Lidocaine Preferentially Inhibits the Function of Purinergic P2X7 Receptors Expressed in Xenopus Oocytes

Okura, Dan; Horishita, Takafumi; Ueno, S.; Yanagihara, Nobuyuki; Sudo, Yuka; Uezono, Yasuhito; Minami, Tomoko; Kawasaki, Takashi; Sata, Takeyoshi

doi:10.1213/ane.0000000000000585

Cited by 16 publications

(21 citation statements)

References 54 publications

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“…As lidocaine has been shown to inhibit, in addition to VGSCs, other membrane-bound signaling molecules involved in oncogenesis 24 25 , the following experiments were employed to more conclusively demonstrate a link between VGSC activity and ERK1/2 phosphorylation and resultant invasive activity in SW620 colon cancer cells. Our previous work has demonstrated that Na V 1.5 VGSC isoform (encoded by SCN5A ) is responsible for invasivity of colon cancer cells as ‘knockdown’ of this isoform with either tetrodotoxin (TTX), a specific inhibitor of VGSCs, or siRNA-mediated targeting led to a significant loss of baseline invasion 4 .…”

Section: Resultsmentioning

confidence: 99%

Voltage-gated Na+ Channel Activity Increases Colon Cancer Transcriptional Activity and Invasion Via Persistent MAPK Signaling

House

Wang

Ceniccola

et al. 2015

Sci Rep

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Functional expression of voltage-gated Na+ channels (VGSCs) has been demonstrated in multiple cancer cell types where channel activity induces invasive activity. The signaling mechanisms by which VGSCs promote oncogenesis remain poorly understood. We explored the signal transduction process critical to VGSC-mediated invasion on the basis of reports linking channel activity to gene expression changes in excitable cells. Coincidentally, many genes transcriptionally regulated by the SCN5A isoform in colon cancer have an over-representation of cis-acting sites for transcription factors phosphorylated by ERK1/2 MAPK. We hypothesized that VGSC activity promotes MAPK activation to induce transcriptional changes in invasion-related genes. Using pharmacological inhibitors/activators and siRNA-mediated gene knockdowns, we correlated channel activity with Rap1-dependent persistent MAPK activation in the SW620 human colon cancer cell line. We further demonstrated that VGSC activity induces downstream changes in invasion-related gene expression via a PKA/ERK/c-JUN/ELK-1/ETS-1 transcriptional pathway. This is the first study illustrating a molecular mechanism linking functional activity of VGSCs to transcriptional activation of invasion-related genes.

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Section: Resultsmentioning

confidence: 99%

Voltage-gated Na+ Channel Activity Increases Colon Cancer Transcriptional Activity and Invasion Via Persistent MAPK Signaling

House

Wang

Ceniccola

et al. 2015

Sci Rep

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“…Furthermore, the protective effects observed in the it-Lido group might not limited to a pan-blockade of Na + channels. Recent reports also describe that lidocaine has a direct inhibitory effect on the purinergic P2X channels (37). Another important result of our study was that P2X channel antagonists iso-PPADS reduced VIBI in a similar way as lidocaine although not being associated with secondary effects of lidocaine such as neurotoxicity or lung edema formation (38).…”

Section: Discussionmentioning

confidence: 99%

Lung Purinoceptor Activation Triggers Ventilator-Induced Brain Injury

González-López

López-Alonso

Pickerodt

et al. 2019

Critical Care Medicine

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Objectives:Mechanical ventilation can cause ventilator-induced brain injury via afferent vagal signaling and hippocampal neurotransmitter imbalances. The triggering mechanisms for vagal signaling during mechanical ventilation are unknown. The objective of this study was to assess whether pulmonary transient receptor potential vanilloid type-4 (TRPV4) mechanoreceptors and vagal afferent purinergic receptors (P2X) act as triggers of ventilator-induced brain injury.Design:Controlled, human in vitro and ex vivo studies, as well as murine in vivo laboratory studies.Setting:Research laboratory.Subjects:Wild-type, TRPV4-deficient C57BL/6J mice, 8–10 weeks old. Human postmortem lung tissue and human lung epithelial cell line BEAS-2B.Intervention:Mice subjected to mechanical ventilation were studied using functional MRI to assess hippocampal activity. The effects of lidocaine (a nonselective ion-channel inhibitor), P2X-purinoceptor antagonist (iso-PPADS), or genetic TRPV4 deficiency on hippocampal dopamine-dependent pro-apoptotic signaling were studied in mechanically ventilated mice. Human lung epithelial cells (BEAS-2B) were used to study the effects of mechanical stretch on TRPV4 and P2X expression and activation. TRPV4 levels were measured in postmortem lung tissue from ventilated and nonventilated patients.Measurements and Main Results:Hippocampus functional MRI analysis revealed considerable changes in response to the increase in tidal volume during mechanical ventilation. Intratracheal lidocaine, iso-PPADS, and TRPV4 genetic deficiency protected mice against ventilationinduced hippocampal pro-apoptotic signaling. Mechanical stretch in both, BEAS-2B cells and ventilated wild-type mice, resulted in TRPV4 activation and reduced Trpv4 and P2x expression. Intratracheal replenishment of adenosine triphosphate in Trpv4–/– mice abrogated the protective effect of TRPV4 deficiency. Autopsy lung tissue from ventilated patients showed decreased lung TRPV4 levels compared with nonventilatedConclusions:TRPV4 mechanosensors and purinergic receptors are involved in the mechanisms of ventilator-induced brain injury. Inhibition of this neural signaling, either using nonspecific or specific inhibitors targeting the TRPV4/adenosine triphosphate/P2X signaling axis, may represent a novel strategy to prevent or treat ventilator-induced brain injury.

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“…The maximum concentration for inhibition is 282 ± 45 μmol/L. [ 30 ] These results are helpful for understanding the mechanism of the analgesic effect of systemically and locally administered lidocaine.…”

Section: Effect Of Lidocaine On Ligand-gated Channelsmentioning

confidence: 99%

A review of the mechanism of the central analgesic effect of lidocaine

Yang

Wei

et al. 2020

Medicine

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Lidocaine, as the only local anesthetic approved for intravenous administration in the clinic, can relieve neuropathic pain, hyperalgesia, and complex regional pain syndrome. Intravenous injection of lidocaine during surgery is considered as an effective strategy to control postoperative pain, but the mechanism of its analgesic effect has not been fully elucidated. This paper intends to review recent studies on the mechanism of the analgesic effect of lidocaine. To the end, we conducted an electronic search of the PubMed database. The search period was from 5 years before June 2019. Lidocaine was used as the search term. A total of 659 documents were obtained, we included 17 articles. These articles combined with the 34 articles found by hand searching made up the 51 articles that were ultimately included. We reviewed the analgesic mechanism of lidocaine in the central nervous system.

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Lidocaine Preferentially Inhibits the Function of Purinergic P2X7 Receptors Expressed in Xenopus Oocytes

Cited by 16 publications

References 54 publications

Voltage-gated Na+ Channel Activity Increases Colon Cancer Transcriptional Activity and Invasion Via Persistent MAPK Signaling

Voltage-gated Na+ Channel Activity Increases Colon Cancer Transcriptional Activity and Invasion Via Persistent MAPK Signaling

Lung Purinoceptor Activation Triggers Ventilator-Induced Brain Injury

A review of the mechanism of the central analgesic effect of lidocaine

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