Flufenamic acid as an ion channel modulator

Abstract

Flufenamic acid has been known since the 1960s to have anti-inflammatory properties attributable to the reduction of prostaglandin synthesis. Thirty years later, flufenamic acid appeared to be an ion channel modulator. Thus, while its use in medicine diminished, its use in ionic channel research expanded. Flufenamic acid commonly not only affects non-selective cation channels and chloride channels, but also modulates potassium, calcium and sodium channels with effective concentrations ranging from 10(-6)M in TRPM4 channel inhibition to 10(-3)M in two-pore outwardly rectifying potassium channel activation. Because flufenamic acid effects develop and reverse rapidly, it is a convenient and widely used tool. However, given the broad spectrum of its targets, experimental results have to be interpreted cautiously. Here we provide an overview of ion channels targeted by flufenamic acid to aid in interpreting its effects at the molecular, cellular, and system levels. If it is used with good practices, flufenamic acid remains a useful tool for ion channel research. Understanding the targets of FFA may help reevaluate its physiological impacts and revive interest in its therapeutic potential.

Figure 1. Anti-inflammatory effect of flufenamic acid

Chemical structure of flufenamic acid and its main targets: cyclooxygenase for anti-inflammatory effect and ion channels for additional effects.

Figure 2. Ion channels targeted by flufenamic acid

Flufenamic acid produces inhibition or activation of ion channels. Coloured bars near ionic channel name correspond to the estimated EC₅₀ for flufenamic effect. References are provided within the text.

Figure 3. Effects of Flufenamic acid on several preparations

A: Inside-out patch-clamp recording of TRPM4 current on rat ventricular isolated myocyte (Vm = +40 mV). FFA produced a dose-dependent and reversible channel inhibition (see Guinamard et al. 2006-b for protocol). B: Action potential recorded by an intracellular microelectrode on isolated mouse ventricle submitted to a hypoxia and reoxygenation protocol (see Simard et al. 2012 for protocol). FFA superfusion reversibly reduced the number of early after depolarization by action potential (EAD/AP). C: Respiratory bursts recorded in rhythmogenic neurons of the preBötzinger complex (preBötC) as well as hypoglossal nerve root (XII) from neonatal mouse brainstem-slice preparations. Whole-cell patch-clamp recordings in preBötC neurons show that 100 μM FFA attenuates respiratory bursts at the whole-cell level by attenuating I_CAN, but has a relatively mild affect motor output from the XII nerve root output (see Picardo et al. 2012 for protocol).