Allopregnanolone as an Adjunct Therapy to Midazolam is More Effective Than Midazolam Alone in Suppressing Soman-Induced Status Epilepticus in Male Rats.

Aims: Humans and animals acutely intoxicated with the organophosphate soman can develop sustained status epilepticus (SE) that rapidly becomes refractory to benzodiazepines. We compared the antiseizure efficacy of midazolam, a current standard of care treatment for OP-induced SE, versus combined therapy with midazolam and allopregnanolone (ALLO) in a rat model of soman-induced SE.

Methods: Soman-intoxicated male rats with robust seizure behavior and high-amplitude electroencephalographic (EEG) activity were administered midazolam (0.

Refractory and Super-Refractory Status Epilepticus in Nerve Agent-Poisoned Rats Following Application of Standard Clinical Treatment Guidelines.

Nerve agents (NAs) induce a severe cholinergic crisis that can lead to status epilepticus (SE). Current guidelines for treatment of NA-induced SE only include prehospital benzodiazepines, which may not fully resolve this life-threatening condition. This study examined the efficacy of general clinical protocols for treatment of SE in the specific context of NA poisoning in adult male rats.

The K7 Modulator, Retigabine, is an Efficacious Antiseizure Drug for Delayed Treatment of Organophosphate-induced Status Epilepticus.

Benzodiazepines are the primary treatment option for organophosphate (OP)-induced status epilepticus (SE), but these antiseizure drugs (ASDs) lose efficacy as treatment is delayed. In the event of a mass civilian or military exposure, significant treatment delays are likely. New ASDs that combat benzodiazepine-resistant, OP-induced SE are critically needed, particularly if they can be efficacious after a long treatment delay.

Comparison of neuropathology in rats following status epilepticus induced by diisopropylfluorophosphate and soman.

The increasing number of cases involving the use of nerve agents as deadly weapons has spurred investigation into the molecular mechanisms underlying nerve agent-induced pathology. The highly toxic nature of nerve agents restrict their use in academic research laboratories. Less toxic organophosphorus (OP) based agents including diisopropylfluorophosphate (DFP) are used as surrogates in academic research laboratories to mimic nerve agent poisoning.

Evaluation of fosphenytoin, levetiracetam, and propofol as treatments for nerve agent-induced seizures in pediatric and adult rats.

Multiple recent instances of nerve agent (NA) exposure in civilian populations have occurred, resulting in a variety of negative effects and lethality in both adult and pediatric populations. Seizures are a prominent effect of NAs that can result in neurological damage and contribute to their lethality. Current anticonvulsant treatments for NAs are approved for adults, but no approved pediatric treatments exist.

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

Purpose: To develop and characterize a mouse model of spontaneous recurrent seizures following nerve agent-induced status epilepticus (SE) and test the efficacy of existing antiepileptic drugs.

Methods: SE was induced in telemeterized male C57Bl6/J mice by soman exposure, and electroencephalographic activity was recorded for 4-6 weeks. Mice were treated with antiepileptic drugs (levetiracetam, valproic acid, phenobarbital) or corresponding vehicles for 14 d after exposure, followed by 14 d of drug washout.

Screening for Efficacious Anticonvulsants and Neuroprotectants in Delayed Treatment Models of Organophosphate-induced Status Epilepticus.

Organophosphorus (OP) compounds are deadly chemicals that exert their intoxicating effects through the irreversible inhibition of acetylcholinesterase (AChE). In addition to an excess of peripheral ailments, OP intoxication induces status epilepticus (SE) which if left untreated may lead to permanent brain damage or death. Benzodiazepines are typically the primary therapies for OP-induced SE, but these drugs lose efficacy as treatment time is delayed.

Validating a model of benzodiazepine refractory nerve agent-induced status epilepticus by evaluating the anticonvulsant and neuroprotective effects of scopolamine, memantine, and phenobarbital.

Introduction: Organophosphorus nerve agents (OPNAs) irreversibly block acetylcholinesterase activity, resulting in accumulation of excess acetylcholine at neural synapses, which can lead to a state of prolonged seizures known as status epilepticus (SE). Benzodiazepines, the current standard of care for SE, become less effective as latency to treatment increases. In a mass civilian OPNA exposure, concurrent trauma and limited resources would likely cause a delay in first response time.

Dexmedetomidine stops benzodiazepine-refractory nerve agent-induced status epilepticus.

Nerve agents are highly toxic chemicals that pose an imminent threat to soldiers and civilians alike. Nerve agent exposure leads to an increase in acetylcholine within the central nervous system, resulting in development of protracted seizures known as status epilepticus (SE). Currently, benzodiazepines are the standard of care for nerve agent-induced SE, but their efficacy quickly wanes as the time to treatment increases.

The role of genetic background in susceptibility to chemical warfare nerve agents across rodent and non-human primate models.

Genetics likely play a role in various responses to nerve agent exposure, as genetic background plays an important role in behavioral, neurological, and physiological responses to environmental stimuli. Mouse strains or selected lines can be used to identify susceptibility based on background genetic features to nerve agent exposure. Additional genetic techniques can then be used to identify mechanisms underlying resistance and sensitivity, with the ultimate goal of developing more effective and targeted therapies.

The synthetic neuroactive steroid SGE-516 reduces status epilepticus and neuronal cell death in a rat model of soman intoxication.

Organophosphorus nerve agents (OPNAs) are irreversible inhibitors of acetylcholinesterase that pose a serious threat to public health because of their use as chemical weapons. Exposure to high doses of OPNAs can dramatically potentiate cholinergic synaptic activity and cause status epilepticus (SE). Current standard of care for OPNA exposure involves treatment with cholinergic antagonists, oxime cholinesterase reactivators, and benzodiazepines.

Anticonvulsant discovery through animal models of status epilepticus induced by organophosphorus nerve agents and pesticides.

Organophosphorus pesticides (OPs) and nerve agents (NAs) are highly toxic chemicals that pose a significant threat to human health worldwide. These compounds induce status epilepticus (SE) by irreversibly blocking the ability of acetylcholinesterase to break down acetylcholine at neural synapses. Animal models of organophosphate-induced SE are a crucial resource for identifying new anticonvulsant therapies.

α2-Adrenergic stimulation of the ventrolateral preoptic nucleus destabilizes the anesthetic state.

The sleep-promoting ventrolateral preoptic nucleus (VLPO) shares reciprocal inhibitory inputs with wake-active neuronal nuclei, including the locus ceruleus. Electrophysiologically, sleep-promoting neurons in the VLPO are directly depolarized by the general anesthetic isoflurane and hyperpolarized by norepinephrine, a wake-promoting neurotransmitter. However, the integration of these competing influences on the VLPO, a sleep- and anesthetic-active structure, has yet to be evaluated in either brain slices in vitro or the intact organism.

Distinctive recruitment of endogenous sleep-promoting neurons by volatile anesthetics and a nonimmobilizer.

Background: Numerous studies demonstrate that anesthetic-induced unconsciousness is accompanied by activation of hypothalamic sleep-promoting neurons, which occurs through both pre- and postsynaptic mechanisms. However, the correlation between drug exposure, neuronal activation, and onset of hypnosis remains incompletely understood. Moreover, the degree to which anesthetics activate both endogenous populations of γ-aminobutyric acid (GABA)ergic sleep-promoting neurons within the ventrolateral preoptic (VLPO) and median preoptic nuclei remains unknown.

Assessing changes in volatile general anesthetic sensitivity of mice after local or systemic pharmacological intervention.

One desirable endpoint of general anesthesia is the state of unconsciousness, also known as hypnosis. Defining the hypnotic state in animals is less straightforward than it is in human patients. A widely used behavioral surrogate for hypnosis in rodents is the loss of righting reflex (LORR), or the point at which the animal no longer responds to their innate instinct to avoid the vulnerability of dorsal recumbency.

Mouse behavioral endophenotypes for schizophrenia.

An endophenotype is a heritable trait that is generally considered to be more highly, associated with a gene-based neurological deficit than a disease phenotype itself. Such, endophenotypic deficits may therefore be observed in the non-affected relatives of disease patients. Once endophenotypes have been established for a given illness, such as schizophrenia, mechanisms of, action may then be established and treatment options developed in order to target such measures.