Flufenamic acid as an ion channel modulator

Guinamard, Romain; Simard, Christophe; Negro, Christopher Del

doi:10.1016/j.pharmthera.2013.01.012

Cited by 120 publications

(120 citation statements)

References 148 publications

(223 reference statements)

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“…First, the most commonly used blocker, FFA, is nonspecific, with effects reported on a wide variety of ion channels, including K + channels (Guinamard et al 2013). Blockade of persistent firing typically requires high concentrations of FFA, compounding concerns about its specificity.…”

Section: Cell-autonomous Biophysical Mechanisms For Generating Persismentioning

confidence: 99%

“…Determining the functional role of ERG currents will likely entail using either molecular approaches or focal delivery of specific blockers. Unlike the relatively nonspecific blocker FFA, which also attenuates ERG currents (Guinamard et al 2013), highly specific blockers are available for ERG channels, including a potent peptide toxin made endogenously by scorpions (Nastainczyk et al 2002). …”

Section: Cell-autonomous Biophysical Mechanisms For Generating Persismentioning

confidence: 99%

See 1 more Smart Citation

Mechanisms of Persistent Activity in Cortical Circuits: Possible Neural Substrates for Working Memory

Zylberberg

Strowbridge

2017

Annu. Rev. Neurosci.

168

165

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A commonly observed neural correlate of working memory is firing that persists after the triggering stimulus disappears. Substantial effort has been devoted to understanding the many potential mechanisms that may underlie memory-associated persistent activity. These rely either on the intrinsic properties of individual neurons or on the connectivity within neural circuits to maintain the persistent activity. Nevertheless, it remains unclear which mechanisms are at play in the many brain areas involved in working memory. Herein, we first summarize the palette of different mechanisms that can generate persistent activity. We then discuss recent work that asks which mechanisms underlie persistent activity in different brain areas. Finally, we discuss future studies that might tackle this question further. Our goal is to bridge between the communities of researchers who study either single-neuron biophysical, or neural circuit, mechanisms that can generate the persistent activity that underlies working memory.

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Section: Cell-autonomous Biophysical Mechanisms For Generating Persismentioning

confidence: 99%

Section: Cell-autonomous Biophysical Mechanisms For Generating Persismentioning

confidence: 99%

Mechanisms of Persistent Activity in Cortical Circuits: Possible Neural Substrates for Working Memory

Zylberberg

Strowbridge

2017

Annu. Rev. Neurosci.

168

165

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“…These compounds have been shown to upor down-regulate the activity of a number of ion channels [38], including TREK1 channels, where they act to enhance current [91,99]. BL-1249, another fenamate-like structure and a putative activator of TREK1-like currents in human bladder myocytes [93] also activated TREK1 channels (Fig.…”

Section: Fenamatesmentioning

confidence: 99%

Two-pore domain potassium channels: potential therapeutic targets for the treatment of pain

Mathie

Veale

2014

Pflugers Arch - Eur J Physiol

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Recent evidence points to a pivotal contribution of a variety of different potassium channels, including two-pore domain potassium (K2P) channels, in chronic pain processing. Expression of several different K2P channel subunits has been detected in nociceptive dorsal root ganglion neurons and trigeminal ganglion neurons, in particular, TREK1, TREK2, TRESK, TRAAK, TASK3 and TWIK1 channels. Of these, the strongest body of evidence from functional studies highlights the importance of TREK1, TRESK and, recently, TREK2 channels. For example, TREK1 knockout mice are more sensitive than wild-type mice to a number of painful stimuli but less sensitive to morphine-induced analgesia. TRESK knockdown mice show behavioural evidence of increased pain and increased sensitivity to painful pressure. Importantly, familial migraine with aura is associated with a dominant-negative mutation in human TRESK channels. Thus, the functional up-regulation of K2P channel activity may be a useful strategy in the development of new therapies for the treatment of pain. Whilst there are few currently available compounds that selectively and directly enhance the activity of TRESK and TREK2 channels, recent advances have been made in terms of identifying compounds that activate TREK1 channels and in understanding how they might act on the channel. Large-scale bio-informatic approaches and the further development of databases of putative ligands, channel structures and putative ligand binding sites on these structures may form the basis for future experimental strategies to detect novel molecules acting to enhance K2P channel activity that would be useful in the treatment of pain.

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“…Although FFA can inhibit several TRP subtypes, as well as other ion channels (Guinamard et al . ), recognized targets include H 2 O 2 ‐sensitive TRPM2 channels (Hill et al . ).…”

Section: Introductionmentioning

confidence: 99%

Inhibitory and excitatory neuromodulation by hydrogen peroxide: translating energetics to information

Lee

Patel

O'Neill

et al. 2015

The Journal of Physiology

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Historically, brain neurochemicals have been broadly classified as energetic or informational. However, increasing evidence implicates metabolic substrates and byproducts as signalling agents, which blurs the boundary between energy and information, and suggests the introduction of a new category for 'translational' substances that convey changes in energy state to information. One intriguing example is hydrogen peroxide (H 2 O 2 ), which is a small, readily diffusible molecule. Produced during mitochondrial respiration, this reactive oxygen species, can mediate dynamic regulation of neuronal activity and transmitter release by activating inhibitory ATP-sensitive K + (K ATP ) channels, as well as a class of excitatory non-selective cation channels, TRPM2. Studies using ex vivo guinea pig brain slices have revealed that activity-generated H 2 O 2 can act via K ATP channels to inhibit dopamine release in dorsal striatum and dopamine neuron activity in the substantia nigra pars compacta. In sharp contrast, endogenously generated H 2 O 2 enhances the excitability of GABAergic projection neurons in the dorsal striatum and substantia nigra pars reticulata by activating TRPM2 channels. These studies suggest that the balance of excitation vs. inhibition produced in a given cell by metabolically generated H 2 O 2 will be dictated by the relative abundance of H 2 O 2 -sensitive ion channel targets that receive this translational signal.

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Flufenamic acid as an ion channel modulator

Cited by 120 publications

References 148 publications

Mechanisms of Persistent Activity in Cortical Circuits: Possible Neural Substrates for Working Memory

Mechanisms of Persistent Activity in Cortical Circuits: Possible Neural Substrates for Working Memory

Two-pore domain potassium channels: potential therapeutic targets for the treatment of pain

Inhibitory and excitatory neuromodulation by hydrogen peroxide: translating energetics to information

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