Isoliquiritigenin, an active ingredient of Glycyrrhiza, elicits antinociceptive effects via inhibition of Nav channels

Miyamura, Yuichi; Hitomi, Suzuro; Omiya, Yuji; Ujihara, Izumi; Kokabu, Shoichiro; Morimoto, Yasuhiro; Ono, Kentaro

doi:10.1007/s00210-020-02030-w

Cited by 12 publications

(7 citation statements)

References 46 publications

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“…This changing membrane potential closes the VGCCs, which in turn reduces [Ca 2+ ] C and neurotransmitter release [31,46]. Although ISL has been shown to modulate Na + and K + channels [3,47,48], the inhibitory effect of ISL on the VGCCs observed in our study is not caused by a change in synaptosomal membrane potential because ISL inhibited the release of glutamate evoked by 4-AP and KCl. Both of these depolarizing treatments are thought to activate VDCCs coupled to glutamate release similarly, and this should be indicated by qualitatively similar modulation if it occurs at the level of the voltage-dependent Ca 2+ channel.…”

Section: Discussionmentioning

confidence: 45%

“…Isoliquiritigenin (ISL, Figure 1A), a flavonoid with a chalcone structure, is the main active ingredient in the Glycyrrhiza glabra L. root. ISL has received attention because of its various pharmacological benefits, including antibacterial, antiviral, antidiabetic, antioxidant, anti-inflammatory, anticarcinogenic, analgesic, and neuroprotective effects [1][2][3]. Regarding its neuroprotective activity, previous animal studies found that ISL can penetrate the blood-brain barrier [4] and protects against brain damage and cognitive impairment induced by kainic acid, lipopolysaccharide (LPS), ischemia, or traumatic brain injury [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

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Natural Product Isoliquiritigenin Activates GABAB Receptors to Decrease Voltage-Gate Ca2+ Channels and Glutamate Release in Rat Cerebrocortical Nerve Terminals

Lin

Hsieh

et al. 2021

Biomolecules

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Reduction in glutamate release is a key mechanism for neuroprotection and we investigated the effect of isoliquiritigenin (ISL), an active ingredient of Glycyrrhiza with neuroprotective activities, on glutamate release in rat cerebrocortical nerve terminals (synaptosomes). ISL produced a concentration-dependent inhibition of glutamate release and reduced the intraterminal [Ca2+] increase. The inhibition of glutamate release by ISL was prevented after removing extracellular Ca2+ or blocking P/Q-type Ca2+ channels. This inhibition was mediated through the γ-aminobutyric acid type B (GABAB) receptors because ISL was unable to inhibit glutamate release in the presence of baclofen (an GABAB agonist) or CGP3548 (an GABAB antagonist) and docking data revealed that ISL interacted with GABAB receptors. Furthermore, the ISL inhibition of glutamate release was abolished through the inhibition of Gi/o-mediated responses or Gβγ subunits, but not by 8-bromoadenosine 3′, 5′-cyclic monophosphate or adenylate cyclase inhibition. The ISL inhibition of glutamate release was also abolished through the inhibition of protein kinase C (PKC), and ISL decreased the phosphorylation of PKC. Thus, we inferred that ISL, through GABAB receptor activation and Gβγ-coupled inhibition of P/Q-type Ca2+ channels, suppressed the PKC phosphorylation to cause a decrease in evoked glutamate release at rat cerebrocortical nerve terminals.

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Section: Discussionmentioning

confidence: 45%

Section: Introductionmentioning

confidence: 99%

Natural Product Isoliquiritigenin Activates GABAB Receptors to Decrease Voltage-Gate Ca2+ Channels and Glutamate Release in Rat Cerebrocortical Nerve Terminals

Lin

Hsieh

et al. 2021

Biomolecules

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“…Kato et al [34] demonstrated the inhibition of the calcium-activated chloride channel TMEM16A using liquiritigenin derived from Glycyrrhiza. Isoliquiritigenin, which is also derived from Glycyrrhiza, is known to inhibit voltage-gated sodium (Nav) channels in peripheral nociceptive neurons [35] and to exert an antagonistic effect on NMDA receptors in the spinal cord [36]. Furthermore, glycyrrhizin and its metabolite, 18β-glycyrrhetinic acid, and a compound found in Glycyrrhizae radix enhanced glutamic acid uptake through glutamate transporter 1 (GLUT-1) in astrocytes [37].…”

Section: Discussionmentioning

confidence: 99%

Analgesic Effect of Boiogito, a Japanese Traditional Kampo Medicine, on Post-Traumatic Knee Osteoarthritis through Inhibition of ERK1/2 Phosphorylation in the Dorsal Horn of the Spinal Cord

et al. 2021

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Boiogito (BO), a Japanese traditional herbal medicine, has been proven to be clinically effective against knee osteoarthritis (KOA)-associated pain. However, the therapeutic mechanism of BO remains unclear. Thus, we investigated the analgesic mechanism of BO using a rat KOA model. KOA was induced by destabilization of the medial meniscus (DMM). Rats were allocated into the following four groups: control, sham, DMM, and DMM + BO groups. Rotarod test was performed to evaluate the pain-related locomotive dysfunction. Expression of phosphorylated extracellular signal-regulated kinase1/2 (pERK1/2) in the spinal dorsal horn was examined using immunofluorescence staining and Western blotting on days 1 and 28 after DMM surgery. A mitogen-activated protein kinase inhibitor, U0126, was intrathecally injected and rotarod test and Western blotting were performed. The rotarod test revealed hampered locomotive function in the DMM group, which was significantly improved upon BO administration. The number of pERK1/2-positive cells was increased in the DMM group, whereas it was significantly decreased in the DMM + BO group. U0126 significantly inhibited ERK1/2 phosphorylation and increased walking time in the rotarod test, suggesting that the DMM-related pain was associated with ERK1/2 phosphorylation in the spinal dorsal horn. In conclusion, BO administration improved the pain-related locomotive dysfunction by suppressing ERK1/2 phosphorylation.

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“… 44 The liquorice-derived trans -chalcone isoliquiritigenin 7 was recently found to exert antinociceptive effects mainly through inhibitory action on voltage-gated sodium (Na v ) channels on sensory nociceptive fibres. 45 In a rodent model, the Iiquorice-derived isoflavane-type isoflavonoid glabridin 5 exhibited anti-inflammatory actions, inhibited cytokine production and showed anti-nociceptive response via activation of calcium-activated potassium (BKCa) channels and downregulation of NO levels and TRPV. 46 Large conductance BKCa channels have been found to exert inhibitory control on sensory input in inflammatory pain.…”

Section: Liquorice: Anti-inflammatory Effects and Mechanismsmentioning

confidence: 99%

Liquorice for pain?

Bell

Moreira

Kalso

et al. 2021

Therapeutic Advances in Psychopharmacology

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Liquorice has a long history of use in traditional Chinese, Ayurvedic and herbal medicine. The liquorice plant contains numerous bioactive compounds, including triterpenes, flavonoids and secondary metabolites, with glycyrrhizin being the main active compound. Liquorice constituents have been found to have anti-inflammatory, antioxidant, antiviral, anticancer, hepatoprotective and neuroprotective properties. In addition, they appear to have antidepressant actions and effects on morphine tolerance. Glycyrrhizin, its metabolite glycyrrhetic (glycyrrhetinic) acid and other liquorice-derived compounds such as isoflavonoids and trans-chalcones, exert potent anti-inflammatory effects via a wide range of mechanisms including high mobility group box 1 protein (HMGB1) inhibition, gap junction blockade and α2A-adrenoceptor antagonism. These properties, together with an increasing body of preclinical studies and a long history of use in herbal medicine, suggest that liquorice constituents may be useful for pain management. Glycyrrhizin is used widely in the confectionary, food and tobacco industries, but has documented adverse effects that may limit clinical use. Whether liquorice plant-derived compounds represent a novel class of analgesics is yet to be established. Having a host of bioactive compounds with a broad range of mechanisms of effect, liquorice is a plant that, in the future, may give rise to new therapies for pain.

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Isoliquiritigenin, an active ingredient of Glycyrrhiza, elicits antinociceptive effects via inhibition of Nav channels

Cited by 12 publications

References 46 publications

Natural Product Isoliquiritigenin Activates GABAB Receptors to Decrease Voltage-Gate Ca2+ Channels and Glutamate Release in Rat Cerebrocortical Nerve Terminals

Natural Product Isoliquiritigenin Activates GABAB Receptors to Decrease Voltage-Gate Ca2+ Channels and Glutamate Release in Rat Cerebrocortical Nerve Terminals

Analgesic Effect of Boiogito, a Japanese Traditional Kampo Medicine, on Post-Traumatic Knee Osteoarthritis through Inhibition of ERK1/2 Phosphorylation in the Dorsal Horn of the Spinal Cord

Liquorice for pain?

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