Antiepileptic activity of preferential inhibitors of persistent sodium current

Lyndsey L. Anderson, Christopher H. Thompson, Nicole A. Hawkins, Ravi D. Nath, Adam A. Petersohn, Sridharan Rajamani, William S. Bush, Wayne N. Frankel, Carlos G. Vanoye, Jennifer A. Kearney, Alfred L. George*

*Corresponding author for this work

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Summary Objective Evidence from basic neurophysiology and molecular genetics has implicated persistent sodium current conducted by voltage-gated sodium (NaV) channels as a contributor to the pathogenesis of epilepsy. Many antiepileptic drugs target NaV channels and modulate neuronal excitability, mainly by a use-dependent block of transient sodium current, although suppression of persistent current may also contribute to the efficacy of these drugs. We hypothesized that a drug or compound capable of preferential inhibition of persistent sodium current would have antiepileptic activity. Methods We examined the antiepileptic activity of two selective persistent sodium current blockers ranolazine, a U.S. Food and Drug Administration (FDA)-approved drug for treatment of angina pectoris, and GS967, a novel compound with more potent effects on persistent current, in the epileptic Scn2aQ54 mouse model. We also examined the effect of GS967 in the maximal electroshock model and evaluated effects of the compound on neuronal excitability, propensity for hilar neuron loss, development of mossy fiber sprouting, and survival of Scn2aQ54 mice. Results We found that ranolazine was capable of reducing seizure frequency by approximately 50% in Scn2aQ54 mice. The more potent persistent current blocker GS967 reduced seizure frequency by >90% in Scn2aQ54 mice and protected against induced seizures in the maximal electroshock model. GS967 greatly attenuated abnormal spontaneous action potential firing in pyramidal neurons acutely isolated from Scn2aQ54 mice. In addition to seizure suppression in vivo, GS967 treatment greatly improved the survival of Scn2a Q54 mice, prevented hilar neuron loss, and suppressed the development of hippocampal mossy fiber sprouting. Significance Our findings indicate that the selective persistent sodium current blocker GS967 has potent antiepileptic activity and that this compound could inform development of new agents.

Original languageEnglish (US)
Pages (from-to)1274-1283
Number of pages10
JournalEpilepsia
Volume55
Issue number8
DOIs
StatePublished - Jan 1 2014

Fingerprint

Anticonvulsants
Sodium
Seizures
Electroshock
Hippocampal Mossy Fibers
Pharmaceutical Preparations
Voltage-Gated Sodium Channels
Neurons
Neurophysiology
Pyramidal Cells
Angina Pectoris
United States Food and Drug Administration
Action Potentials
6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)(1,2,4)triazolo(4,3-a)pyridine
Molecular Biology
Epilepsy
Therapeutics
Ranolazine

Keywords

  • Epilepsy
  • Mossy fiber sprouting
  • Neurophysiology
  • Sodium channel

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

Cite this

Anderson, Lyndsey L. ; Thompson, Christopher H. ; Hawkins, Nicole A. ; Nath, Ravi D. ; Petersohn, Adam A. ; Rajamani, Sridharan ; Bush, William S. ; Frankel, Wayne N. ; Vanoye, Carlos G. ; Kearney, Jennifer A. ; George, Alfred L. / Antiepileptic activity of preferential inhibitors of persistent sodium current. In: Epilepsia. 2014 ; Vol. 55, No. 8. pp. 1274-1283.
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abstract = "Summary Objective Evidence from basic neurophysiology and molecular genetics has implicated persistent sodium current conducted by voltage-gated sodium (NaV) channels as a contributor to the pathogenesis of epilepsy. Many antiepileptic drugs target NaV channels and modulate neuronal excitability, mainly by a use-dependent block of transient sodium current, although suppression of persistent current may also contribute to the efficacy of these drugs. We hypothesized that a drug or compound capable of preferential inhibition of persistent sodium current would have antiepileptic activity. Methods We examined the antiepileptic activity of two selective persistent sodium current blockers ranolazine, a U.S. Food and Drug Administration (FDA)-approved drug for treatment of angina pectoris, and GS967, a novel compound with more potent effects on persistent current, in the epileptic Scn2aQ54 mouse model. We also examined the effect of GS967 in the maximal electroshock model and evaluated effects of the compound on neuronal excitability, propensity for hilar neuron loss, development of mossy fiber sprouting, and survival of Scn2aQ54 mice. Results We found that ranolazine was capable of reducing seizure frequency by approximately 50{\%} in Scn2aQ54 mice. The more potent persistent current blocker GS967 reduced seizure frequency by >90{\%} in Scn2aQ54 mice and protected against induced seizures in the maximal electroshock model. GS967 greatly attenuated abnormal spontaneous action potential firing in pyramidal neurons acutely isolated from Scn2aQ54 mice. In addition to seizure suppression in vivo, GS967 treatment greatly improved the survival of Scn2a Q54 mice, prevented hilar neuron loss, and suppressed the development of hippocampal mossy fiber sprouting. Significance Our findings indicate that the selective persistent sodium current blocker GS967 has potent antiepileptic activity and that this compound could inform development of new agents.",
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Antiepileptic activity of preferential inhibitors of persistent sodium current. / Anderson, Lyndsey L.; Thompson, Christopher H.; Hawkins, Nicole A.; Nath, Ravi D.; Petersohn, Adam A.; Rajamani, Sridharan; Bush, William S.; Frankel, Wayne N.; Vanoye, Carlos G.; Kearney, Jennifer A.; George, Alfred L.

In: Epilepsia, Vol. 55, No. 8, 01.01.2014, p. 1274-1283.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Antiepileptic activity of preferential inhibitors of persistent sodium current

AU - Anderson, Lyndsey L.

AU - Thompson, Christopher H.

AU - Hawkins, Nicole A.

AU - Nath, Ravi D.

AU - Petersohn, Adam A.

AU - Rajamani, Sridharan

AU - Bush, William S.

AU - Frankel, Wayne N.

AU - Vanoye, Carlos G.

AU - Kearney, Jennifer A.

AU - George, Alfred L.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Summary Objective Evidence from basic neurophysiology and molecular genetics has implicated persistent sodium current conducted by voltage-gated sodium (NaV) channels as a contributor to the pathogenesis of epilepsy. Many antiepileptic drugs target NaV channels and modulate neuronal excitability, mainly by a use-dependent block of transient sodium current, although suppression of persistent current may also contribute to the efficacy of these drugs. We hypothesized that a drug or compound capable of preferential inhibition of persistent sodium current would have antiepileptic activity. Methods We examined the antiepileptic activity of two selective persistent sodium current blockers ranolazine, a U.S. Food and Drug Administration (FDA)-approved drug for treatment of angina pectoris, and GS967, a novel compound with more potent effects on persistent current, in the epileptic Scn2aQ54 mouse model. We also examined the effect of GS967 in the maximal electroshock model and evaluated effects of the compound on neuronal excitability, propensity for hilar neuron loss, development of mossy fiber sprouting, and survival of Scn2aQ54 mice. Results We found that ranolazine was capable of reducing seizure frequency by approximately 50% in Scn2aQ54 mice. The more potent persistent current blocker GS967 reduced seizure frequency by >90% in Scn2aQ54 mice and protected against induced seizures in the maximal electroshock model. GS967 greatly attenuated abnormal spontaneous action potential firing in pyramidal neurons acutely isolated from Scn2aQ54 mice. In addition to seizure suppression in vivo, GS967 treatment greatly improved the survival of Scn2a Q54 mice, prevented hilar neuron loss, and suppressed the development of hippocampal mossy fiber sprouting. Significance Our findings indicate that the selective persistent sodium current blocker GS967 has potent antiepileptic activity and that this compound could inform development of new agents.

AB - Summary Objective Evidence from basic neurophysiology and molecular genetics has implicated persistent sodium current conducted by voltage-gated sodium (NaV) channels as a contributor to the pathogenesis of epilepsy. Many antiepileptic drugs target NaV channels and modulate neuronal excitability, mainly by a use-dependent block of transient sodium current, although suppression of persistent current may also contribute to the efficacy of these drugs. We hypothesized that a drug or compound capable of preferential inhibition of persistent sodium current would have antiepileptic activity. Methods We examined the antiepileptic activity of two selective persistent sodium current blockers ranolazine, a U.S. Food and Drug Administration (FDA)-approved drug for treatment of angina pectoris, and GS967, a novel compound with more potent effects on persistent current, in the epileptic Scn2aQ54 mouse model. We also examined the effect of GS967 in the maximal electroshock model and evaluated effects of the compound on neuronal excitability, propensity for hilar neuron loss, development of mossy fiber sprouting, and survival of Scn2aQ54 mice. Results We found that ranolazine was capable of reducing seizure frequency by approximately 50% in Scn2aQ54 mice. The more potent persistent current blocker GS967 reduced seizure frequency by >90% in Scn2aQ54 mice and protected against induced seizures in the maximal electroshock model. GS967 greatly attenuated abnormal spontaneous action potential firing in pyramidal neurons acutely isolated from Scn2aQ54 mice. In addition to seizure suppression in vivo, GS967 treatment greatly improved the survival of Scn2a Q54 mice, prevented hilar neuron loss, and suppressed the development of hippocampal mossy fiber sprouting. Significance Our findings indicate that the selective persistent sodium current blocker GS967 has potent antiepileptic activity and that this compound could inform development of new agents.

KW - Epilepsy

KW - Mossy fiber sprouting

KW - Neurophysiology

KW - Sodium channel

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