Refinement of the rodent pentylenetetrazole proconvulsion assay, which is a good predictor of convulsions in repeat-dose toxicology studies

Breidenbach, Laura; Hempel, K; Mittelstadt, Scott W.; Lynch, James J.

doi:10.1016/j.vascn.2019.106653

Cited by 2 publications

(3 citation statements)

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“…In these experiments, the doses used for retigabine or compound 60 were 3 and 0.3 mg/kg, respectively, representing the minimum effective doses calculated from previous experiments. In several acute seizure animal models, including the PTZ model herein investigated, high mortality rates are observed . In our experiments, only about 37% (7/19) of vehicle-treated mice survived at the end of the 60 min observation period (Figure E).…”

Section: Resultsmentioning

confidence: 59%

“…In several acute seizure animal models, including the PTZ model herein investigated, high mortality rates are observed. 46 In our experiments, only about 37% (7/19) of vehicle-treated mice survived at the end of the 60 min observation period (Figure 5E). In agreement with its strong antiseizure effect, compound 60 dose-dependently reduced mortality, with 87% (13/15) animals treated with 0.3 mg/kg and all animals (8/8) treated with the highest dose of 1 mg/kg surviving; instead, no protective effect on mortality was observed with the highest dose of retigabine (3 mg/kg), with only 40% (4/10) of mice surviving.…”

Section: ■ Introductionmentioning

confidence: 58%

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Beyond Retigabine: Design, Synthesis, and Pharmacological Characterization of a Potent and Chemically Stable Neuronal Kv7 Channel Activator with Anticonvulsant Activity

et al. 2022

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Neuronal Kv7 channels represent important pharmacological targets for hyperexcitability disorders including epilepsy. Retigabine is the prototype Kv7 activator clinically approved for seizure treatment; however, severe side effects associated with long-term use have led to its market discontinuation. Building upon the recently described cryoEM structure of Kv7.2 complexed with retigabine and on previous structure–activity relationship studies, a small library of retigabine analogues has been designed, synthesized, and characterized for their Kv7 opening ability using both fluorescence- and electrophysiology-based assays. Among all tested compounds, 60 emerged as a potent and photochemically stable neuronal Kv7 channel activator. Compared to retigabine, compound 60 displayed a higher brain/plasma distribution ratio, a longer elimination half-life, and more potent and effective anticonvulsant effects in an acute seizure model in mice. Collectively, these data highlight compound 60 as a promising lead compound for the development of novel Kv7 activators for the treatment of hyperexcitability diseases.

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Section: Resultsmentioning

confidence: 59%

Section: ■ Introductionmentioning

confidence: 58%

Beyond Retigabine: Design, Synthesis, and Pharmacological Characterization of a Potent and Chemically Stable Neuronal Kv7 Channel Activator with Anticonvulsant Activity

et al. 2022

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“…SAGE‐718 (10, 30 and 50 mg·kg −1 ) did not significantly affect clonic or tonic seizure latency compared with vehicle‐treated mice (Table S4; Figure 8c) at the doses measured. In contrast, diazepam, a benzodiazepine and GABA A receptor PAM, significantly increased latency to both tonic and clonic seizures compared with vehicle‐treated mice, while theophylline, an adenosine receptor antagonist and proconvulsant (Breidenbach et al, 2020), significantly decreased latency to tonic, but not clonic, seizures compared with vehicle‐treated mice. In test mice, SAGE‐718 doses of 10, 30 and 50 mg·kg −1 reached plasma concentrations of 330 ± 80, 338 ± 204 and 445 ± 324 ng·ml −1 , respectively (n = 3, mean ± SD), while brain concentrations were 336 ± 102, 303 ± 195 and 304 ± 236 ng·g −1 , respectively.…”

Section: Resultsmentioning

confidence: 95%

Pharmacological characterization of SAGE‐718, a novel positive allosteric modulator of N‐methyl‐d‐aspartate receptors

Beckley,

Aman,

Ackley

et al. 2023

British J Pharmacology

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Background and PurposeSelect neuroactive steroids (NAS) tune neural activity by modulating excitatory and inhibitory neurotransmission, including the endogenous cholesterol metabolite 24(S)‐hydroxycholesterol (24(S)‐HC), which is a N‐methyl‐d‐aspartate receptor (NMDAR) positive allosteric modulator (PAM). NMDAR PAMs are potentially an effective pharmacotherapeutic strategy to treat conditions associated with NMDAR hypofunction.Experimental ApproachesUsing in vitro and in vivo electrophysiological recording experiments and behavioral approaches, we evaluated the effect of SAGE‐718, a novel NAS NMDAR PAM currently in clinical development for the treatment of cognitive impairment, on NMDAR function and endpoints that are altered by NMDAR hypoactivity, and assessed its safety profile.Key ResultsSAGE‐718 potentiated NMDAR at GluN1/GluN2A‐D with equipotency and increased NMDAR EPSP amplitude without affecting decay kinetics in striatal medium spiny neurons. SAGE‐718 increased the rate of unblock of the NMDAR open channel blocker ketamine on GluN1/GluN2A in vitro and accelerated the rate of return on the ketamine‐evoked increase in gamma frequency band power, as measured with EEG, suggesting that PAM activity is driven by increased channel open probability. SAGE‐718 ameliorated deficits due to NMDAR hypofunction, including social deficits induced by subchronic administration of phencyclidine, and behavioral and electrophysiological deficits from cholesterol and 24(S)‐HC depletion caused by 7‐Dehydrocholesterol reductase inhibition. Finally, SAGE‐718 did not produce epileptiform activity in a seizure model or neurodegeneration following chronic dosing.Conclusions and ImplicationsThese findings provide strong evidence that SAGE‐718 is a NAS NMDAR PAM with a mechanism that is well suited as a treatment for conditions associated with NMDAR hypofunction.

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Refinement of the rodent pentylenetetrazole proconvulsion assay, which is a good predictor of convulsions in repeat-dose toxicology studies

Cited by 2 publications

References 28 publications

Beyond Retigabine: Design, Synthesis, and Pharmacological Characterization of a Potent and Chemically Stable Neuronal Kv7 Channel Activator with Anticonvulsant Activity

Beyond Retigabine: Design, Synthesis, and Pharmacological Characterization of a Potent and Chemically Stable Neuronal Kv7 Channel Activator with Anticonvulsant Activity

Pharmacological characterization of SAGE‐718, a novel positive allosteric modulator of N‐methyl‐d‐aspartate receptors

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