Antinociceptive Efficacy of Retigabine and Flupirtine for Gout Arthritis Pain

Zhang, Fan; Liu, Shuna; Jin, Lu; Tang, LiangQinDaoErJi; Zhao, Xu; Yang, Tianshuo; Wang, Yiyue; Huo, Binghui; Liu, Ruiyu; Li, Han

doi:10.1159/000505934

Cited by 14 publications

(8 citation statements)

References 28 publications

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“…Retigabine and flupirtine have shown antinociceptive effects in a rat model of gout. It is believed that Kv7 channels generate low-threshold, inactivating voltage-gated potassium currents that play an important role in regulating the excitability of nociceptive neurons [ 225 ]. To date, the analgesic effect of RTG has been demonstrated in models of pain due to neuroplasticity, bone cancer [ 226 ], inflammation [ 227 ], nerve degeneration [ 228 ], and the application of capsaicin to the viscera [ 229 ].…”

Section: Mitochondrial Voltage-dependent Potassium Channelsmentioning

confidence: 99%

Alternative Targets for Modulators of Mitochondrial Potassium Channels

et al. 2022

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Mitochondrial potassium channels control potassium influx into the mitochondrial matrix and thus regulate mitochondrial membrane potential, volume, respiration, and synthesis of reactive oxygen species (ROS). It has been found that pharmacological activation of mitochondrial potassium channels during ischemia/reperfusion (I/R) injury activates cytoprotective mechanisms resulting in increased cell survival. In cancer cells, the inhibition of these channels leads to increased cell death. Therefore, mitochondrial potassium channels are intriguing targets for the development of new pharmacological strategies. In most cases, however, the substances that modulate the mitochondrial potassium channels have a few alternative targets in the cell. This may result in unexpected or unwanted effects induced by these compounds. In our review, we briefly present the various classes of mitochondrial potassium (mitoK) channels and describe the chemical compounds that modulate their activity. We also describe examples of the multidirectional activity of the activators and inhibitors of mitochondrial potassium channels.

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Section: Mitochondrial Voltage-dependent Potassium Channelsmentioning

confidence: 99%

Alternative Targets for Modulators of Mitochondrial Potassium Channels

et al. 2022

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“…Therefore, MSU crystals were prepared and used to establish the GA rat model. The main clinical features of GA attack are inflammatory cell infiltration, joint swelling, severe pain and obvious hindered mobility of affected joints [1,4,7]. In the present study, we discovered that the paw volume and gait score were increased and the joint dysfunction was enhanced by MSU, which indicated that the MSU‐induced GA rat model was successfully established.…”

Section: Discussionmentioning

confidence: 50%

“…The onset of GA is triggered by the accumulation of excessive uric acid and MSU crystal formation in the joints and surrounding tissues [1,4]. Therefore, MSU crystals were prepared and used to establish the GA rat model.…”

Section: Discussionmentioning

confidence: 99%

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MiR-223-3p inhibits inflammation and pyroptosis in monosodium urate-induced rats and fibroblast-like synoviocytes by targeting NLRP3

Tian

Zhou

Xiang

et al. 2021

Clinical and Experimental Immunology

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Summary Down‐regulated miR‐223‐3p was found in rheumatoid arthritis. This study aimed to further explore the level and role of miR‐223‐3p in gout arthritis (GA). After monosodium urate (MSU)‐induced GA rat and fibroblast‐like synoviocytes (FLSs) models were established, the rat paw volume and gait score were documented and the FLSs were transfected with miR‐223‐3p mimic/inhibitor or NLR family pyrin domain containing 3 (NLRP3) over‐expression plasmids. The MiR‐223‐3p target was found through bioinformatics and the dual‐luciferase reporter. The rat joint pathological damage was observed by hematoxylin and eosin staining. The levels of interleukin (IL)‐1β, tumor necrosis factor (TNF)‐α and articular elastase in rats were detected by enzyme‐linked immunosorbent assay (ELISA). The viability and pyroptosis of FLSs were detected by methyl thiazolyl tetrazolium (MTT) and flow cytometry. The expressions of miR‐223‐3p, NLRP3, cleaved caspase‐1, IL‐1β, apoptosis‐associated speck‐like protein (AS) and cleaved N‐terminal gasdermin D (GSDMD) in FLSs or rat synovial tissues were detected by reverse transcription–quantitative polymerase chain reaction (RT‐qPCR), immunofluorescence, Western blot or immunohistochemistry analysis. MSU increased the paw volume, gait score, inflammation in synovial tissues and increased the levels of IL‐1β, TNF‐α and articular elastase in rats. MSU decreased the viability and increased the pyroptosis of FLSs, up‐regulated the expression of NLRP3, ASC, cleaved caspase‐1, cleaved N‐terminal GSDM, and IL‐1β, and down‐regulated miR‐223‐3p expression in synovial tissues of rat joints and FLSs. MiR‐223‐3p mimic reversed the effect of MSU on lowering cell viability, increasing pyroptosis in FLSs, while miR‐223‐3p inhibitor further enhanced the effect of MSU on FLSs. NLRP3 was a target of miR‐223‐3p. Also, NLRP3 over‐expression reversed the effects of miR‐223‐3p on MSU‐induced FLSs. MiR‐223‐3p inhibited pyroptosis in MSU‐induced rats and FLSs by targeting NLRP3.

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“…The concentration-response curve from our MEA assay suggests that retigabine can achieve a 50% reduction of spontaneous firing with sub-micromolar concentrations. Prior studies that have assessed the effect of retigabine in pain models in many cases have assessed only a single dose or a small number of concentrations in the 1-10 µM range (Roza and Lopez-Garcia, 2008;Xu et al, 2010;Du et al, 2014;Hayashi et al, 2014;Abd-Elsayed et al, 2015;Li et al, 2019;Zhang et al, 2020). Taken together, this study and previous results implicate Kv7.2/ Kv7.3 channels as effective modulators of sensory neuron excitability and suggest that compounds that specifically target Kv7.2/Kv7.3 currents in sensory neurons, including human sensory neurons, might provide an effective approach toward pain relief.…”

Section: Figurementioning

confidence: 99%

Kv7-specific activators hyperpolarize resting membrane potential and modulate human iPSC-derived sensory neuron excitability

Estacion

Liu²,

Cheng³

et al. 2023

Front. Pharmacol.

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Chronic pain is highly prevalent and remains a significant unmet global medical need. As part of a search for modulatory genes that confer pain resilience, we have studied two family cohorts where one individual reported much less pain than other family members that share the same pathogenic gain-of-function Nav1.7 mutation that confers hyperexcitability on pain-signaling dorsal root ganglion (DRG) neurons. In each of these kindreds, the pain-resilient individual carried a gain-of-function variant in Kv7.2 or Kv7.3, two potassium channels that stabilize membrane potential and reduce excitability. Our observation in this molecular genetic study that these gain-of-function Kv7.2 and 7.3 variants reduce DRG neuron excitability suggests that agents that activate or open Kv7 channels should attenuate sensory neuron firing. In the present study, we assess the effects on sensory neuron excitability of three Kv7 modulators—retigabine (Kv7.2 thru Kv7.5 activator), ICA-110381 (Kv7.2/Kv7.3 specific activator), and as a comparator ML277 (Kv7.1 specific activator)—in a “human-pain-in-a-dish” model (human iPSC-derived sensory neurons, iPSC-SN). Multi-electrode-array (MEA) recordings demonstrated inhibition of firing with retigabine and ICA-110381 (but not with ML277), with the concentration-response curve indicating that retigabine can achieve a 50% reduction of firing with sub-micromolar concentrations. Current-clamp recording demonstrated that retigabine hyperpolarized iPSC-SN resting potential and increased threshold. This study implicates Kv7.2/Kv7.3 channels as effective modulators of sensory neuron excitability, and suggest that compounds that specifically target Kv7.2/Kv7.3 currents in sensory neurons, including human sensory neurons, might provide an effective approach toward pain relief.

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Antinociceptive Efficacy of Retigabine and Flupirtine for Gout Arthritis Pain

Cited by 14 publications

References 28 publications

Alternative Targets for Modulators of Mitochondrial Potassium Channels

Alternative Targets for Modulators of Mitochondrial Potassium Channels

MiR-223-3p inhibits inflammation and pyroptosis in monosodium urate-induced rats and fibroblast-like synoviocytes by targeting NLRP3

Kv7-specific activators hyperpolarize resting membrane potential and modulate human iPSC-derived sensory neuron excitability

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