Dexmedetomidine Inhibits Voltage-Gated Sodium Channels via <i>α</i>2-Adrenoceptors in Trigeminal Ganglion Neurons

Im, Sang-Taek; Jo, Youn Yi; Han, Gayoung; Jo, Hyun Jung; Kim, Yong Ho

doi:10.1155/2018/1782719

Cited by 14 publications

(14 citation statements)

References 28 publications

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“…39 It has been found that DEX could inhibit voltage-gated sodium channels via a2-adrenoceptors in trigeminal ganglion neurons. 40 It is suggested that DEX activates its receptors and inhibits sodium channels induced by lidocaine, resulting in the reverse of inactivated SIRT1 and leading to inhibition of apoptosis. Further studies are needed to verify the interaction between DEX receptors, lidocaine receptor, and SIRT1/FOXO3a signaling (Figure 9).…”

Section: Discussionmentioning

confidence: 99%

Dexmedetomidine protects against lidocaine-induced neurotoxicity through SIRT1 downregulation-mediated activation of FOXO3a

Zheng

Guo

et al. 2020

Hum Exp Toxicol

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Lidocaine, a typical local anesthetic, has been shown to directly induce neurotoxicity in clinical settings. Dexmedetomidine (DEX) is an alpha-2-adrenoreceptor agonist that has been used as anxiolytic, sedative, and analgesic agent which has recently found to protect against lidocaine-induced neurotoxicity. Nicotinamide adenine dinucleotide-dependent deacetylase sirtuin-1 (SIRT1)/forkhead box O3 (FOXO3a) signaling is critical for maintaining neuronal function and regulation of the apoptotic pathway. In the present study, we designed in vitro and in vivo models to investigate the potential effects of lidocaine and DEX on SIRT1 and FOXO3a and to verify whether SIRT1/FOXO3a-mediated regulation of apoptosis is involved in DEX-induced neuroprotective effects against lidocaine. We found that in both PC12 cells and brains of mice, lidocaine decreased SIRT1 level through promoting the degradation of SIRT1 protein. Lidocaine also increased FOXO3a protein level and increased the acetylation of SIRT1 through inhibiting SIRT1. Upregulation of SIRT1 or downregulation of FOXO3a significantly inhibited lidocaine-induced changes in both cell viability and apoptosis. DEX significantly inhibited the lidocaine-induced decrease of SIRT1 protein level and increase of FOXO3a protein level and acetylation of FOXO3a. Downregulation of SIRT1 or upregulation of FOXO3a suppressed DEX-induced neuroprotective effects against lidocaine. The data suggest that SIRT1/FOXO3a is a potential novel target for alleviating lidocaine-induced neurotoxicity and provide more theoretical support for the use of DEX as an effective adjunct to alleviate chronic neurotoxicity induced by lidocaine.

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Section: Discussionmentioning

confidence: 99%

Dexmedetomidine protects against lidocaine-induced neurotoxicity through SIRT1 downregulation-mediated activation of FOXO3a

Zheng

Guo

et al. 2020

Hum Exp Toxicol

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“…DRG cells were grown in a Neurobasal medium (with 2% B27 supplement, Invitrogen), at 37 °C, with 5% CO2. DRG neurons were grown for 18 h before use 41 , 42 . Whole-cell current-clamp recordings were performed at room temperature to measure currents with HEKA EPC10 (HEKA).…”

Section: Methodsmentioning

confidence: 99%

“…The extracellular solution contained (in mM): 140 NaCl, 5 KCl, 2 CaCl 2 , 1 MgCl 2 , 10 HEPES, and 10 D-glucose, adjusted to pH 7.3 with NaOH, osmolarity 300-310 mOsm. Voltage-clamp experiments were performed at a holding potential of -60 mV 15 , 41 , 42 .…”

Section: Methodsmentioning

confidence: 99%

Resolvin D3 controls mouse and human TRPV1-positive neurons and preclinical progression of psoriasis

Lee

Tonello

et al. 2020

Theranostics

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Rationale: Psoriasis is a chronic inflammatory disease caused by a complex interplay between the immune and nervous systems with recurrent scaly skin plaques, thickened stratum corneum, infiltration and activation of inflammatory cells, and itch. Despite an increasing availability of immune therapies, they often have adverse effects, high costs, and dissociated effects on inflammation and itch. Activation of sensory neurons innervating the skin and TRPV1 (transient receptor potential vanilloid 1) are emerging as critical components in the pathogenesis of psoriasis, but little is known about their endogenous inhibitors. Recent studies have demonstrated that resolvins, endogenous lipid mediators derived from omega-3 fatty acids, are potent inhibitors of TRP channels and may offer new therapies for psoriasis without known adverse effects. Methods: We used behavioral, electrophysiological and biochemical approaches to investigate the therapeutic effects of resolvin D3 (RvD3), a novel family member of resolvins, in a preclinical model of psoriasis consisting of repeated topical applications of imiquimod (IMQ) to murine skin, which provokes inflammatory lesions that resemble human psoriasis. Results: We report that RvD3 specifically reduced TRPV1-dependent acute pain and itch in mice. Mechanistically, RvD3 inhibited capsaicin-induced TRPV1 currents in dissociated dorsal root ganglion (DRG) neurons via the N-formyl peptide receptor 2 (i.e. ALX/FPR2), a G-protein coupled receptor. Single systemic administration of RvD3 (2.8 mg/kg) reversed itch after IMQ, and repeated administration largely prevented the development of both psoriasiform itch and skin inflammation with concomitant decreased in calcitonin gene-related peptide (CGRP) expression in DRG neurons. Accordingly, specific knockdown of CGRP in DRG was sufficient to prevent both psoriasiform itch and skin inflammation similar to the effects following RvD3 administration. Finally, we elevated the translational potential of this study by showing that RvD3 significantly inhibited capsaicin-induced TRPV1 activity and CGRP release in human DRG neurons. Conclusions: Our findings demonstrate a novel role for RvD3 in regulating TRPV1/CGRP in mouse and human DRG neurons and identify RvD3 and its neuronal pathways as novel therapeutic targets to treat psoriasis.

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“…DRG neurons were grown for 18 hours before use. 22,23 Whole-cell current-clamp recordings were performed at room temperature to measure currents with HEKA EPC10 (HEKA). The patch pipettes were pulled from borosilicate capillaries (Chase Scientific Glass Inc., Rockwood, CA, USA).…”

Section: Whole-cell Patch Clamp Recordings In Cultured Mouse Drg Neuronsmentioning

confidence: 99%

“…Voltage-clamp experiments were performed at a holding potential of -60 mV. 10,22,23 Ca2 + imaging of cultured human DRG neurons.…”

Section: Whole-cell Patch Clamp Recordings In Cultured Mouse Drg Neuronsmentioning

confidence: 99%

Resolvin D3 controls mouse and human nociceptive functions and preclinical progression of psoriasis

Lee

Tonello

et al. 2019

Preprint

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Psoriasis is a chronic inflammatory skin disease caused by a complex interplay between the immune and nervous systems. Here, we found that resolvin D3 (RvD3) significantly prevented both skin inflammation and itch in a preclinical animal model of psoriasis induced by repeated applications of imiquimod. We also found that RvD3 anti-psoriatic effects resulted from the inhibition of nociceptive functions, which inhibition was replicated in human nociceptive neurons. We conclude that RvD3 and targeting nociceptive functions are promising strategies to treat psoriasis.

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Dexmedetomidine Inhibits Voltage-Gated Sodium Channels via α2-Adrenoceptors in Trigeminal Ganglion Neurons

Cited by 14 publications

References 28 publications

Dexmedetomidine protects against lidocaine-induced neurotoxicity through SIRT1 downregulation-mediated activation of FOXO3a

Dexmedetomidine protects against lidocaine-induced neurotoxicity through SIRT1 downregulation-mediated activation of FOXO3a

Resolvin D3 controls mouse and human TRPV1-positive neurons and preclinical progression of psoriasis

Resolvin D3 controls mouse and human nociceptive functions and preclinical progression of psoriasis

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