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The novel persistent sodium current inhibitor PRAX‐562 has potent anticonvulsant activity with improved protective index relative to standard of care sodium channel blockers

OBJECTIVE: This study investigates the effects of PRAX‐562 on sodium current (I(Na)), intrinsic neuronal excitability, and protection from evoked seizures to determine whether a preferential persistent I(Na) inhibitor would exhibit improved preclinical efficacy and tolerability compared to two stand...

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Autores principales: Kahlig, Kristopher M., Scott, Liam, Hatch, Robert J., Griffin, Andrew, Martinez Botella, Gabriel, Hughes, Zoë A., Wittmann, Marion
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9304232/
https://www.ncbi.nlm.nih.gov/pubmed/35037706
http://dx.doi.org/10.1111/epi.17149
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author Kahlig, Kristopher M.
Scott, Liam
Hatch, Robert J.
Griffin, Andrew
Martinez Botella, Gabriel
Hughes, Zoë A.
Wittmann, Marion
author_facet Kahlig, Kristopher M.
Scott, Liam
Hatch, Robert J.
Griffin, Andrew
Martinez Botella, Gabriel
Hughes, Zoë A.
Wittmann, Marion
author_sort Kahlig, Kristopher M.
collection PubMed
description OBJECTIVE: This study investigates the effects of PRAX‐562 on sodium current (I(Na)), intrinsic neuronal excitability, and protection from evoked seizures to determine whether a preferential persistent I(Na) inhibitor would exhibit improved preclinical efficacy and tolerability compared to two standard voltage‐gated sodium channel (Na(V)) blockers. METHODS: Inhibition of I(Na) was characterized using patch clamp analysis. The effect on intrinsic excitability was measured using evoked action potentials recorded from hippocampal CA1 pyramidal neurons in mouse brain slices. Anticonvulsant activity was evaluated using the maximal electroshock seizure (MES) model, and tolerability was assessed by measuring spontaneous locomotor activity (sLMA). RESULTS: PRAX‐562 potently and preferentially inhibited persistent I(Na) induced by ATX‐II or the SCN8A mutation N1768D (half‐maximal inhibitory concentration [IC(50)] = 141 and 75 nmol·L(–1), respectively) relative to peak I(Na) tonic/resting block (60× preference). PRAX‐562 also exhibited potent use‐dependent block (31× preference to tonic block). This profile is considerably different from standard Na(V) blockers, including carbamazepine (CBZ; persistent I(Na) IC(50) = 77 500 nmol·L(–1), preference ratios of 30× [tonic block], less use‐dependent block observed at various frequencies). In contrast to CBZ, PRAX‐562 reduced neuronal intrinsic excitability with only a minor reduction in action potential amplitude. PRAX‐562 (10 mg/kg po) completely prevented evoked seizures without affecting sLMA (MES unbound brain half‐maximal efficacious concentration = 4.3 nmol·L(–1), sLMA half‐maximal tolerated concentration = 69.7 nmol·L(–1), protective index [PI] = 16×). In contrast, CBZ and lamotrigine (LTG) had PIs of approximately 5.5×, with significant overlap between doses that were anticonvulsant and that reduced locomotor activity. SIGNIFICANCE: PRAX‐562 demonstrated robust preclinical anticonvulsant activity similar to CBZ but improved compared to LTG. PRAX‐562 exhibited significantly improved preclinical tolerability compared with standard Na(V) blockers (CBZ and LTG), potentially due to the preference for persistent I(Na). Preferential targeting of persistent I(Na) may represent a differentiated therapeutic option for diseases of hyperexcitability, where standard Na(V) blockers have demonstrated efficacy but poor tolerability.
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spelling pubmed-93042322022-07-28 The novel persistent sodium current inhibitor PRAX‐562 has potent anticonvulsant activity with improved protective index relative to standard of care sodium channel blockers Kahlig, Kristopher M. Scott, Liam Hatch, Robert J. Griffin, Andrew Martinez Botella, Gabriel Hughes, Zoë A. Wittmann, Marion Epilepsia Research Article OBJECTIVE: This study investigates the effects of PRAX‐562 on sodium current (I(Na)), intrinsic neuronal excitability, and protection from evoked seizures to determine whether a preferential persistent I(Na) inhibitor would exhibit improved preclinical efficacy and tolerability compared to two standard voltage‐gated sodium channel (Na(V)) blockers. METHODS: Inhibition of I(Na) was characterized using patch clamp analysis. The effect on intrinsic excitability was measured using evoked action potentials recorded from hippocampal CA1 pyramidal neurons in mouse brain slices. Anticonvulsant activity was evaluated using the maximal electroshock seizure (MES) model, and tolerability was assessed by measuring spontaneous locomotor activity (sLMA). RESULTS: PRAX‐562 potently and preferentially inhibited persistent I(Na) induced by ATX‐II or the SCN8A mutation N1768D (half‐maximal inhibitory concentration [IC(50)] = 141 and 75 nmol·L(–1), respectively) relative to peak I(Na) tonic/resting block (60× preference). PRAX‐562 also exhibited potent use‐dependent block (31× preference to tonic block). This profile is considerably different from standard Na(V) blockers, including carbamazepine (CBZ; persistent I(Na) IC(50) = 77 500 nmol·L(–1), preference ratios of 30× [tonic block], less use‐dependent block observed at various frequencies). In contrast to CBZ, PRAX‐562 reduced neuronal intrinsic excitability with only a minor reduction in action potential amplitude. PRAX‐562 (10 mg/kg po) completely prevented evoked seizures without affecting sLMA (MES unbound brain half‐maximal efficacious concentration = 4.3 nmol·L(–1), sLMA half‐maximal tolerated concentration = 69.7 nmol·L(–1), protective index [PI] = 16×). In contrast, CBZ and lamotrigine (LTG) had PIs of approximately 5.5×, with significant overlap between doses that were anticonvulsant and that reduced locomotor activity. SIGNIFICANCE: PRAX‐562 demonstrated robust preclinical anticonvulsant activity similar to CBZ but improved compared to LTG. PRAX‐562 exhibited significantly improved preclinical tolerability compared with standard Na(V) blockers (CBZ and LTG), potentially due to the preference for persistent I(Na). Preferential targeting of persistent I(Na) may represent a differentiated therapeutic option for diseases of hyperexcitability, where standard Na(V) blockers have demonstrated efficacy but poor tolerability. John Wiley and Sons Inc. 2022-01-17 2022-03 /pmc/articles/PMC9304232/ /pubmed/35037706 http://dx.doi.org/10.1111/epi.17149 Text en © 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Research Article
Kahlig, Kristopher M.
Scott, Liam
Hatch, Robert J.
Griffin, Andrew
Martinez Botella, Gabriel
Hughes, Zoë A.
Wittmann, Marion
The novel persistent sodium current inhibitor PRAX‐562 has potent anticonvulsant activity with improved protective index relative to standard of care sodium channel blockers
title The novel persistent sodium current inhibitor PRAX‐562 has potent anticonvulsant activity with improved protective index relative to standard of care sodium channel blockers
title_full The novel persistent sodium current inhibitor PRAX‐562 has potent anticonvulsant activity with improved protective index relative to standard of care sodium channel blockers
title_fullStr The novel persistent sodium current inhibitor PRAX‐562 has potent anticonvulsant activity with improved protective index relative to standard of care sodium channel blockers
title_full_unstemmed The novel persistent sodium current inhibitor PRAX‐562 has potent anticonvulsant activity with improved protective index relative to standard of care sodium channel blockers
title_short The novel persistent sodium current inhibitor PRAX‐562 has potent anticonvulsant activity with improved protective index relative to standard of care sodium channel blockers
title_sort novel persistent sodium current inhibitor prax‐562 has potent anticonvulsant activity with improved protective index relative to standard of care sodium channel blockers
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9304232/
https://www.ncbi.nlm.nih.gov/pubmed/35037706
http://dx.doi.org/10.1111/epi.17149
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