Age differences in organophosphorus nerve agent-induced seizure, blood brain barrier integrity, and neurodegeneration in midazolam-treated rats.

Exposure to organophosphorus nerve agents irreversibly inhibits acetylcholinesterase and may lead to cholinergic crisis and seizures. Although benzodiazepines are the standard of care after nerve agent-induced status epilepticus, when treatment is delayed for up to 30 min or more, refractory status epilepticus can develop. Adult male rodents are often utilized for evaluation of therapeutic efficacy against nerve agent exposure.

Alterations in GABA receptor-mediated inhibition triggered by status epilepticus and their role in epileptogenesis and increased anxiety.

The triggers of status epilepticus (SE) in non-epileptic patients can vary widely, from idiopathic causes to exposure to chemoconvulsants. Regardless of its etiology, prolonged SE can cause significant brain damage, commonly resulting in the development of epilepsy, which is often accompanied by increased anxiety. GABA receptor (GABAR)-mediated inhibition has a central role among the mechanisms underlying brain damage and the ensuing epilepsy and anxiety.

Efficacy of Lacosamide and Rufinamide as Adjuncts to Midazolam-Ketamine Treatment Against Cholinergic-Induced Status Epilepticus in Rats.

Benzodiazepine pharmacoresistance develops when treatment of status epilepticus (SE) is delayed. This response may result from gamma-aminobutyric acid A receptors (GABAR) internalization that follows prolonged SE; this receptor trafficking results in fewer GABAR in the synapse to restore inhibition. Increase in synaptic N-methyl-D-aspartate receptors (NMDAR) also occurs in rodent models of SE.

Mechanisms of Organophosphate Toxicity and the Role of Acetylcholinesterase Inhibition.

Organophosphorus compounds (OPs) have applications in agriculture (e.g., pesticides), industry (e.

Evaluation of Midazolam-Ketamine-Allopregnanolone Combination Therapy against Cholinergic-Induced Status Epilepticus in Rats.

Status epilepticus (SE) is a life-threatening development of self-sustaining seizures that becomes resistant to benzodiazepines when treatment is delayed. Benzodiazepine pharmacoresistance is thought in part to result from internalization of synaptic GABA receptors, which are the main target of the drug. The naturally occurring neurosteroid allopregnanolone is a therapy of interest against SE for its ability to modulate all isoforms of GABA receptors.

Preventing Long-Term Brain Damage by Nerve Agent-Induced Status Epilepticus in Rat Models Applicable to Infants: Significant Neuroprotection by Tezampanel Combined with Caramiphen but Not by Midazolam Treatment.

Acute exposure to nerve agents induces a peripheral cholinergic crisis and prolonged status epilepticus (SE), causing death or long-term brain damage. To provide preclinical data pertinent to the protection of infants and newborns, we compared the antiseizure and neuroprotective effects of treating soman-induced SE with midazolam (MDZ) versus tezampanel (LY293558) in combination with caramiphen (CRM) in 12- and 7-day-old rats. The anticonvulsants were administered 1 hour after soman exposure; neuropathology data were collected up to 6 months postexposure.

Treatment of cholinergic-induced status epilepticus with polytherapy targeting GABA and glutamate receptors.

Despite new antiseizure medications, the development of cholinergic-induced refractory status epilepticus (RSE) continues to be a therapeutic challenge as pharmacoresistance to benzodiazepines and other antiseizure medications quickly develops. Studies conducted by Epilepsia. 2005;46:142 demonstrated that the initiation and maintenance of cholinergic-induced RSE are associated with trafficking and inactivation of gamma-aminobutyric acid A receptors (GABA R) thought to contribute to the development of benzodiazepine pharmacoresistance.

GABAergic circuits of the basolateral amygdala and generation of anxiety after traumatic brain injury.

Traumatic brain injury (TBI) has reached epidemic proportions around the world and is a major public health concern in the United States. Approximately 2.8 million individuals sustain a traumatic brain injury and are treated in an Emergency Department yearly in the U.

Novel Genetically Modified Mouse Model to Assess Soman-Induced Toxicity and Medical Countermeasure Efficacy: Human Acetylcholinesterase Knock-in Serum Carboxylesterase Knockout Mice.

The identification of improved medical countermeasures against exposure to chemical warfare nerve agents (CWNAs), a class of organophosphorus compounds, is dependent on the choice of animal model used in preclinical studies. CWNAs bind to acetylcholinesterase and prevent the catalysis of acetylcholine, causing a plethora of peripheral and central physiologic manifestations, including seizure. Rodents are widely used to elucidate the effects of CWNA-induced seizure, albeit with a caveat: they express carboxylesterase activity in plasma.

Treatment of acetylcholinesterase inhibitor-induced seizures with polytherapy targeting GABA and glutamate receptors.

The initiation and maintenance of cholinergic-induced status epilepticus (SE) are associated with decreased synaptic gamma-aminobutyric acid A receptors (GABAR) 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 GABAR 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 GABAR 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.

Cannabidiol reduces soman-induced lethality and seizure severity in female plasma carboxylesterase knockout mice treated with midazolam.

Cannabidiol, approved for treatment of pediatric refractory epilepsy, has anti-seizure effects in various animal seizure models. Chemical warfare nerve agents, including soman, are organophosphorus chemicals that can induce seizure and death if untreated or if treatment is delayed. Our objective was to evaluate whether cannabidiol would ameliorate soman-induced toxicity using a mouse model that similar to humans lacks plasma carboxylesterase.

Acetylcholinesterase inhibitors (nerve agents) as weapons of mass destruction: History, mechanisms of action, and medical countermeasures.

Nerve agents are organophosphorus acetylcholinesterase inhibitors. Acute exposure to nerve agents can cause rapid death. In this review, we summarize the history of nerve agent development and use in warfare, the mechanisms by which these agents cause death or long-term brain damage, and the treatments for preventing death or long-term morbidity.

Ketamine as adjunct to midazolam treatment following soman-induced status epilepticus reduces seizure severity, epileptogenesis, and brain pathology in plasma carboxylesterase knockout mice.

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 (GABA) 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.

Electroencephalographic analysis in soman-exposed 21-day-old rats and the effects of midazolam or LY293558 with caramiphen.

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.

Delayed midazolam dose effects against soman in male and female plasma carboxylesterase knockout mice.

Chemical warfare nerve agent exposure leads to status epilepticus that may progress to epileptogenesis and severe brain pathology when benzodiazepine treatment is delayed. We evaluated the dose-response effects of delayed midazolam (MDZ) on toxicity induced by soman (GD) in the plasma carboxylesterase knockout (Es1 ) mouse, which, similar to humans, lacks plasma carboxylesterase. Initially, we compared the median lethal dose (LD ) of GD exposure in female Es1 mice across estrous with male mice and observed a greater LD during estrus compared with proestrus or with males.

Dataset of EEG power integral, spontaneous recurrent seizure and behavioral responses following combination drug therapy in soman-exposed rats.

This article investigated the efficacy of the combination of antiepileptic drug therapy in protecting against soman-induced seizure severity, epileptogenesis and performance deficits. Adult male rats with implanted telemetry transmitters for continuous recording of electroencephalographic (EEG) activity were exposed to soman and treated with atropine sulfate and the oxime HI-6 one minute after soman exposure and with midazolam, ketamine and/or valproic acid 40 min after seizure onset. Rats exposed to soman and treated with medical countermeasures were evaluated for survival, seizure severity, the development of spontaneous recurrent seizure and performance deficits; combination anti-epileptic drug therapy was compared with midazolam monotherapy.

Early polytherapy for benzodiazepine-refractory status epilepticus.

The transition from single seizures to status epilepticus (SE) is associated with malaptive trafficking of synaptic gamma-aminobutyric acid (GABA) and glutamate receptors. The receptor trafficking hypothesis proposes that these changes are key events in the development of pharmacoresistance to antiepileptic drugs (AEDs) during SE, and that blocking their expression will help control drug-refractory SE (RSE). We tested this hypothesis in a model of SE induced by very high-dose lithium and pilocarpine (RSE), and in a model of SE induced by sc soman.

Neurosteroid and benzodiazepine combination therapy reduces status epilepticus and long-term effects of whole-body sarin exposure in rats.

Objective: Our objective was to evaluate the protective efficacy of the neurosteroid pregnanolone (3α-hydroxy-5β pregnan-20-one), a GABA receptor-positive allosteric modulator, as an adjunct to benzodiazepine therapy against the chemical warfare nerve agent (CWNA) sarin (GB), using whole-body exposure, an operationally relevant route of exposure to volatile GB.

Methods: Rats implanted with telemetry transmitters for the continuous measurement of cortical electroencephalographic (EEG) activity were exposed for 60 minutes to 3.0 LCt of GB via whole-body exposure.

Soman-induced status epilepticus, epileptogenesis, and neuropathology in carboxylesterase knockout mice treated with midazolam.

Objective: Exposure to chemical warfare nerve agents (CWNAs), such as soman (GD), can induce status epilepticus (SE) that becomes refractory to benzodiazepines when treatment is delayed, leading to increased risk of epileptogenesis, severe neuropathology, and long-term behavioral and cognitive deficits. Rodent models, widely used to evaluate novel medical countermeasures (MCMs) against CWNA exposure, normally express plasma carboxylesterase, an enzyme involved in the metabolism of certain organophosphorus compounds. To better predict the efficacy of novel MCMs against CWNA exposure in human casualties, it is crucial to use appropriate animal models that mirror the human condition.

Full Protection Against Soman-Induced Seizures and Brain Damage by LY293558 and Caramiphen Combination Treatment in Adult Rats.

Acute exposure to nerve agents induces status epilepticus (SE), which causes brain damage or death. LY293558, an antagonist of AMPA and GluK1 kainate receptors is a very effective anticonvulsant and neuroprotectant against soman; however, some neuronal damage is still present after treatment of soman-exposed rats with LY293558. Here, we have tested whether combining LY293558 with an NMDA receptor antagonist can eliminate the residual damage.

Exposure to nerve agents: from status epilepticus to neuroinflammation, brain damage, neurogenesis and epilepsy.

Epilepsy is a common neurological disorder characterized by an initial injury due to stroke, traumatic brain injury, brain infection, or febrile seizures causing status epilepticus (SE). This phenomenon precedes recurrent (secondary) seizures, the latent period (period without seizures) and downstream appearance of spontaneous recurrent seizures (SRS). Epilepsy inducers include the organophosphorous (OP) compounds modified as chemical warfare nerve agents, such as soman.

Combined diazepam and HDAC inhibitor treatment protects against seizures and neuronal damage caused by soman exposure.

The occurrence of status epilepticus (SE) is considered the main cause of brain lesions and morphological alterations, such as hippocampal neuron loss, that result in chronic epilepsy. Previous work demonstrated the convulsive and widespread neuropathological effects of soman, an organophosphorus compound that causes SE and severe recurrent seizures as a result of exposure. Seizures begin rapidly after exposure, can continue for hours, and contribute to prolonged physical incapacitation of the victim.

Spontaneous recurrent seizures after status epilepticus induced by soman in Sprague-Dawley rats.

Purpose: Exposure to toxic levels of organophosphorus (OP) nerve agents can lead to seizures, respiratory failure, and, if untreated, death. The cholinesterase inhibitor soman belongs to the class of OP nerve agents and can cause status epilepticus (SE) and brain damage due to neuroexcitotoxicity. In the present study, electroencephalographic seizures are characterized through telemetry implants in rats exposed to soman, followed by treatment with therapeutics similar to those administered after nerve agent exposure.

Analyzing large data sets acquired through telemetry from rats exposed to organophosphorous compounds: an EEG study.

The organophosphorous compound soman is an acetylcholinesterase inhibitor that causes damage to the brain. Exposure to soman causes neuropathology as a result of prolonged and recurrent seizures. In the present study, long-term recordings of cortical EEG were used to develop an unbiased means to quantify measures of seizure activity in a large data set while excluding other signal types.