Imidazenil prevention of alprazolam-induced acquisition deficit in patas monkeys is devoid of tolerance

Auta, James; Guidotti, Alessandro; Costa, E.

doi:10.1073/pnas.97.5.2314

Cited by 20 publications

(9 citation statements)

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“…4). Of note, unlike DZP, IMI in combination with HUP at a dose that reduces DFP-induced lethality fails to induce sedation, amnesia, and muscle relaxation (6,29). Prophylactic treatment against OP exposure could be given before intoxication.…”

Section: Doses Of Hup That Protect Mice Against Dfp-induced Mortalitymentioning

confidence: 99%

“…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). Furthermore, in non-human primates, IMI is virtually devoid of tolerance and dependence liability (29,30).…”

mentioning

confidence: 99%

“…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). Furthermore, in non-human primates, IMI is virtually devoid of tolerance and dependence liability (29,30). The IMI clearance rate in vivo is slower (in rats the t1 ͞2 is 180 min, and in non-human primates its t1 ͞2 is Ͼ8 h) than that of DZP (26).…”

mentioning

confidence: 99%

“…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).…”

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confidence: 99%

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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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Section: Doses Of Hup That Protect Mice Against Dfp-induced Mortalitymentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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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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“…Compared with full agonists, imidazenil (for example) did not induce cognitive deficits nor was development of tolerance observed after long-term administration in animal models (Auta et al, 2000;Costa and Guidotti, 1996). However, the anxiolytic activity of imidazenil found in animals could not be reproduced in humans and was not clearly separate from sedation (Atack, 2003).…”

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Characterization in Rats of the Anxiolytic Potential of ELB139 [1-(4-Chlorophenyl)-4-piperidin-1-yl-1,5-dihydro-imidazol-2-on], a New Agonist at the Benzodiazepine Binding Site of the GABA_A Receptor

Langen¹,

Egerland²,

Bernöster³

et al. 2005

J Pharmacol Exp Ther

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Benzodiazepines are among the most effective drugs for the treatment of anxiety disorders. However, their use is limited by undesired side effects, including sedation, development of tolerance, and drug abuse. The aim of this study was to evaluate the pharmacological profile of ELB139 [1-(4-chlorophenyl)-4-piperidin-1-yl-1,5-dihydro-imidazol-2-on] in different models of anxiety and to correlate these effects with its activity in vitro. ELB139 binds with an IC 50 of 1390 nM to the flunitrazepam binding site in rat forebrain cortical membranes. In rat hippocampal neurons, ELB139 potentiated GABA-induced currents without reaching the maximum effect of diazepam, indicating a partial benzodiazepine agonism. The potentiation was antagonized by the benzodiazepine antagonist flumazenil. ELB139 (10 and 30 mg/kg p.o.) was active in three different animal models of anxiety, i.e., in the elevated plus-maze, the light and dark box, and the Vogel conflict test. The anxiolytic activity in the elevated plus-maze was almost completely reversed by flumazenil (5 mg/kg i.p.), indicating that interaction with the benzodiazepine binding site is central to the pharmacological activity. No hint of sedation was observed at the doses tested in the three anxiety models and the open field. Also, no development of tolerance was observed within 6 weeks b.i.d. treatment with ELB139 in the elevated plus-maze test. In summary, ELB139 elicits strong effects on anxietyrelated behavior in rats mediated by its benzodiazepine-like activity without showing sedation or the development of tolerance, a major side effect of benzodiazepines. These characteristics make the compound a prime candidate for clinical development.

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Tolerance and Dependence to Ligands of the Benzodiazepine Recognition Sites Expressed by GABAA Receptors

Costa¹,

Auta²,

Guidotti³

2001

Pharmacology of GABA and Glycine Neurotransmission

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Imidazenil prevention of alprazolam-induced acquisition deficit in patas monkeys is devoid of tolerance

Cited by 20 publications

References 20 publications

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

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

Characterization in Rats of the Anxiolytic Potential of ELB139 [1-(4-Chlorophenyl)-4-piperidin-1-yl-1,5-dihydro-imidazol-2-on], a New Agonist at the Benzodiazepine Binding Site of the GABA_A Receptor

Tolerance and Dependence to Ligands of the Benzodiazepine Recognition Sites Expressed by GABAA Receptors

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Imidazenil prevention of alprazolam-induced acquisition deficit in patas monkeys is devoid of tolerance

Cited by 20 publications

References 20 publications

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

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

Characterization in Rats of the Anxiolytic Potential of ELB139 [1-(4-Chlorophenyl)-4-piperidin-1-yl-1,5-dihydro-imidazol-2-on], a New Agonist at the Benzodiazepine Binding Site of the GABAA Receptor

Tolerance and Dependence to Ligands of the Benzodiazepine Recognition Sites Expressed by GABAA Receptors

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Product

Resources

About

Characterization in Rats of the Anxiolytic Potential of ELB139 [1-(4-Chlorophenyl)-4-piperidin-1-yl-1,5-dihydro-imidazol-2-on], a New Agonist at the Benzodiazepine Binding Site of the GABA_A Receptor