and related comorbidities. Unfortunately, no specific pediatric OP neurotoxicity model currently exists. In this study, we developed and characterized a pediatric rat model of status epilepticus (SE) induced by the OP diisopropylfluorophosphate (DFP) and examined its impact on long-term neurological outcomes. Postnatal day 21 rats were exposed to a DFP regimen with standard antidotes. Progressive behavioral deteriorations were assessed over a three-month period. Development of epileptic seizures, ictal discharges, high-frequency oscillations (HFOs), and interictal spikes were monitored by video-electroencephalography recordings. Histology-stereology analysis was performed to assess neurodegeneration, neuroinflammation, and morphologic abnormalities. DFP-exposed, post-SE animals exhibited significantly elevated levels of anxiety and depression than age-matched controls at 1, 2, and 3 months post-exposure. DFP-exposed animals displayed aggressive behavior and a marked decline in object recognition memory, as well as prominent impairment in spatial learning and memory. DFP-exposed animals had striking electrographic abnormalities with the occurrence of displayed epileptic seizures, ictal discharges, HFOs, and interictal spikes, suggesting chronic epilepsy. Neuropathological analysis showed substantially fewer principal neurons and inhibitory interneurons with a marked increase in reactive microglia and neuroinflammation in the hippocampus and other brain regions. DFP-exposed animals also exhibited mossy fiber sprouting indicating impaired network formations. Long-term epileptic seizures and neuropsychiatric functional deficits induced by DFP were consistent with neuropathological defects. Collectively, this pediatric model displays many hallmarks of chronic sequelae reminiscent of children exposed to OPs, suggesting that it will be a valuable tool for investigating pathologic mechanisms and potential treatment strategies to attenuate long-term OP neurotoxicity. SIGNIFICANCE STATEMENT: Millions of children are exposed to organophosphates (OPs) used in agriculture or chemical incidents. This study investigated the long-term impact of neonatal exposure to the OP chemical diisopropylfluorophosphate (DFP) on neurobehavioral and neurodevelopmental outcomes in adulthood. DFP exposure caused long-lasting behavioral abnormalities, epileptic seizures, and bilateral brain defects with an array of neurological sequelae seen in children's OP neurotoxicity. Thus, this model provides a novel tool to explore therapeutic interventions that mitigate long-term neurotoxic effects of children exposed to OP-induced seizures and status epilepticus.
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Affiliation(s)
- Tanveer Singh
- Department of Neuroscience and Experimental Therapeutics, Texas A&M University School of Medicine, Bryan, Texas (T.S., S.R., X.W., D.S.R.) and Institute of Pharmacology and Neurotherapeutics, Texas A&M University Health Science Center, Bryan, Texas (T.S., S.R., X.W., D.S.R.)
| | - Sreevidhya Ramakrishnan
- Department of Neuroscience and Experimental Therapeutics, Texas A&M University School of Medicine, Bryan, Texas (T.S., S.R., X.W., D.S.R.) and Institute of Pharmacology and Neurotherapeutics, Texas A&M University Health Science Center, Bryan, Texas (T.S., S.R., X.W., D.S.R.)
| | - Xin Wu
- Department of Neuroscience and Experimental Therapeutics, Texas A&M University School of Medicine, Bryan, Texas (T.S., S.R., X.W., D.S.R.) and Institute of Pharmacology and Neurotherapeutics, Texas A&M University Health Science Center, Bryan, Texas (T.S., S.R., X.W., D.S.R.)
| | - Doodipala Samba Reddy
- Department of Neuroscience and Experimental Therapeutics, Texas A&M University School of Medicine, Bryan, Texas (T.S., S.R., X.W., D.S.R.) and Institute of Pharmacology and Neurotherapeutics, Texas A&M University Health Science Center, Bryan, Texas (T.S., S.R., X.W., D.S.R.)
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Lavonas EJ, Akpunonu PD, Arens AM, Babu KM, Cao D, Hoffman RS, Hoyte CO, Mazer-Amirshahi ME, Stolbach A, St-Onge M, Thompson TM, Wang GS, Hoover AV, Drennan IR. 2023 American Heart Association Focused Update on the Management of Patients With Cardiac Arrest or Life-Threatening Toxicity Due to Poisoning: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2023; 148:e149-e184. [PMID: 37721023 DOI: 10.1161/cir.0000000000001161] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/19/2023]
Abstract
In this focused update, the American Heart Association provides updated guidance for resuscitation of patients with cardiac arrest, respiratory arrest, and refractory shock due to poisoning. Based on structured evidence reviews, guidelines are provided for the treatment of critical poisoning from benzodiazepines, β-adrenergic receptor antagonists (also known as β-blockers), L-type calcium channel antagonists (commonly called calcium channel blockers), cocaine, cyanide, digoxin and related cardiac glycosides, local anesthetics, methemoglobinemia, opioids, organophosphates and carbamates, sodium channel antagonists (also called sodium channel blockers), and sympathomimetics. Recommendations are also provided for the use of venoarterial extracorporeal membrane oxygenation. These guidelines discuss the role of atropine, benzodiazepines, calcium, digoxin-specific immune antibody fragments, electrical pacing, flumazenil, glucagon, hemodialysis, hydroxocobalamin, hyperbaric oxygen, insulin, intravenous lipid emulsion, lidocaine, methylene blue, naloxone, pralidoxime, sodium bicarbonate, sodium nitrite, sodium thiosulfate, vasodilators, and vasopressors for the management of specific critical poisonings.
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Vasanthi SS, Rao NS, Samidurai M, Massey N, Meyer C, Gage M, Kharate M, Almanza A, Wachter L, Mafuta C, Trevino L, Carlo AM, Bryant E, Corson BE, Wohlgemuth M, Ostrander M, Showman L, Wang C, Thippeswamy T. Disease-modifying effects of a glial-targeted inducible nitric oxide synthase inhibitor (1400W) in mixed-sex cohorts of a rat soman (GD) model of epilepsy. J Neuroinflammation 2023; 20:163. [PMID: 37438764 PMCID: PMC10337207 DOI: 10.1186/s12974-023-02847-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 07/05/2023] [Indexed: 07/14/2023] Open
Abstract
BACKGROUND Acute exposure to seizurogenic organophosphate (OP) nerve agents (OPNA) such as diisopropylfluorophosphate (DFP) or soman (GD), at high concentrations, induce immediate status epilepticus (SE), reactive gliosis, neurodegeneration, and epileptogenesis as a consequence. Medical countermeasures (MCMs-atropine, oximes, benzodiazepines), if administered in < 20 min of OPNA exposure, can control acute symptoms and mortality. However, MCMs alone are inadequate to prevent OPNA-induced brain injury and behavioral dysfunction in survivors. We have previously shown that OPNA exposure-induced SE increases the production of inducible nitric oxide synthase (iNOS) in glial cells in both short- and long- terms. Treating with a water soluble and highly selective iNOS inhibitor, 1400W, for 3 days significantly reduced OPNA-induced brain changes in those animals that had mild-moderate SE in the rat DFP model. However, such mitigating effects and the mechanisms of 1400W are unknown in a highly volatile nerve agent GD exposure. METHODS Mixed-sex cohort of adult Sprague Dawley rats were exposed to GD (132 μg/kg, s.c.) and immediately treated with atropine (2 mg/kg, i.m) and HI-6 (125 mg/kg, i.m.). Severity of seizures were quantified for an hour and treated with midazolam (3 mg/kg, i.m.). An hour post-midazolam, 1400W (20 mg/kg, i.m.) or vehicle was administered daily for 2 weeks. After behavioral testing and EEG acquisition, animals were euthanized at 3.5 months post-GD. Brains were processed for neuroinflammatory and neurodegeneration markers. Serum and CSF were used for nitrooxidative and proinflammatory cytokines assays. RESULTS We demonstrate a significant long-term (3.5 months post-soman) disease-modifying effect of 1400W in animals that had severe SE for > 20 min of continuous convulsive seizures. 1400W significantly reduced GD-induced motor and cognitive dysfunction; nitrooxidative stress (nitrite, ROS; increased GSH: GSSG); proinflammatory cytokines in the serum and some in the cerebrospinal fluid (CSF); epileptiform spikes and spontaneously recurring seizures (SRS) in males; reactive gliosis (GFAP + C3 and IBA1 + CD68-positive glia) as a measure of neuroinflammation, and neurodegeneration (especially parvalbumin-positive neurons) in some brain regions. CONCLUSION These findings demonstrate the long-term disease-modifying effects of a glial-targeted iNOS inhibitor, 1400W, in a rat GD model by modulating reactive gliosis, neurodegeneration (parvalbumin-positive neurons), and neuronal hyperexcitability.
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Affiliation(s)
- Suraj S. Vasanthi
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011 USA
| | - Nikhil S. Rao
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011 USA
| | - Manikandan Samidurai
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011 USA
| | - Nyzil Massey
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011 USA
| | - Christina Meyer
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011 USA
| | - Meghan Gage
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011 USA
| | - Mihir Kharate
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011 USA
| | - Aida Almanza
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011 USA
| | - Logan Wachter
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011 USA
| | - Candide Mafuta
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011 USA
| | - Lily Trevino
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011 USA
| | - Adriana M. Carlo
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011 USA
| | - Elijah Bryant
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011 USA
| | - Brooke E. Corson
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011 USA
| | - Morgan Wohlgemuth
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011 USA
| | - Morgan Ostrander
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011 USA
| | - Lucas Showman
- W.M. Keck Metabolomics Research Laboratory, College of Veterinary Medicine, Iowa State University, Ames, 50011 USA
| | - Chong Wang
- Department of Veterinary Diagnostic and Production Animal Medicine and Statistics, College of Veterinary Medicine, Iowa State University, Ames, 50011 USA
| | - Thimmasettappa Thippeswamy
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011 USA
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Yoon IY, Ryu JH, Do SH, Min B, Koo CH. Etomidate versus Propofol for Electroconvulsive Therapy in Patients with Major Depressive Disorders in Terms of Clinical Responses to Treatment: A Retrospective Analysis. Brain Sci 2023; 13:1023. [PMID: 37508956 PMCID: PMC10377494 DOI: 10.3390/brainsci13071023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 06/25/2023] [Accepted: 06/30/2023] [Indexed: 07/30/2023] Open
Abstract
General anesthetic agents may be associated with the clinical efficacy of electroconvulsive therapy (ECT), as they may influence seizure quality and duration. Hence, a retrospective study was conducted to compare the clinical effects and seizure variables of etomidate and propofol during ECT. Patients treated with ECT under anesthesia with etomidate (n = 43) or propofol (n = 12) were retrospectively analyzed. Seizure variables (seizure duration, intensity, and threshold) and hemodynamic changes during ECT were assessed and recorded. Clinical responses to treatment were evaluated using the Clinical Global Impression scale and mood at discharge after the course of ECT. Adverse effects were also recorded. The demographic characteristics were similar between the two groups. There were no significant differences in the Clinical Global Impression scale scores, mood at discharge, and adverse effects between the two groups (p > 0.05); however, etomidate was associated with a significantly longer motor (42.0 vs. 23.65 s, p < 0.001) and electroencephalogram (51.8 vs. 33.5 s, p < 0.001) seizure duration than propofol. In conclusion, etomidate showed more favorable seizure profiles than propofol during ECT; however, both agents (etomidate and propofol) were associated with similar clinical efficacy profiles at discharge.
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Affiliation(s)
- In-Young Yoon
- Department of Psychiatry, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea
- Department of Psychiatry, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Jung-Hee Ryu
- Department of Anesthesia and Pain Medicine, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea
- Department of Anesthesia and Pain Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Sang-Hwan Do
- Department of Anesthesia and Pain Medicine, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea
- Department of Anesthesia and Pain Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Beomjun Min
- Chung Psychiatric Clinic, Seoul 06614, Republic of Korea
| | - Chang-Hoon Koo
- Department of Anesthesia and Pain Medicine, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea
- Department of Anesthesia and Pain Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
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Ramsay RE, Becker D, Vazquez B, Birnbaum AK, Misra SN, Carrazana E, Rabinowicz AL. Acute Abortive Therapies for Seizure Clusters in Long-Term Care. J Am Med Dir Assoc 2023:S1525-8610(23)00405-X. [PMID: 37253432 DOI: 10.1016/j.jamda.2023.04.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 04/10/2023] [Accepted: 04/11/2023] [Indexed: 06/01/2023]
Abstract
OBJECTIVES To describe acute seizure treatment for the long-term care setting, emphasizing rescue (acute abortive) medications for on-site management of acute unexpected seizures and seizure clusters. DESIGN Narrative review. SETTING AND PARTICIPANTS People with seizures in long-term care, including group residences. METHODS PubMed was searched using keywords that pertained to rescue medications, seizure emergencies/epilepsy, seizure action plans, and long-term care. RESULTS Seizure disorder, including epilepsy, is prevalent in long-term care residences, and rescue medications can be used for on-site treatment. Diazepam rectal gel, intranasal midazolam, and diazepam nasal spray are US Food and Drug Administration (FDA)-approved seizure-cluster rescue medications, and intravenous diazepam and lorazepam are approved for status epilepticus. Benzodiazepines differ by formulation, route of administration, absorption, and metabolism. Intranasal formulations are easy and ideal for public use and when rectal treatment is challenging (eg, wheelchair). Intranasal, intrabuccal, and rectal formulations do not require specialized training to administer and are easier for staff at all levels of training compared with intravenous treatment. Off-label rescue medications may have anecdotal support; however, potential disadvantages include variable absorption and onset of action as well as potential risks to patients and caregivers/care partners. Delivery of intravenous-administered rescue medications is delayed by the time needed to set up and deliver the medication and is subject to dosing errors. Seizure action plans that include management of acute seizures can optimize the quality and timing of treatment, which may reduce emergency service needs and prevent progression to status epilepticus. CONCLUSIONS AND IMPLICATIONS Seizure disorder is prevalent across all ages but is increased in older adults and in those with intellectual and developmental disabilities. Prompt intervention may reduce negative outcomes associated with acute unexpected seizures and seizure clusters. Seizure action plans that include acute seizures can improve the treatment response by detailing the necessary information for staff to provide immediate treatment.
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Affiliation(s)
- R Eugene Ramsay
- International Center for Epilepsy, St. Bernard Parish Medical Center, New Orleans, LA, USA.
| | - Danielle Becker
- Department of Neurology, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Blanca Vazquez
- Comprehensive Epilepsy Center, New York University, New York, NY, USA
| | - Angela K Birnbaum
- Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA
| | | | - Enrique Carrazana
- Neurelis, Inc, San Diego, CA, USA; John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA
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Vasanthi SS, Rao NS, Samidurai M, Massey N, Meyer C, Gage M, Kharate M, Almanza A, Wachter L, Mafuta C, Trevino L, Carlo AM, Bryant E, Corson BE, Wohlgemuth M, Ostrander M, Wang C, Thippeswamy T. Disease-Modifying Effects of a Glial-targeted Inducible Nitric Oxide Synthase Inhibitor (1400W) in Mixed-sex Cohorts of a Rat Soman (GD) Model of Epilepsy. RESEARCH SQUARE 2023:rs.3.rs-2883247. [PMID: 37214912 PMCID: PMC10197763 DOI: 10.21203/rs.3.rs-2883247/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
Background Acute exposure to seizurogenic organophosphate (OP) nerve agents (OPNA) such as diisopropylfluorophosphate (DFP) or soman (GD), at high concentrations, induce immediate status epilepticus (SE), reactive gliosis, neurodegeneration, and epileptogenesis as a consequence. Medical countermeasures (MCMs- atropine, oximes, benzodiazepines), if administered in < 20 minutes of OPNA exposure, can control acute symptoms and mortality. However, MCMs alone are inadequate to prevent OPNA-induced brain injury and behavioral dysfunction in survivors. We have previously shown that OPNA exposure-induced SE increases the production of inducible nitric oxide synthase (iNOS) in glial cells in both short- and long- terms. Treating with a water soluble and highly selective iNOS inhibitor, 1400W, for three days significantly reduced OPNA-induced brain changes in those animals that had mild-moderate SE in the rat DFP model. However, such mitigating effects and the mechanisms of 1400W are unknown in a highly volatile nerve agent GD exposure. Methods Mixed-sex cohort of adult Sprague Dawley rats were exposed to GD (132µg/kg, s.c.) and immediately treated with atropine (2mg/kg, i.m) and HI-6 (125mg/kg, i.m.). Severity of seizures were quantified for an hour and treated with midazolam (3mg/kg, i.m.). An hour post-midazolam, 1400W (20mg/kg, i.m.) or vehicle was administered daily for two weeks. After behavioral testing and EEG acquisition, animals were euthanized at 3.5 months post-GD. Brains were processed for neuroinflammatory and neurodegeneration markers. Serum and CSF were used for nitrooxidative and proinflammatory cytokines assays. Results We demonstrate a significant long-term (3.5 months post-soman) disease-modifying effect of 1400W in animals that had severe SE for > 20min of continuous convulsive seizures. 1400W significantly reduced GD-induced motor and cognitive dysfunction; nitrooxidative stress (nitrite, ROS; increased GSH: GSSG); proinflammatory cytokines in the serum and some in the cerebrospinal fluid (CSF); epileptiform spikes and spontaneously recurring seizures (SRS) in males; reactive gliosis (GFAP + C3 and IBA1 + CD68 positive glia) as a measure of neuroinflammation, and neurodegeneration (including parvalbumin positive neurons) in some brain regions. Conclusion These findings demonstrate the long-term disease-modifying effects of a glial-targeted iNOS inhibitor, 1400W, in a rat GD model by modulating reactive gliosis, neurodegeneration, and neuronal hyperexcitability.
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Massey N, Vasanthi SS, Samidurai M, Gage M, Rao N, Meyer C, Thippeswamy T. 1400 W, a selective inducible nitric oxide synthase inhibitor, mitigates early neuroinflammation and nitrooxidative stress in diisopropylfluorophosphate-induced short-term neurotoxicity rat model. Front Mol Neurosci 2023; 16:1125934. [PMID: 37008784 PMCID: PMC10064070 DOI: 10.3389/fnmol.2023.1125934] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 02/27/2023] [Indexed: 03/19/2023] Open
Abstract
Organophosphate nerve agent (OPNA) exposure induces acute and long-term neurological deficits. OPNA exposure at sub-lethal concentrations induces irreversible inhibition of acetylcholinesterase and cholinergic toxidrome and develops status epilepticus (SE). Persistent seizures have been associated with increased production of ROS/RNS, neuroinflammation, and neurodegeneration. A total of 1400W is a novel small molecule, which irreversibly inhibits inducible nitric oxide synthase (iNOS) and has been shown to effectively reduce ROS/RNS generation. In this study, we investigated the effects of 1400W treatment for a week or two weeks at 10 mg/kg or 15 mg/kg per day in the rat diisopropylfluorophosphate (DFP) model. 1400W significantly reduced the number of microglia, astroglia, and NeuN+FJB positive cells compared to the vehicle in different regions of the brain. 1400W also significantly reduced nitrooxidative stress markers and proinflammatory cytokines in the serum. However, neither of the two concentrations of 1400W for two weeks of treatment had any significant effect on epileptiform spike rate and spontaneous seizures during the treatment period in mixed sex cohorts, males, or females. No significant sex differences were found in response to DFP exposure or 1400W treatment. In conclusion, 1400W treatment at 15 mg/kg per day for two weeks was more effective in significantly reducing DFP-induced nitrooxidative stress, neuroinflammatory and neurodegenerative changes.
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Review of Possible Therapies in Treatment of Novichoks Poisoning and HAZMAT/CBRNE Approaches: State of the Art. J Clin Med 2023; 12:jcm12062221. [PMID: 36983219 PMCID: PMC10054273 DOI: 10.3390/jcm12062221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/02/2023] [Accepted: 03/11/2023] [Indexed: 03/16/2023] Open
Abstract
Novichoks-organophosphorus compounds belong to the nerve agents group, constituting the fourth generation of chemical warfare agents. The tremendous toxicity of Novichoks is assumed to be several times greater than that of VX, whereas no published experimental research supports this. They were surreptitiously created during the Cold War by the Soviet Union. Novichok’s toxic action mechanism consists of the inhibition of acetylcholinesterase activity. The review includes data on treating poisoning caused by OPs which could be used as guidelines for the therapy in case of Novichok exposure and HAZMAT/CBRNE approaches. Novichoks pose a severe threat due to their toxicity; however, there is insufficient information about the identity of A-series nerve agents. Filling in the missing data gaps will accelerate progress in improving protection against Novichoks and developing optimal therapy for treating poisoning casualties. Furthermore, introducing solutions to protect medical personnel in contact with a hazardous substance increases the chances of saving casualties of HAZMAT/CBRNE incidents.
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Santana Maldonado C, Weir A, Rumbeiha WK. A comprehensive review of treatments for hydrogen sulfide poisoning: past, present, and future. Toxicol Mech Methods 2023; 33:183-196. [PMID: 36076319 DOI: 10.1080/15376516.2022.2121192] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
Abstract
Hydrogen sulfide (H2S) poisoning remains a significant source of occupational fatalities and is the second most common cause of toxic gas-induced deaths. It is a rapidly metabolized systemic toxicant targeting the mitochondria, among other organelles. Intoxication is mostly acute, but chronic or in-between exposure scenarios also occur. Some genetic defects in H2S metabolism lead to lethal chronic H2S poisoning. In acute exposures, the neural, respiratory, and cardiovascular systems are the primary target organs resulting in respiratory distress, convulsions, hypotension, and cardiac irregularities. Some survivors of acute poisoning develop long-term sequelae, particularly in the central nervous system. Currently, treatment for H2S poisoning is primarily supportive care as there are no FDA-approved drugs. Besides hyperbaric oxygen treatment, drugs in current use for the management of H2S poisoning are controversial. Novel potential drugs are under pre-clinical research development, most of which target binding the H2S. However, there is an acute need to discover new drugs to prevent and treat H2S poisoning, including reducing mortality and morbidity, preventing sequalae from acute exposures, and for treating cumulative pathology from chronic exposures. In this paper, we perform a comprehensive review of H2S poisoning including perspectives on past, present, and future.
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Affiliation(s)
| | - Abigail Weir
- Molecular Biosciences, University of California, Davis, Davis, CA, USA
| | - Wilson K Rumbeiha
- Molecular Biosciences, University of California, Davis, Davis, CA, USA
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Charejoo A, Arabfard M, Jafari A, Nourian YH. A complete, evidence-based review on novichok poisoning based on epidemiological aspects and clinical management. FRONTIERS IN TOXICOLOGY 2023; 4:1004705. [PMID: 36762227 PMCID: PMC9905702 DOI: 10.3389/ftox.2022.1004705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 12/30/2022] [Indexed: 01/26/2023] Open
Abstract
Background: The whole world has learned about the existence of a highly toxic neuro-paralytic substance called Novichok. A wide range of neuro-paralytic toxins were used during the wars of decades ago, which also had harmful and irreversible effects. Fortunately, the establishment of conventions prohibiting the use of these weapons prevented the adverse clinical consequences of these compounds. What we did in the present study was to evaluate the clinical features of Novichok, how to manage exposure to it, and to evaluate the prognostic aspects associated with this poisoning agent. Methods: The manuscript especial databases including Medline, Web of knowledge, Google scholar, and Scopus were deeply searched by the two blinded investigators for all eligible studies based on the considered keywords. Initially 98 articles were initially collected by database searching that considering eligibility criteria, 83 articles were finally eligible for the final assessment. There is a lack of clinical trials and case-cohort studies on general population about treatment and side effects when it comes to human nerve agents and most of the data in our search is based on animal studies. Results: In evaluating various clinical, auto physiological and prognostic aspects of exposure to these substances, special attention was necessary to the following points. First, Novichok agents are considered more potent than other toxic agents. Pathophysiologically, these agents irreversibly bind acetylcholinesterase and produce a rapid cholinergic toxidrome which is responsible for the clinical manifestations as well as the potential dangerous and life threatening side effects caused by these agents. Uniquely, these agents are thought to also target every neuron in the central and peripheral nervous system. As a managerial and therapeutic approach, early and timely treatment of its related complication along with prevents massive exposure and decontamination in addition to rapid resuscitation can prohibit debilitating neuropathy and death due to facing it. Conclusion: The present review highlights the importance of recognizing the potential acute toxic effects of Novichok agents, diagnostic and therapeutic approaches (life-saving antidotal therapy) to complications and ultimately the application of guidelines to improve the prognosis of exposure to these agents for both victims and medical community.
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Neurotoxicity evoked by organophosphates and available countermeasures. Arch Toxicol 2023; 97:39-72. [PMID: 36335468 DOI: 10.1007/s00204-022-03397-w] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 10/11/2022] [Indexed: 11/07/2022]
Abstract
Organophosphorus compounds (OP) are a constant problem, both in the military and in the civilian field, not only in the form of acute poisoning but also for their long-lasting consequences. No antidote has been found that satisfactorily protects against the toxic effects of organophosphates. Likewise, there is no universal cure to avert damage after poisoning. The key mechanism of organophosphate toxicity is the inhibition of acetylcholinesterase. The overstimulation of nicotinic or muscarinic receptors by accumulated acetylcholine on a synaptic cleft leads to activation of the glutamatergic system and the development of seizures. Further consequences include generation of reactive oxygen species (ROS), neuroinflammation, and the formation of various other neuropathologists. In this review, we present neuroprotection strategies which can slow down the secondary nerve cell damage and alleviate neurological and neuropsychiatric disturbance. In our opinion, there is no unequivocal approach to ensure neuroprotection, however, sooner the neurotoxicity pathway is targeted, the better the results which can be expected. It seems crucial to target the key propagation pathways, i.e., to block cholinergic and, foremostly, glutamatergic cascades. Currently, the privileged approach oriented to stimulating GABAAR by benzodiazepines is of limited efficacy, so that antagonizing the hyperactivity of the glutamatergic system could provide an even more efficacious approach for terminating OP-induced seizures and protecting the brain from permanent damage. Encouraging results have been reported for tezampanel, an antagonist of GluK1 kainate and AMPA receptors, especially in combination with caramiphen, an anticholinergic and anti-glutamatergic agent. On the other hand, targeting ROS by antioxidants cannot or already developed neuroinflammation does not seem to be very productive as other processes are also involved.
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Figueiredo TH, Aroniadou-Anderjaska V, Pidoplichko VI, Apland JP, Braga MFM. Antiseizure and Neuroprotective Efficacy of Midazolam in Comparison with Tezampanel (LY293558) against Soman-Induced Status Epilepticus. TOXICS 2022; 10:409. [PMID: 35893842 PMCID: PMC9330837 DOI: 10.3390/toxics10080409] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 07/19/2022] [Accepted: 07/20/2022] [Indexed: 12/12/2022]
Abstract
Acute exposure to nerve agents induces status epilepticus (SE), which can cause death or long-term brain damage. Diazepam is approved by the FDA for the treatment of nerve agent-induced SE, and midazolam (MDZ) is currently under consideration to replace diazepam. However, animal studies have raised questions about the neuroprotective efficacy of benzodiazepines. Here, we compared the antiseizure and neuroprotective efficacy of MDZ (5 mg/kg) with that of tezampanel (LY293558; 10 mg/kg), an AMPA/GluK1 receptor antagonist, administered 1 h after injection of the nerve agent, soman (1.2 × LD50), in adult male rats. Both of the anticonvulsants promptly stopped SE, with MDZ having a more rapid effect. However, SE reoccurred to a greater extent in the MDZ-treated group, resulting in a significantly longer total duration of SE within 24 h post-exposure compared with the LY293558-treated group. The neuroprotective efficacy of the two drugs was studied in the basolateral amygdala, 30 days post-exposure. Significant neuronal and inter-neuronal loss, reduced ratio of interneurons to the total number of neurons, and reduction in spontaneous inhibitory postsynaptic currents accompanied by increased anxiety were found in the MDZ-treated group. The rats treated with LY293558 did not differ from the control rats (not exposed to soman) in any of these measurements. Thus, LY293558 has significantly greater efficacy than midazolam in protecting against prolonged seizures and brain damage caused by acute nerve agent exposure.
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Affiliation(s)
- Taiza H. Figueiredo
- Department of Anatomy, Physiology, and Genetics, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA; (T.H.F.); (V.A.-A.); (V.I.P.)
| | - Vassiliki Aroniadou-Anderjaska
- Department of Anatomy, Physiology, and Genetics, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA; (T.H.F.); (V.A.-A.); (V.I.P.)
- Department of Psychiatry, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
| | - Volodymyr I. Pidoplichko
- Department of Anatomy, Physiology, and Genetics, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA; (T.H.F.); (V.A.-A.); (V.I.P.)
| | - James P. Apland
- Neuroscience Branch, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Aberdeen, MD 21010, USA;
| | - Maria F. M. Braga
- Department of Anatomy, Physiology, and Genetics, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA; (T.H.F.); (V.A.-A.); (V.I.P.)
- Department of Psychiatry, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
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François S, Mondot S, Gerard Q, Bel R, Knoertzer J, Berriche A, Cavallero S, Baati R, Orset C, Dal Bo G, Thibault K. Long-Term Anxiety-Like Behavior and Microbiota Changes Induced in Mice by Sublethal Doses of Acute Sarin Surrogate Exposure. Biomedicines 2022; 10:biomedicines10051167. [PMID: 35625901 PMCID: PMC9138233 DOI: 10.3390/biomedicines10051167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 05/07/2022] [Accepted: 05/16/2022] [Indexed: 12/10/2022] Open
Abstract
Anxiety disorder is one of the most reported complications following organophosphorus (OP) nerve agent (NA) exposure. The goal of this study was to characterize the long-term behavioral impact of a single low dose exposure to 4-nitrophenyl isopropyl methylphosphonate (NIMP), a sarin surrogate. We chose two different sublethal doses of NIMP, each corresponding to a fraction of the median lethal dose (one mild and one convulsive), and evaluated behavioral changes over a 6-month period following exposure. Mice exposed to both doses showed anxious behavior which persisted for six-months post-exposure. A longitudinal magnetic resonance imaging examination did not reveal any anatomical changes in the amygdala throughout the 6-month period. While no cholinesterase activity change or neuroinflammation could be observed at the latest timepoint in the amygdala of NIMP-exposed mice, important modifications in white blood cell counts were noted, reflecting a perturbation of the systemic immune system. Furthermore, intestinal inflammation and microbiota changes were observed at 6-months in NIMP-exposed animals regardless of the dose received. This is the first study to identify long-term behavioral impairment, systemic homeostasis disorganization and gut microbiota alterations following OP sublethal exposure. Our findings highlight the importance of long-term care for victims of NA exposure, even in asymptomatic cases.
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Affiliation(s)
- Sabine François
- Department of Radiation Biological Effects, Armed Forces Biomedical Research Institute, 91220 Bretigny sur Orge, France; (S.F.); (S.C.)
| | - Stanislas Mondot
- Micalis Institute, AgroParisTech, Université Paris-Saclay, INRAE, 78350 Jouy-en-Josas, France;
| | - Quentin Gerard
- Department of Toxicology and Chemical Risks, Armed Forces Biomedical Research Institute, 91220 Bretigny sur Orge, France; (Q.G.); (R.B.); (J.K.); (A.B.)
- Institut Blood and Brain@caen-normandie Cyceron, Caen-Normandie University, UNICAEN, INSERM, UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), 14000 Caen, France;
| | - Rosalie Bel
- Department of Toxicology and Chemical Risks, Armed Forces Biomedical Research Institute, 91220 Bretigny sur Orge, France; (Q.G.); (R.B.); (J.K.); (A.B.)
| | - Julie Knoertzer
- Department of Toxicology and Chemical Risks, Armed Forces Biomedical Research Institute, 91220 Bretigny sur Orge, France; (Q.G.); (R.B.); (J.K.); (A.B.)
| | - Asma Berriche
- Department of Toxicology and Chemical Risks, Armed Forces Biomedical Research Institute, 91220 Bretigny sur Orge, France; (Q.G.); (R.B.); (J.K.); (A.B.)
- CEA, 92260 Fontenay aux Roses, France
| | - Sophie Cavallero
- Department of Radiation Biological Effects, Armed Forces Biomedical Research Institute, 91220 Bretigny sur Orge, France; (S.F.); (S.C.)
| | - Rachid Baati
- ICPEES UMR CNRS 7515, Institut de Chimie des Procédés, pour l’Energie, l’Environnement, et la Santé, 67000 Strasbourg, France;
| | - Cyrille Orset
- Institut Blood and Brain@caen-normandie Cyceron, Caen-Normandie University, UNICAEN, INSERM, UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), 14000 Caen, France;
| | - Gregory Dal Bo
- Department of Toxicology and Chemical Risks, Armed Forces Biomedical Research Institute, 91220 Bretigny sur Orge, France; (Q.G.); (R.B.); (J.K.); (A.B.)
- Correspondence: (G.D.B.); (K.T.)
| | - Karine Thibault
- Department of Toxicology and Chemical Risks, Armed Forces Biomedical Research Institute, 91220 Bretigny sur Orge, France; (Q.G.); (R.B.); (J.K.); (A.B.)
- Correspondence: (G.D.B.); (K.T.)
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Countermeasures in organophosphorus intoxication: pitfalls and prospects. Trends Pharmacol Sci 2022; 43:593-606. [DOI: 10.1016/j.tips.2022.04.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 04/14/2022] [Accepted: 04/17/2022] [Indexed: 11/24/2022]
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Gage M, Putra M, Gomez-Estrada C, Golden M, Wachter L, Gard M, Thippeswamy T. Differential Impact of Severity and Duration of Status Epilepticus, Medical Countermeasures, and a Disease-Modifier, Saracatinib, on Brain Regions in the Rat Diisopropylfluorophosphate Model. Front Cell Neurosci 2021; 15:772868. [PMID: 34720886 PMCID: PMC8555467 DOI: 10.3389/fncel.2021.772868] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 09/28/2021] [Indexed: 11/29/2022] Open
Abstract
Acute organophosphate (OP) toxicity poses a significant threat to both military and civilian personnel as it can lead to a variety of cholinergic symptoms including the development of status epilepticus (SE). Depending on its severity, SE can lead to a spectrum of neurological changes including neuroinflammation and neurodegeneration. In this study, we determined the impact of SE severity and duration on disease promoting parameters such as gliosis and neurodegeneration and the efficacy of a disease modifier, saracatinib (AZD0530), a Src/Fyn tyrosine kinase inhibitor. Animals were exposed to 4 mg/kg diisopropylfluorophosphate (DFP, s.c.) followed by medical countermeasures. We had five experimental groups: controls (no DFP), animals with no continuous convulsive seizures (CS), animals with ∼20-min continuous CS, 31-60-min continuous CS, and > 60-min continuous CS. These groups were then assessed for astrogliosis, microgliosis, and neurodegeneration 8 days after DFP exposure. The 31-60-min and > 60-min groups, but not ∼20-min group, had significantly upregulated gliosis and neurodegeneration in the hippocampus compared to controls. In the piriform cortex and amygdala, however, all three continuous CS groups had significant upregulation in both gliosis and neurodegeneration. In a separate cohort of animals that had ∼20 and > 60-min of continuous CS, we administered saracatinib for 7 days beginning three hours after DFP. There was bodyweight loss and mortality irrespective of the initial SE severity and duration. However, in survived animals, saracatinib prevented spontaneous recurrent seizures (SRS) during the first week in both severity groups. In the ∼20-min CS group, compared to the vehicle, saracatinib significantly reduced neurodegeneration in the piriform cortex and amygdala. There were no significant differences in the measured parameters between the naïve control and saracatinib on its own (without DFP) groups. Overall, this study demonstrates the differential effects of the initial SE severity and duration on the localization of gliosis and neurodegeneration. We have also demonstrated the disease-modifying potential of saracatinib. However, its’ dosing regimen should be optimized based on initial severity and duration of CS during SE to maximize therapeutic effects and minimize toxicity in the DFP model as well as in other OP models such as soman.
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Affiliation(s)
- Meghan Gage
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, United States.,Neuroscience Interdepartmental Program, Iowa State University, Ames, IA, United States
| | - Marson Putra
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, United States.,Neuroscience Interdepartmental Program, Iowa State University, Ames, IA, United States
| | - Crystal Gomez-Estrada
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, United States
| | - Madison Golden
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, United States
| | - Logan Wachter
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, United States
| | - Megan Gard
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, United States
| | - Thimmasettappa Thippeswamy
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, United States.,Neuroscience Interdepartmental Program, Iowa State University, Ames, IA, United States
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Roy A, Geetha RV, Magesh A, Vijayaraghavan R, Ravichandran V. Autoinjector - A smart device for emergency cum personal therapy. Saudi Pharm J 2021; 29:1205-1215. [PMID: 34703373 PMCID: PMC8523323 DOI: 10.1016/j.jsps.2021.09.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 09/11/2021] [Indexed: 12/18/2022] Open
Abstract
Autoinjectors are self-injectable devices; they are important class of medical devices which can deliver drugs through subcutaneous or intramuscular route. They enclose prefilled syringes or cartridges which are driven by a spring system. The major benefits of this device are easy self-administration, improved patient compliance, reduced anxiety, and dosage accuracy. Immediate treatment during emergency conditions such as anaphylaxis, migraine, and status epilepticus or for chronic conditions like psoriasis, diabetes, multiple sclerosis, and rheumatoid arthritis, Reformulation of first-generation biologics, technical advancements, innovative designs, patient compliance, overwhelming interest for self-administration all these made entry of more and more autoinjectors into use. In this review, intensive efforts have been made for exploring the different types of currently available autoinjectors for the management of emergency and chronic diseases.
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Affiliation(s)
- Anitha Roy
- Department of Pharmacology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India
| | - Royapuram Veeraragavan Geetha
- Department of Microbiology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India
| | - Anitha Magesh
- Department of Research and Development, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India
| | - Rajagopalan Vijayaraghavan
- Department of Research and Development, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India
| | - Veerasamy Ravichandran
- Pharmaceutical Chemistry Unit, Faculty of Pharmacy, AIMST University, Semeling-08100, Bedong, Malaysia.,Centre of Excellence for Biomaterials Engineering, AIMST University, Semeling-08100, Bedong, Malaysia.,Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India
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Du Y, Gao J, Zhang H, Meng X, Qiu D, Gao X, Zheng A. Brain-targeting delivery of MMB4 DMS using carrier-free nanomedicine CRT-MMB4@MDZ. Drug Deliv 2021; 28:1822-1835. [PMID: 34515590 PMCID: PMC8439216 DOI: 10.1080/10717544.2021.1968977] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Brain-targeting delivery of 1,1′-methylenebis[4-[(hydroxyimino)methyl]-pyridinium] dimethanesulfonate (MMB4 DMS) is limited by its hydrophilic property and chemical instability. In order to solve this problem, herein, we develop a facile protocol through combining antisolvent precipitation and emulsion-solvent evaporation method to synthesize midazolam (MDZ) coated MMB4 DMS (MMB4@MDZ) nanoparticles. The as-prepared MMB4@MDZ had a MMB4 DMS nanocrystal (MMB4-NC) core and a MDZ shell. The MDZ shell prevented the MMB4-NC core from contacting the aqueous environment, and thus, guaranteed the chemical stability of MMB4 DMS. Most charmingly, the iron mimic cyclic peptide CRTIGPSVC (CRT) was modified on MMB4@MDZ surfaces to produce CRT-MMB4@MDZ which was endowed with ability to absorb transferrin (Tf)-abundant corona. Taking advantages of the Tf-abundant corona, CRT-MMB4@MDZ achieved transferrin receptor (TfR)-mediated brain-targeting delivery. With the fascinating chemical stability and brain-targeting delivery effect, CRT-MMB4@MDZ showed great clinical transform prospect as a brand-new nanomedicine. Of particular importance, this work promised not only a core–shell carrier-free nanomedicine platform for effective delivery of unstable water-soluble drug, but also a protein corona-manipulating strategy for targeting delivery.
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Affiliation(s)
- Yimeng Du
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Jing Gao
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Hui Zhang
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Xiaohui Meng
- Beijing National Laboratory for Molecular Sciences, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China
| | - Dong Qiu
- Beijing National Laboratory for Molecular Sciences, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China
| | - Xiang Gao
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Aiping Zheng
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China
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36
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Reddy DS, Zaayman M, Kuruba R, Wu X. Comparative profile of refractory status epilepticus models following exposure of cholinergic agents pilocarpine, DFP, and soman. Neuropharmacology 2021; 191:108571. [PMID: 33878303 DOI: 10.1016/j.neuropharm.2021.108571] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 03/24/2021] [Accepted: 04/13/2021] [Indexed: 12/12/2022]
Abstract
Status epilepticus (SE) is a medical emergency with continuous seizure activity that causes profound neuronal damage, morbidity, or death. SE incidents can arise spontaneously but mostly are elicited by seizurogenic triggers. Chemoconvulsants such as the muscarinic agonist pilocarpine and, organophosphates (OP) such as the pesticide diisopropylfluorophosphate (DFP) and, the nerve agent soman, can induce SE. Pilocarpine, DFP, and soman share a common feature of cholinergic crisis that transitions into a state of refractory SE, but their comparative profiles remain unclear. Here, we evaluated the comparative convulsant profile of pilocarpine, DFP, and soman to produce refractory SE and brain damage in rats. Behavioral and electrographic seizures were monitored for 24 h after exposure, and the extent of brain injury was determined by histological markers of neuronal injury and degeneration. Seizures were elicited rather slowly after pilocarpine as compared to DFP or soman, which caused rapid onset of spiking that swiftly developed into persistent SE. Time-course of SE activity after DFP was comparable to that after soman, a potent nerve agent. Diazepam controlled pilocarpine-induced SE, but it was ineffective in reducing OP-induced SE. All three agents produced modestly different degrees of neuronal injury and neurodegeneration in the brain. These results reveal distinct convulsant and neuronal injury patterns following exposure to cholinergic agonists, OP pesticides, and nerve agents. A battery of SE models, especially SE induced by cholinergic agents and other etiologies including epilepsy and brain tumors, is essential to identify novel anticonvulsant therapies for the management of refractory SE.
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Affiliation(s)
- Doodipala Samba Reddy
- Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center College of Medicine, Bryan, TX, 77807, USA.
| | - Marcus Zaayman
- Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center College of Medicine, Bryan, TX, 77807, USA
| | - Ramkumar Kuruba
- Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center College of Medicine, Bryan, TX, 77807, USA
| | - Xin Wu
- Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center College of Medicine, Bryan, TX, 77807, USA
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Lumley L, Niquet J, Marrero-Rosado B, Schultz M, Rossetti F, de Araujo Furtado M, Wasterlain C. Treatment of acetylcholinesterase inhibitor-induced seizures with polytherapy targeting GABA and glutamate receptors. Neuropharmacology 2021; 185:108444. [PMID: 33359073 PMCID: PMC7944923 DOI: 10.1016/j.neuropharm.2020.108444] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 10/30/2020] [Accepted: 12/17/2020] [Indexed: 12/12/2022]
Abstract
The initiation and maintenance of cholinergic-induced status epilepticus (SE) are associated with decreased synaptic gamma-aminobutyric acid A receptors (GABAAR) and increased N-methyl-d-aspartate receptors (NMDAR) and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR). We hypothesized that trafficking of synaptic GABAAR and glutamate receptors is maladaptive and contributes to the pharmacoresistance to antiseizure drugs; targeting these components should ameliorate the pathophysiological consequences of refractory SE (RSE). We review studies of rodent models of cholinergic-induced SE, in which we used a benzodiazepine allosteric GABAAR modulator to correct loss of inhibition, concurrent with the NMDA antagonist ketamine to reduce excitation caused by increased synaptic localization of NMDAR and AMPAR, which are NMDAR-dependent. Models included lithium/pilocarpine-induced SE in rats and soman-induced SE in rats and in Es1-/- mice, which similar to humans lack plasma carboxylesterase, and may better model soman toxicity. These model human soman toxicity and are refractory to benzodiazepines administered at 40 min after seizure onset, when enough synaptic GABAAR may not be available to restore inhibition. Ketamine-midazolam combination reduces seizure severity, epileptogenesis, performance deficits and neuropathology following cholinergic-induced SE. Supplementing that treatment with valproate, which targets a non-benzodiazepine site, effectively terminates RSE, providing further benefit against cholinergic-induced SE. The therapeutic index of drug combinations is also reviewed and we show the improved efficacy of simultaneous administration of midazolam, ketamine and valproate compared to sequential drug administration. These data suggest that future clinical trials should treat both the lack of sufficient inhibition and the excess excitation that characterize RSE, and include early combination drug therapies. This article is part of the special issue entitled 'Acetylcholinesterase Inhibitors: From Bench to Bedside to Battlefield'.
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Affiliation(s)
- Lucille Lumley
- Neuroscience Department, US Army Medical Research Institute of Chemical Defense (USAMRICD), Aberdeen Proving Ground, MD, USA.
| | - Jerome Niquet
- Department of Neurology, David Geffen School of Medicine at UCLA, Epilepsy Research Laboratory (151), Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA
| | - Brenda Marrero-Rosado
- Neuroscience Department, US Army Medical Research Institute of Chemical Defense (USAMRICD), Aberdeen Proving Ground, MD, USA
| | - Mark Schultz
- Neuroscience Department, US Army Medical Research Institute of Chemical Defense (USAMRICD), Aberdeen Proving Ground, MD, USA
| | - Franco Rossetti
- Military Psychiatry and Neuroscience Department, Walter Reed Army Institute of Research, Silver Spring, MD, USA
| | | | - Claude Wasterlain
- Department of Neurology, David Geffen School of Medicine at UCLA, Epilepsy Research Laboratory (151), Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA
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Yu C, Zhao M, Pan Z, Bo Y, Zhao W, He X, Zhang J. Butyrylcholinesterase nanodepots with enhanced prophylactic and therapeutic performance for acute organophosphorus poisoning management. J Mater Chem B 2021; 9:1877-1887. [PMID: 33533366 DOI: 10.1039/d0tb02478c] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Acute organophosphorus pesticide poisoning (AOPP) is a worldwide health concern that has threatened human lives for decades, which attacks acetylcholinesterase (AChE) and causes nervous system disorders. Classical treatment options are associated with short in vivo half-life and side effects. As a potential alternative, delivery of mammalian-derived butyrylcholinesterase (BChE) offers a cost-effective way to block organophosphorus attack on acetylcholinesterase, a key enzyme in the neurotransmitter cycle. Yet the use of exotic BChE as a prophylactic or therapeutic agent is compromised by short plasma residence, immune response and unfavorable biodistribution. To overcome these obstacles, BChE nanodepots (nBChE) composed of a BChE core/polymorpholine shell structure were prepared via in situ polymerization, which showed enhanced stability, prolonged plasma circulation, attenuated antigenicity and reduced accumulation in non-targeted tissues. In vivo administration of nBChE pre- or post-organophosphorus exposure in a BALB/C mouse model resulted in potent prophylactic and therapeutic efficiency. To our knowledge, this is the first systematic delivery of non-human BChE to tackle AOPP. In addition, this work also opens up a new avenue for real applications in both research and clinical settings to cope with acute intoxication-related diseases.
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Affiliation(s)
- Congwei Yu
- College of Science, China Agricultural University, Beijing 100193, P. R. China.
| | - Ming Zhao
- School of Materials Science and Engineering, Harbin Institute of Technology, Shenzhen 518055, P. R. China.
| | - Zuchen Pan
- School of Materials Science and Engineering, Harbin Institute of Technology, Shenzhen 518055, P. R. China. and Research Centre of Printed Flexible Electronics, School of Materials Science and Engineering, Harbin Institute of Technology, Shenzhen 518055, P. R. China
| | - Yiyang Bo
- School of Materials Science and Engineering, Harbin Institute of Technology, Shenzhen 518055, P. R. China. and Research Centre of Printed Flexible Electronics, School of Materials Science and Engineering, Harbin Institute of Technology, Shenzhen 518055, P. R. China
| | - Weiwei Zhao
- School of Materials Science and Engineering, Harbin Institute of Technology, Shenzhen 518055, P. R. China. and Research Centre of Printed Flexible Electronics, School of Materials Science and Engineering, Harbin Institute of Technology, Shenzhen 518055, P. R. China
| | - Xiongkui He
- College of Science, China Agricultural University, Beijing 100193, P. R. China.
| | - Jiaheng Zhang
- School of Materials Science and Engineering, Harbin Institute of Technology, Shenzhen 518055, P. R. China. and Research Centre of Printed Flexible Electronics, School of Materials Science and Engineering, Harbin Institute of Technology, Shenzhen 518055, P. R. China
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Clinical pharmacokinetic and pharmacodynamic profile of midazolam nasal spray. Epilepsy Res 2021; 171:106567. [PMID: 33607532 DOI: 10.1016/j.eplepsyres.2021.106567] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 12/01/2020] [Accepted: 02/01/2021] [Indexed: 12/12/2022]
Abstract
The benzodiazepine midazolam (MDZ) is commonly used as first-line treatment in patients with acute seizures. This review summarizes the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of MDZ nasal spray (MDZ-NS), which can be administered by non-health care providers in the outpatient, ambulatory setting. Intranasal administration leads to rapid (tmax 9.0-21.5 min), consistent, and extensive absorption of MDZ, with fast distribution to the central nervous system (CNS), as demonstrated by the onset of sedation within 10 min after administration and the occurrence of peak psychomotor impairment at approximately 17-120 min after administration. Rapid plasma clearance of MDZ and its active metabolite 1-OH-MDZ (t½ 3.6-8.1 h) results in a return to baseline alertness and psychomotor functionality by approximately 240 min post dose. The lack of first-pass metabolism reduces the potential for drug-drug interactions compared with oral dosing. Age (≥ 12 years), sex, race, body weight, body mass index, normal to moderately impaired renal function, and concomitant administration of cytochrome P450 (CYP)3A-inducing drugs are not considered important factors for MDZ-NS dosing. However, coadministration of MDZ-NS with moderate or strong CYP3A4 inhibitors should be avoided, and MDZ-NS should be used with caution when coadministered with mild CYP3A4 inhibitors, as these may result in prolonged MDZ effects owing to a decrease in plasma clearance. Taken together, the PK and PD properties of MDZ-NS, with a short tmax that translates into rapid CNS PD effects of sedation and psychomotor impairment, demonstrate rapid CNS penetration and onset of action, supporting its use for acute treatment of seizure clusters.
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Choi SK. Nanomaterial-Enabled Sensors and Therapeutic Platforms for Reactive Organophosphates. NANOMATERIALS (BASEL, SWITZERLAND) 2021; 11:224. [PMID: 33467113 PMCID: PMC7830340 DOI: 10.3390/nano11010224] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 12/29/2020] [Accepted: 01/14/2021] [Indexed: 01/15/2023]
Abstract
Unintended exposure to harmful reactive organophosphates (OP), which comprise a group of nerve agents and agricultural pesticides, continues to pose a serious threat to human health and ecosystems due to their toxicity and prolonged stability. This underscores an unmet need for developing technologies that will allow sensitive OP detection, rapid decontamination and effective treatment of OP intoxication. Here, this article aims to review the status and prospect of emerging nanotechnologies and multifunctional nanomaterials that have shown considerable potential in advancing detection methods and treatment modalities. It begins with a brief introduction to OP types and their biochemical basis of toxicity followed by nanomaterial applications in two topical areas of primary interest. One topic relates to nanomaterial-based sensors which are applicable for OP detection and quantitative analysis by electrochemical, fluorescent, luminescent and spectrophotometric methods. The other topic is directed on nanotherapeutic platforms developed as OP remedies, which comprise nanocarriers for antidote drug delivery and nanoscavengers for OP inactivation and decontamination. In summary, this article addresses OP-responsive nanomaterials, their design concepts and growing impact on advancing our capability in the development of OP sensors, decontaminants and therapies.
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Affiliation(s)
- Seok Ki Choi
- Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan Medical School, Ann Arbor, MI 48109, USA;
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA
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Aroniadou-Anderjaska V, Apland JP, Figueiredo TH, De Araujo Furtado M, Braga MF. Acetylcholinesterase inhibitors (nerve agents) as weapons of mass destruction: History, mechanisms of action, and medical countermeasures. Neuropharmacology 2020; 181:108298. [DOI: 10.1016/j.neuropharm.2020.108298] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 08/21/2020] [Accepted: 09/02/2020] [Indexed: 02/07/2023]
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Alozi M, Rawas-Qalaji M. Treating organophosphates poisoning: management challenges and potential solutions. Crit Rev Toxicol 2020; 50:764-779. [DOI: 10.1080/10408444.2020.1837069] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Affiliation(s)
- Maria Alozi
- College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates
| | - Mutasem Rawas-Qalaji
- College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- Dr. Kiran C. Patel College of Allopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL, USA
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Reddy SD, Wu X, Kuruba R, Sridhar V, Reddy DS. Magnetic resonance imaging analysis of long-term neuropathology after exposure to the nerve agent soman: correlation with histopathology and neurological dysfunction. Ann N Y Acad Sci 2020; 1480:116-135. [PMID: 32671850 PMCID: PMC7708405 DOI: 10.1111/nyas.14431] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Revised: 05/09/2020] [Accepted: 06/17/2020] [Indexed: 12/14/2022]
Abstract
Nerve agents (NAs) produce acute and long-term brain injury and dysfunction, as evident from the Japan and Syria incidents. Magnetic resonance imaging (MRI) is a versatile technique to examine such chronic anatomical, functional, and neuronal damage in the brain. The objective of this study was to investigate long-term structural and neuronal lesion abnormalities in rats exposed to acute soman intoxication. T2-weighted MRI images of 10 control and 17 soman-exposed rats were acquired using a Siemens MRI system at 90 days after soman exposure. Quantification of brain tissue volumes and T2 signal intensity was conducted using the Inveon Research Workplace software and the extent of damage was correlated with histopathology and cognitive function. Soman-exposed rats showed drastic hippocampal atrophy with neuronal loss and reduced hippocampal volume (HV), indicating severe damage, but had similar T2 relaxation times to the control group, suggesting limited scarring and fluid density changes despite the volume decrease. Conversely, soman-exposed rats displayed significant increases in lateral ventricle volumes and T2 times, signifying strong cerebrospinal fluid expansion in compensation for tissue atrophy. The total brain volume, thalamic volume, and thalamic T2 time were similar in both groups, however, suggesting that some brain regions remained more intact long-term after soman intoxication. The MRI neuronal lesions were positively correlated with the histological markers of neurodegeneration and neuroinflammation 90 days after soman exposure. The predominant MRI hippocampal atrophy (25%) was highly consistent with massive reduction (35%) of neuronal nuclear antigen-positive (NeuN+ ) principal neurons and parvalbumin-positive (PV+ ) inhibitory interneurons within this brain region. The HV was significantly correlated with both inflammatory markers of GFAP+ astrogliosis and IBA1+ microgliosis. The reduced HV was also directly correlated with significant memory deficits in the soman-exposed cohort, confirming a possible neurobiological basis for neurological dysfunction. Together, these findings provide powerful insight on long-term region-specific neurodegenerative patterns after soman exposure and demonstrate the feasibility of in vivo neuroimaging to monitor neuropathology, predict the risk of neurological deficits, and evaluate response to medical countermeasures for NAs.
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Affiliation(s)
- Sandesh D Reddy
- Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas
- Biomedical Engineering, College of Engineering, Texas A&M University, College Station, Texas
| | - Xin Wu
- Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas
| | - Ramkumar Kuruba
- Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas
| | - Vidya Sridhar
- Texas A&M Institute for Preclinical Studies, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas
| | - Doodipala Samba Reddy
- Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas
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Marrero-Rosado BM, de Araujo Furtado M, Kundrick ER, Walker KA, Stone MF, Schultz CR, Nguyen DA, Lumley LA. Ketamine as adjunct to midazolam treatment following soman-induced status epilepticus reduces seizure severity, epileptogenesis, and brain pathology in plasma carboxylesterase knockout mice. Epilepsy Behav 2020; 111:107229. [PMID: 32575012 PMCID: PMC7541728 DOI: 10.1016/j.yebeh.2020.107229] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 06/03/2020] [Accepted: 06/04/2020] [Indexed: 12/18/2022]
Abstract
Delayed treatment of cholinergic seizure results in benzodiazepine-refractory status epilepticus (SE) that is thought, at least in part, to result from maladaptive trafficking of N-methyl-d-aspartate (NMDA) and gamma-aminobutyric acid type A (GABAA) receptors, the effects of which may be ameliorated by combination therapy with the NMDA receptor antagonist ketamine. Our objective was to establish whether ketamine and midazolam dual therapy would improve outcome over midazolam monotherapy following soman (GD) exposure when evaluated in a mouse model that, similar to humans, lacks plasma carboxylesterase, greatly reducing endogenous scavenging of GD. In the current study, continuous cortical electroencephalographic activity was evaluated in male and female plasma carboxylesterase knockout mice exposed to a seizure-inducing dose of GD and treated with midazolam or with midazolam and ketamine combination at 40 min after seizure onset. Ketamine and midazolam combination reduced GD-induced lethality, seizure severity, and the number of mice that developed spontaneous recurrent seizure (SRS) compared with midazolam monotherapy. In addition, ketamine-midazolam combination treatment reduced GD-induced neuronal degeneration and microgliosis. These results support that combination of antiepileptic drug therapies aimed at correcting the maladaptive GABAA and NMDA receptor trafficking reduces the detrimental effects of GD exposure. Ketamine may be a beneficial adjunct to midazolam in reducing the epileptogenesis and neuroanatomical damage that follows nerve agent exposure and pharmacoresistant SE.
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Affiliation(s)
- Brenda M. Marrero-Rosado
- U.S. Army Medical Research Institute of Chemical Defense, 8350 Ricketts Point Road, Aberdeen Proving Ground, MD 21010
| | - Marcio de Araujo Furtado
- Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD, 20814,BioSEaD, LLC. 451 Hungerford Drive, Rockville, MD, 20850
| | - Erica R. Kundrick
- U.S. Army Medical Research Institute of Chemical Defense, 8350 Ricketts Point Road, Aberdeen Proving Ground, MD 21010
| | - Katie A. Walker
- U.S. Army Medical Research Institute of Chemical Defense, 8350 Ricketts Point Road, Aberdeen Proving Ground, MD 21010
| | - Michael F. Stone
- U.S. Army Medical Research Institute of Chemical Defense, 8350 Ricketts Point Road, Aberdeen Proving Ground, MD 21010
| | - Caroline R. Schultz
- U.S. Army Medical Research Institute of Chemical Defense, 8350 Ricketts Point Road, Aberdeen Proving Ground, MD 21010
| | - Donna A. Nguyen
- U.S. Army Medical Research Institute of Chemical Defense, 8350 Ricketts Point Road, Aberdeen Proving Ground, MD 21010
| | - Lucille A. Lumley
- U.S. Army Medical Research Institute of Chemical Defense, 8350 Ricketts Point Road, Aberdeen Proving Ground, MD 21010
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Acute administration of diazepam or midazolam minimally alters long-term neuropathological effects in the rat brain following acute intoxication with diisopropylfluorophosphate. Eur J Pharmacol 2020; 886:173538. [PMID: 32898549 DOI: 10.1016/j.ejphar.2020.173538] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 09/01/2020] [Accepted: 09/03/2020] [Indexed: 12/30/2022]
Abstract
Acute intoxication with organophosphorus cholinesterase inhibitors (OPs) can trigger seizures that rapidly progress to life-threatening status epilepticus. Diazepam, long considered the standard of care for treating OP-induced seizures, is being replaced by midazolam. Whether midazolam is more effective than diazepam in mitigating the persistent effects of acute OP intoxication has not been rigorously evaluated. We compared the efficacy of diazepam vs. midazolam in preventing persistent neuropathology in adult male Sprague-Dawley rats acutely intoxicated with the OP diisopropylfluorophosphate (DFP). Subjects were administered pyridostigmine bromide (0.1 mg/kg, i.p.) 30 min prior to injection with DFP (4 mg/kg, s.c.) or vehicle (saline) followed 1 min later by atropine sulfate (2 mg/kg, i.m.) and pralidoxime (25 mg/kg, i.m.), and 40 min later by diazepam (5 mg/kg, i.p.), midazolam (0.73 mg/kg, i.m.), or vehicle. At 3 and 6 months post-exposure, neurodegeneration, reactive astrogliosis, microglial activation, and oxidative stress were assessed in multiple brain regions using quantitative immunohistochemistry. Brain mineralization was evaluated by in vivo micro-computed tomography (micro-CT). Acute DFP intoxication caused persistent neurodegeneration, neuroinflammation, and brain mineralization. Midazolam transiently mitigated neurodegeneration, and both benzodiazepines partially protected against reactive astrogliosis in a brain region-specific manner. Neither benzodiazepine attenuated microglial activation or brain mineralization. These findings indicate that neither benzodiazepine effectively protects against persistent neuropathological changes, and suggest that midazolam is not significantly better than diazepam. Overall, this study highlights the need for improved neuroprotective strategies for treating humans in the event of a chemical emergency involving OPs.
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46
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Belinskaia DA, Goncharov NV. Theoretical and Practical Aspects of Albumin Esterase Activity. RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY 2020. [DOI: 10.1134/s1068162020030036] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Reddy DS, Perumal D, Golub V, Habib A, Kuruba R, Wu X. Phenobarbital as alternate anticonvulsant for organophosphate-induced benzodiazepine-refractory status epilepticus and neuronal injury. Epilepsia Open 2020; 5:198-212. [PMID: 32524045 PMCID: PMC7278559 DOI: 10.1002/epi4.12389] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2019] [Revised: 02/08/2020] [Accepted: 02/24/2020] [Indexed: 12/19/2022] Open
Abstract
Objective Organophosphates (OPs) such as diisopropylfluorophosphate (DFP) and soman are lethal chemical agents that can produce seizures, refractory status epilepticus (SE), and brain damage. There are few optimal treatments for late or refractory SE. Phenobarbital is a second‐line drug for SE, usually after lorazepam, diazepam, or midazolam have failed to stop SE. Practically, 40 minutes or less is often necessary for first responders to arrive and assist in a chemical incident. However, it remains unclear whether administration of phenobarbital 40 minutes after OP intoxication is still effective. Here, we investigated the efficacy of phenobarbital treatment at 40 minutes postexposure to OP intoxication. Methods Acute refractory SE was induced in rats by DFP injection as per a standard paradigm. After 40 minutes, subjects were given phenobarbital intramuscularly (30‐100 mg/kg) and progression of seizure activity was monitored by video‐EEG recording. The extent of brain damage was assessed 3 days after DFP injections by neuropathology analysis of neurodegeneration and neuronal injury by unbiased stereology. Results Phenobarbital produced a dose‐dependent seizure protection. A substantial decrease in SE was evident at 30 and 60 mg/kg, and a complete seizure termination was noted at 100 mg/kg within 40 minutes after treatment. Neuropathology findings showed significant neuroprotection in 100 mg/kg cohorts in brain regions associated with SE. Although higher doses resulted in greater protection against refractory SE and neuronal damage, they did not positively correlate with improved survival rate. Moreover, phenobarbital caused serious adverse effects including anesthetic or comatose state and even death. Significance Phenobarbital appears as an alternate anticonvulsant for OP‐induced refractive SE in hospital settings. A careful risk‐benefit analysis is required because of negative outcomes on survival and cardio‐respiratory function. However, the need for sophisticated support and critical monitoring in hospital may preclude its use as medical countermeasure in mass casualty situations.
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Affiliation(s)
- Doodipala Samba Reddy
- Department of Neuroscience and Experimental Therapeutics College of Medicine Texas A&M University Health Science Center Bryan TX USA
| | - Dheepthi Perumal
- Department of Neuroscience and Experimental Therapeutics College of Medicine Texas A&M University Health Science Center Bryan TX USA
| | - Victoria Golub
- Department of Neuroscience and Experimental Therapeutics College of Medicine Texas A&M University Health Science Center Bryan TX USA
| | - Andy Habib
- Department of Neuroscience and Experimental Therapeutics College of Medicine Texas A&M University Health Science Center Bryan TX USA
| | - Ramkumar Kuruba
- Department of Neuroscience and Experimental Therapeutics College of Medicine Texas A&M University Health Science Center Bryan TX USA
| | - Xin Wu
- Department of Neuroscience and Experimental Therapeutics College of Medicine Texas A&M University Health Science Center Bryan TX USA
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48
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De Araujo Furtado M, Aroniadou-Anderjaska V, Figueiredo TH, Apland JP, Braga MFM. Electroencephalographic analysis in soman-exposed 21-day-old rats and the effects of midazolam or LY293558 with caramiphen. Ann N Y Acad Sci 2020; 1479:122-133. [PMID: 32237259 DOI: 10.1111/nyas.14331] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 02/25/2020] [Accepted: 02/27/2020] [Indexed: 12/19/2022]
Abstract
Acute nerve agent exposure induces status epilepticus (SE), which can cause brain damage or death. Research aiming at developing effective therapies for controlling nerve agent-induced SE is commonly performed in adult rats. The characteristics of nerve agent-induced SE in young rats are less clear; relevant knowledge is necessary for developing effective pediatric therapies. Here, we have used electroencephalographic (EEG) recordings and analysis to study seizures in postnatal day 21 rats exposed to 1.2 × LD50 of soman, and compared the antiseizure efficacy of midazolam (MDZ)-currently considered by the Food and Drug Administration to replace diazepam for treating SE in victims of nerve agent exposure-with that of LY293558, an AMPA/GluK1 receptor antagonist, administered in combination with caramiphen, an antimuscarinic with N-methyl-d-aspartate receptor antagonistic properties. Prolonged SE developed in 80% of the rats and was reflected in behavioral seizures/convulsions. Both MDZ and LY293558 + caramiphen stopped the SE induced by soman, but there was a significant recurrence of seizures within 24 h postexposure only in the MDZ-treated group, as revealed in the raw EEG data and their representation in the frequency domain using a fast Fourier transform and in spectral analysis over 24 hours. In contrast to the high efficacy of LY293558 + caramiphen, MDZ is not an effective treatment for SE induced by soman in young animals.
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Affiliation(s)
- Marcio De Araujo Furtado
- Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland
| | - Vassiliki Aroniadou-Anderjaska
- Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland.,Department of Psychiatry, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland
| | - Taiza H Figueiredo
- Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland
| | - James P Apland
- Neurotoxicology Branch, the United States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland
| | - Maria F M Braga
- Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland.,Department of Psychiatry, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland
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Amend N, Niessen KV, Seeger T, Wille T, Worek F, Thiermann H. Diagnostics and treatment of nerve agent poisoning—current status and future developments. Ann N Y Acad Sci 2020; 1479:13-28. [DOI: 10.1111/nyas.14336] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 02/25/2020] [Accepted: 03/05/2020] [Indexed: 12/20/2022]
Affiliation(s)
- Niko Amend
- Bundeswehr Institute of Pharmacology and Toxicology Munich Germany
| | - Karin V. Niessen
- Bundeswehr Institute of Pharmacology and Toxicology Munich Germany
| | - Thomas Seeger
- Bundeswehr Institute of Pharmacology and Toxicology Munich Germany
| | - Timo Wille
- Bundeswehr Institute of Pharmacology and Toxicology Munich Germany
| | - Franz Worek
- Bundeswehr Institute of Pharmacology and Toxicology Munich Germany
| | - Horst Thiermann
- Bundeswehr Institute of Pharmacology and Toxicology Munich Germany
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50
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Cavalcante SFDA, Simas ABC, Barcellos MC, de Oliveira VGM, Sousa RB, Cabral PADM, Kuča K, França TCC. Acetylcholinesterase: The "Hub" for Neurodegenerative Diseases and Chemical Weapons Convention. Biomolecules 2020; 10:E414. [PMID: 32155996 PMCID: PMC7175162 DOI: 10.3390/biom10030414] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 03/02/2020] [Accepted: 03/03/2020] [Indexed: 12/12/2022] Open
Abstract
This article describes acetylcholinesterase (AChE), an enzyme involved in parasympathetic neurotransmission, its activity, and how its inhibition can be pharmacologically useful for treating dementia, caused by Alzheimer's disease, or as a warfare method due to the action of nerve agents. The chemical concepts related to the irreversible inhibition of AChE, its reactivation, and aging are discussed, along with a relationship to the current international legislation on chemical weapons.
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Affiliation(s)
- Samir F. de A. Cavalcante
- Institute of Chemical, Biological, Radiological and Nuclear Defense (IDQBRN), Brazilian Army Technological Center (CTEx), Avenida das Américas 28705, Rio de Janeiro 23020-470, Brazil; (M.C.B.); (V.G.M.d.O.); (R.B.S.); (P.A.d.M.C.)
- Walter Mors Institute of Research on Natural Products (IPPN), Federal University of Rio de Janeiro (UFRJ), CCS, Bloco H, Rio de Janeiro 21941-902, Brazil
- Department of Chemistry, Faculty of Science, University of Hradec Králové, Rokitanskeho 62, 50003 Hradec Králové, Czech Republic
| | - Alessandro B. C. Simas
- Walter Mors Institute of Research on Natural Products (IPPN), Federal University of Rio de Janeiro (UFRJ), CCS, Bloco H, Rio de Janeiro 21941-902, Brazil
| | - Marcos C. Barcellos
- Institute of Chemical, Biological, Radiological and Nuclear Defense (IDQBRN), Brazilian Army Technological Center (CTEx), Avenida das Américas 28705, Rio de Janeiro 23020-470, Brazil; (M.C.B.); (V.G.M.d.O.); (R.B.S.); (P.A.d.M.C.)
| | - Victor G. M. de Oliveira
- Institute of Chemical, Biological, Radiological and Nuclear Defense (IDQBRN), Brazilian Army Technological Center (CTEx), Avenida das Américas 28705, Rio de Janeiro 23020-470, Brazil; (M.C.B.); (V.G.M.d.O.); (R.B.S.); (P.A.d.M.C.)
| | - Roberto B. Sousa
- Institute of Chemical, Biological, Radiological and Nuclear Defense (IDQBRN), Brazilian Army Technological Center (CTEx), Avenida das Américas 28705, Rio de Janeiro 23020-470, Brazil; (M.C.B.); (V.G.M.d.O.); (R.B.S.); (P.A.d.M.C.)
| | - Paulo A. de M. Cabral
- Institute of Chemical, Biological, Radiological and Nuclear Defense (IDQBRN), Brazilian Army Technological Center (CTEx), Avenida das Américas 28705, Rio de Janeiro 23020-470, Brazil; (M.C.B.); (V.G.M.d.O.); (R.B.S.); (P.A.d.M.C.)
| | - Kamil Kuča
- Department of Chemistry, Faculty of Science, University of Hradec Králové, Rokitanskeho 62, 50003 Hradec Králové, Czech Republic
| | - Tanos C. C. França
- Department of Chemistry, Faculty of Science, University of Hradec Králové, Rokitanskeho 62, 50003 Hradec Králové, Czech Republic
- Laboratory of Molecular Modelling Applied to Chemical and Biological Defense (LMACBD), Military Institute of Engineering (IME), Praça General Tibúrcio 80, Rio de Janeiro 22290-270, Brazil
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