Effects of imidazenil, a new benzodiazepine receptor partial agonist, in the treatment of convulsions in organophosphate intoxications

Rump, S; Gidynska, T.; Gałecka, Elżbieta; Antkowiak, Oktawiusz; Nawrocka, Małgorzata; Kowalczyk, Marek

doi:10.1007/bf03033323

Cited by 7 publications

(4 citation statements)

References 15 publications

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“…Like NAs, paraoxon and DFP lead to benzodiazepine‐refractory SE . However, several groups have found that the alternative benzodiazepine imidazenil may offer better and more potent seizure control than diazepam . Thus far, no other studies have been published using OP models to test novel anticonvulsants, but this will change with the recent announcement of the National Institute of Neurological Disorders and Stroke's CounterACT Neurotherapeutics Screening Program .…”

Section: Pesticide Modelsmentioning

confidence: 99%

“…65 However, several groups have found that the alternative benzodiazepine imidazenil may offer better and more potent seizure control than diazepam. 66,67 Thus far, no other studies have been published using OP models to test novel anticonvulsants, but this will change with the recent announcement of the National Institute of Neurological Disorders and Stroke's CounterACT Neurotherapeutics Screening Program. 68 A number of anticonvulsant studies have been performed using pilocarpine to induce SE, which has been argued to be a good surrogate for organophosphate exposure.…”

Section: Pesticide Modelsmentioning

confidence: 99%

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

McCarren

McDonough

2016

Annals of the New York Academy of Sciences

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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. Here, we describe the development of various animal models of SE induced by NA or OP exposure. Experiments in nonhuman primates, rats, mice, and guinea pigs have helped to identify novel therapeutic targets in the central nervous system, with particular success at modulating GABAergic and glutamatergic receptors. The anticonvulsants identified by NA- and OP-induced SE models are well poised for fast advancement into clinical development, and their potential utility in the broader field of epilepsy should make them all the more attractive for commercial pursuit.

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Section: Pesticide Modelsmentioning

confidence: 99%

Section: Pesticide Modelsmentioning

confidence: 99%

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

McCarren

McDonough

2016

Annals of the New York Academy of Sciences

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“…Clearly, controlled studies of the effects of OP anticholinesterases cannot be carried out in humans. Studies of the mechanisms and pharmacology of OPinduced seizures have therefore been performed using animal models, usually mice (75)(76)(77)(78)(79)(80)(81), rats (77,(82)(83)(84)(85) or guinea-pigs (84,(86)(87)(88), but occasionally primates (89-94), and the majority of these have used nerve agents to induce seizure activity.…”

Section: Animal Modelsmentioning

confidence: 99%

Seizure activity post organophosphate exposure

Tattersall¹

2009

Front Biosci

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Electrographic seizures are a feature of organophosphate anticholinesterase intoxication. Clinical studies of pesticide poisonings suggest that seizures are more common in children than in adults. Since flaccid paralysis, a characteristic sign of organophosphate poisoning, can mask convulsions, the most reliable indicator of seizures is the electroencephalogram, but this has not been widely used in clinical studies. Seizures can rapidly progress to status epilepticus, contributing to mortality and, in survivors, to neuronal damage and neurological impairment. Anticonvulsant drugs can significantly reduce the lethal and toxic effects of these compounds. A benzodiazepine, usually diazepam, is the treatment currently indicated for control of seizures. Animal studies have indicated that the early phase of seizure activity (0-5 min after seizure onset) is purely cholinergic, predominantly involving muscarinic mechanisms. Seizure activity subsequently progresses through mixed cholinergic and noncholinergic modulation (5-40 min) into a final noncholinergic phase. Neuropathology caused by seizures is most likely associated with glutamatergic excitotoxicity. Future prospects for improved treatments include new benzodiazepines, glutamate receptor antagonists, antimuscarinics with additional antiglutamatergic activity and adenosine receptor antagonists.

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“…Thus, IMI elicits a potent anticonvulsant and anxiolytic action at doses that are virtually devoid of sedative and amnesic effects (6,(25)(26)(27)(28)(29)(30)(31). Of note, IMI also potently antagonizes diisopropyl fluorophosphate (DFP)-induced seizures and mortality in rodents (6,32). This drug, at doses up to 60-fold greater than those producing anxiolytic and anticonvulsant actions, antagonizes the sedative and amnesic actions of DZP or alprazolam without causing tolerance (26)(27)(28)(29)(30)33).…”

mentioning

confidence: 99%

The combination of huperzine A and imidazenil is an effective strategy to prevent diisopropyl fluorophosphate toxicity in mice

Pibiri

Kozikowski

Pinna

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Diisopropyl fluorophosphate (DFP) causes neurotoxicity related to an irreversible inhibition of acetylcholinesterase (AChE). Management of this intoxication includes: (i) pretreatment with reversible blockers of AChE, (ii) blockade of muscarinic receptors with atropine, and (iii) facilitation of GABAA receptor signal transduction by benzodiazepines. The major disadvantage associated with this treatment combination is that it must to be repeated frequently and, in some cases, protractedly. Also, the use of diazepam (DZP) and congeners includes unwanted side effects, including sedation, amnesia, cardiorespiratory depression, and anticonvulsive tolerance. To avoid these treatment complications but safely protect against DFP-induced seizures and other CNS toxicity, we adopted the strategy of administering mice with (i) small doses of huperzine A (HUP), a reversible and long-lasting (half-life Ϸ5 h) inhibitor of AChE, and (ii) imidazenil (IMI), a potent positive allosteric modulator of GABA action selective for ␣5-containing GABAA receptors. Coadministration of HUP (50 g/kg s.c., 15 min before DFP) with IMI (2 mg/kg s.c., 30 min before DFP) prevents DFP-induced convulsions and the associated neuronal damage and mortality, allowing complete recovery within 18 -24 h. In HUP-pretreated mice, the ED50 of IMI to block DFP-induced mortality is Ϸ10 times lower than that of DZP and is devoid of sedation. Our data show that a combination of HUP with IMI is a prophylactic, potent, and safe therapeutic strategy to overcome DFP toxicity.GABAA receptor ͉ neurotoxicity

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Effects of imidazenil, a new benzodiazepine receptor partial agonist, in the treatment of convulsions in organophosphate intoxications

Cited by 7 publications

References 15 publications

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

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

Seizure activity post organophosphate exposure

The combination of huperzine A and imidazenil is an effective strategy to prevent diisopropyl fluorophosphate toxicity in mice

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