Flufenamic acid decreases neuronal excitability through modulation of voltage-gated sodium channel gating

Hau Jie Yau, Gytis Baranauskas, Marco Martina*

*Corresponding author for this work

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

The electrophysiological phenotype of individual neurons critically depends on the biophysical properties of the voltage-gated channels they express. Differences in sodium channel gating are instrumental in determining the different firing phenotypes of pyramidal cells and interneurons; moreover, sodium channel modulation represents an important mechanism of action for many widely used CNS drugs. Flufenamic acid (FFA) is a non-steroidal anti-inflammatory drug that has been long used as a blocker of calcium-dependent cationic conductances. Here we show that FFA inhibits voltage-gated sodium currents in hippocampal pyramidal neurons; this effect is dose-dependent with IC50= 189 μm. We used whole-cell and nucleated patch recordings to investigate the mechanisms of FFA modulation of TTX-sensitive voltage-gated sodium current. Our data show that flufenamic acid slows down the inactivation process of the sodium current, while shifting the inactivation curve ~10 mV toward more hyperpolarized potentials. The recovery from inactivation is also affected in a voltage-dependent way, resulting in slower recovery at hyperpolarized potentials. Recordings from acute slices demonstrate that FFA reduces repetitive- and abolishes burst-firing in CA1 pyramidal neurons. A computational model based on our data was employed to better understand the mechanisms of FFA action. Simulation data support the idea that FFA acts via a novel mechanism by reducing the voltage dependence of the sodium channel fast inactivation rates. These effects of FFA suggest that it may be an effective anti-epileptic drug. Neuronal action potentials are generated by the interaction of two main voltage-gated conductances, one selectively permeable to sodium and the other to potassium ions. The gating properties of the ionic channels mediating these currents play a critical role in determining the threshold, frequency and shape of action potentials and therefore the modality of inter-neuronal communication. We studied the effects of flufenamic acid (FFA), a non-steroidal anti-inflammatory drug, on sodium channels. Our results show that FFA at near-clinical concentration has an inhibitory action on sodium currents. Biophysical analysis and computational simulations show that FFA acts by changing the voltage dependence of channels' inactivation process. This effect heavily reduces the ability of neurons to discharge trains of action potentials, although the properties of individual action potentials are only slightly affected. The specific mode of action of FFA suggests that this molecule may be useful as anti-epileptic drug.

Original languageEnglish (US)
Pages (from-to)3869-3882
Number of pages14
JournalJournal of Physiology
Volume588
Issue number20
DOIs
StatePublished - Oct 1 2010

Fingerprint

Flufenamic Acid
Voltage-Gated Sodium Channels
Sodium Channels
Sodium
Action Potentials
Pyramidal Cells
Pharmaceutical Preparations
Anti-Inflammatory Agents
Phenotype
Neurons
Interneurons
Ion Channels
Inhibitory Concentration 50

ASJC Scopus subject areas

  • Physiology

Cite this

@article{bcb50836fd024a3cae28fa00e4d11156,
title = "Flufenamic acid decreases neuronal excitability through modulation of voltage-gated sodium channel gating",
abstract = "The electrophysiological phenotype of individual neurons critically depends on the biophysical properties of the voltage-gated channels they express. Differences in sodium channel gating are instrumental in determining the different firing phenotypes of pyramidal cells and interneurons; moreover, sodium channel modulation represents an important mechanism of action for many widely used CNS drugs. Flufenamic acid (FFA) is a non-steroidal anti-inflammatory drug that has been long used as a blocker of calcium-dependent cationic conductances. Here we show that FFA inhibits voltage-gated sodium currents in hippocampal pyramidal neurons; this effect is dose-dependent with IC50= 189 μm. We used whole-cell and nucleated patch recordings to investigate the mechanisms of FFA modulation of TTX-sensitive voltage-gated sodium current. Our data show that flufenamic acid slows down the inactivation process of the sodium current, while shifting the inactivation curve ~10 mV toward more hyperpolarized potentials. The recovery from inactivation is also affected in a voltage-dependent way, resulting in slower recovery at hyperpolarized potentials. Recordings from acute slices demonstrate that FFA reduces repetitive- and abolishes burst-firing in CA1 pyramidal neurons. A computational model based on our data was employed to better understand the mechanisms of FFA action. Simulation data support the idea that FFA acts via a novel mechanism by reducing the voltage dependence of the sodium channel fast inactivation rates. These effects of FFA suggest that it may be an effective anti-epileptic drug. Neuronal action potentials are generated by the interaction of two main voltage-gated conductances, one selectively permeable to sodium and the other to potassium ions. The gating properties of the ionic channels mediating these currents play a critical role in determining the threshold, frequency and shape of action potentials and therefore the modality of inter-neuronal communication. We studied the effects of flufenamic acid (FFA), a non-steroidal anti-inflammatory drug, on sodium channels. Our results show that FFA at near-clinical concentration has an inhibitory action on sodium currents. Biophysical analysis and computational simulations show that FFA acts by changing the voltage dependence of channels' inactivation process. This effect heavily reduces the ability of neurons to discharge trains of action potentials, although the properties of individual action potentials are only slightly affected. The specific mode of action of FFA suggests that this molecule may be useful as anti-epileptic drug.",
author = "Yau, {Hau Jie} and Gytis Baranauskas and Marco Martina",
year = "2010",
month = "10",
day = "1",
doi = "10.1113/jphysiol.2010.193037",
language = "English (US)",
volume = "588",
pages = "3869--3882",
journal = "Journal of Physiology",
issn = "0022-3751",
publisher = "Wiley-Blackwell",
number = "20",

}

Flufenamic acid decreases neuronal excitability through modulation of voltage-gated sodium channel gating. / Yau, Hau Jie; Baranauskas, Gytis; Martina, Marco.

In: Journal of Physiology, Vol. 588, No. 20, 01.10.2010, p. 3869-3882.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Flufenamic acid decreases neuronal excitability through modulation of voltage-gated sodium channel gating

AU - Yau, Hau Jie

AU - Baranauskas, Gytis

AU - Martina, Marco

PY - 2010/10/1

Y1 - 2010/10/1

N2 - The electrophysiological phenotype of individual neurons critically depends on the biophysical properties of the voltage-gated channels they express. Differences in sodium channel gating are instrumental in determining the different firing phenotypes of pyramidal cells and interneurons; moreover, sodium channel modulation represents an important mechanism of action for many widely used CNS drugs. Flufenamic acid (FFA) is a non-steroidal anti-inflammatory drug that has been long used as a blocker of calcium-dependent cationic conductances. Here we show that FFA inhibits voltage-gated sodium currents in hippocampal pyramidal neurons; this effect is dose-dependent with IC50= 189 μm. We used whole-cell and nucleated patch recordings to investigate the mechanisms of FFA modulation of TTX-sensitive voltage-gated sodium current. Our data show that flufenamic acid slows down the inactivation process of the sodium current, while shifting the inactivation curve ~10 mV toward more hyperpolarized potentials. The recovery from inactivation is also affected in a voltage-dependent way, resulting in slower recovery at hyperpolarized potentials. Recordings from acute slices demonstrate that FFA reduces repetitive- and abolishes burst-firing in CA1 pyramidal neurons. A computational model based on our data was employed to better understand the mechanisms of FFA action. Simulation data support the idea that FFA acts via a novel mechanism by reducing the voltage dependence of the sodium channel fast inactivation rates. These effects of FFA suggest that it may be an effective anti-epileptic drug. Neuronal action potentials are generated by the interaction of two main voltage-gated conductances, one selectively permeable to sodium and the other to potassium ions. The gating properties of the ionic channels mediating these currents play a critical role in determining the threshold, frequency and shape of action potentials and therefore the modality of inter-neuronal communication. We studied the effects of flufenamic acid (FFA), a non-steroidal anti-inflammatory drug, on sodium channels. Our results show that FFA at near-clinical concentration has an inhibitory action on sodium currents. Biophysical analysis and computational simulations show that FFA acts by changing the voltage dependence of channels' inactivation process. This effect heavily reduces the ability of neurons to discharge trains of action potentials, although the properties of individual action potentials are only slightly affected. The specific mode of action of FFA suggests that this molecule may be useful as anti-epileptic drug.

AB - The electrophysiological phenotype of individual neurons critically depends on the biophysical properties of the voltage-gated channels they express. Differences in sodium channel gating are instrumental in determining the different firing phenotypes of pyramidal cells and interneurons; moreover, sodium channel modulation represents an important mechanism of action for many widely used CNS drugs. Flufenamic acid (FFA) is a non-steroidal anti-inflammatory drug that has been long used as a blocker of calcium-dependent cationic conductances. Here we show that FFA inhibits voltage-gated sodium currents in hippocampal pyramidal neurons; this effect is dose-dependent with IC50= 189 μm. We used whole-cell and nucleated patch recordings to investigate the mechanisms of FFA modulation of TTX-sensitive voltage-gated sodium current. Our data show that flufenamic acid slows down the inactivation process of the sodium current, while shifting the inactivation curve ~10 mV toward more hyperpolarized potentials. The recovery from inactivation is also affected in a voltage-dependent way, resulting in slower recovery at hyperpolarized potentials. Recordings from acute slices demonstrate that FFA reduces repetitive- and abolishes burst-firing in CA1 pyramidal neurons. A computational model based on our data was employed to better understand the mechanisms of FFA action. Simulation data support the idea that FFA acts via a novel mechanism by reducing the voltage dependence of the sodium channel fast inactivation rates. These effects of FFA suggest that it may be an effective anti-epileptic drug. Neuronal action potentials are generated by the interaction of two main voltage-gated conductances, one selectively permeable to sodium and the other to potassium ions. The gating properties of the ionic channels mediating these currents play a critical role in determining the threshold, frequency and shape of action potentials and therefore the modality of inter-neuronal communication. We studied the effects of flufenamic acid (FFA), a non-steroidal anti-inflammatory drug, on sodium channels. Our results show that FFA at near-clinical concentration has an inhibitory action on sodium currents. Biophysical analysis and computational simulations show that FFA acts by changing the voltage dependence of channels' inactivation process. This effect heavily reduces the ability of neurons to discharge trains of action potentials, although the properties of individual action potentials are only slightly affected. The specific mode of action of FFA suggests that this molecule may be useful as anti-epileptic drug.

UR - http://www.scopus.com/inward/record.url?scp=77958191432&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77958191432&partnerID=8YFLogxK

U2 - 10.1113/jphysiol.2010.193037

DO - 10.1113/jphysiol.2010.193037

M3 - Article

C2 - 20724367

AN - SCOPUS:77958191432

VL - 588

SP - 3869

EP - 3882

JO - Journal of Physiology

JF - Journal of Physiology

SN - 0022-3751

IS - 20

ER -