Blockade of T-type calcium channels by 6-prenylnaringenin, a hop component, alleviates neuropathic and visceral pain in mice

Sekiguchi, Fumiko; Fujita, T.; Deguchi, Takahiro; Yamaoka, Sakura; Tomochika, Ken; Tsubota, Maho; Ono, Sumire; Horaguchi, Yamato; Ichii, Maki; Ichikawa, Mio; Ueno, Yumiko; Koike, Nene; Tanino, Tadatoshi; Nguyen, Hong Ha; Okada, Takuya; Nishikawa, Hiroyuki; Yoshida, Shigeru; Ohkubo, Tsuyako; Toyooka, Naoki; Murata, Kazuya; Matsuda, Hideaki; Kawabata, Atsufumi

doi:10.1016/j.neuropharm.2018.06.020

Cited by 24 publications

(53 citation statements)

References 54 publications

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“…Mouse model of visceral hypersensitivity and in irritable bowel syndrome [ 272 ]. Mouse model of inflammatory and neuropathic pain [ 273 ] (2S)-6-prenylnaringenin can block Cav3.2 current [ 150 ] Apoptotic pathway in myocardial cells [ 155 ] Autophagy pathway [ 158 ] CACNA2D1 Calcium voltage-gated channel auxiliary subunit alpha2delta 1 Cav1.3 L-type None Conventional knockout mouse using a construct targeting exon 2 of alpha (2)/delta-1 [ 274 ]. α2 δ1 Tg model for neuropathic pain [ 275 , 276 ] None None CACNA2D2 Calcium voltage-gated channel auxiliary subunit alpha2delta 2 Cav1.3 L-type None The “ducky’ du (2 J) mouse model of ataxia and absence epilepsy [ 277 ].…”

Section: Resultsmentioning

confidence: 99%

Calcium channelopathies and intellectual disability: a systematic review

Kessi

Chen

Peng

et al. 2021

Orphanet J Rare Dis

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Background Calcium ions are involved in several human cellular processes including corticogenesis, transcription, and synaptogenesis. Nevertheless, the relationship between calcium channelopathies (CCs) and intellectual disability (ID)/global developmental delay (GDD) has been poorly investigated. We hypothesised that CCs play a major role in the development of ID/GDD and that both gain- and loss-of-function variants of calcium channel genes can induce ID/GDD. As a result, we performed a systematic review to investigate the contribution of CCs, potential mechanisms underlying their involvement in ID/GDD, advancements in cell and animal models, treatments, brain anomalies in patients with CCs, and the existing gaps in the knowledge. We performed a systematic search in PubMed, Embase, ClinVar, OMIM, ClinGen, Gene Reviews, DECIPHER and LOVD databases to search for articles/records published before March 2021. The following search strategies were employed: ID and calcium channel, mental retardation and calcium channel, GDD and calcium channel, developmental delay and calcium channel. Main body A total of 59 reports describing 159 cases were found in PubMed, Embase, ClinVar, and LOVD databases. Variations in ten calcium channel genes including CACNA1A, CACNA1C, CACNA1I, CACNA1H, CACNA1D, CACNA2D1, CACNA2D2, CACNA1E, CACNA1F, and CACNA1G were found to be associated with ID/GDD. Most variants exhibited gain-of-function effect. Severe to profound ID/GDD was observed more for the cases with gain-of-function variants as compared to those with loss-of-function. CACNA1E, CACNA1G, CACNA1F, CACNA2D2 and CACNA1A associated with more severe phenotype. Furthermore, 157 copy number variations (CNVs) spanning calcium genes were identified in DECIPHER database. The leading genes included CACNA1C, CACNA1A, and CACNA1E. Overall, the underlying mechanisms included gain- and/ or loss-of-function, alteration in kinetics (activation, inactivation) and dominant-negative effects of truncated forms of alpha1 subunits. Forty of the identified cases featured cerebellar atrophy. We identified only a few cell and animal studies that focused on the mechanisms of ID/GDD in relation to CCs. There is a scarcity of studies on treatment options for ID/GDD both in vivo and in vitro. Conclusion Our results suggest that CCs play a major role in ID/GDD. While both gain- and loss-of-function variants are associated with ID/GDD, the mechanisms underlying their involvement need further scrutiny.

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Section: Resultsmentioning

confidence: 99%

Calcium channelopathies and intellectual disability: a systematic review

Kessi

Chen

Peng

et al. 2021

Orphanet J Rare Dis

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“…Actually, the role of Ca v 3.2 T-channels may be more critical in processing of visceral pain than somatic pain, considering the previous findings that deletion of Ca v 3.2 gene in mice abolished pathological colonic and bladder pain in mice, 6,7) while it did not reduce somatic neuropathic pain, most probably due to compensation. 23) In conclusion, bepridil and pimozide, existing medicines capable of blocking T-channels, alleviate colonic and bladder pain, and may serve as seeds for the development of new medicines for visceral pain treatment.…”

Section: Discussionmentioning

confidence: 99%

“…5,20) There is also evidence for the involvement of serotonin 5-HT 2A receptor blockade in the effect of chlorpromazine on visceral pain. 19) It has been shown that the affinity of pimozide and chlorpromazine to 5-HT 2A receptors is one-sixth and a half of clozapine, respectively, 21,22) indicating that pimozide has one-third affinity of chlorpromazine to 5-HT 2A . Therefore, the possibility of the contribution of 5-HT 2A blockade to the effect of pimozide on visceral pain cannot be ruled out.…”

Section: Discussionmentioning

confidence: 99%

Effects of Bepridil and Pimozide, Existing Medicines Capable of Blocking T-Type Ca<sup>2+</sup> Channels, on Visceral Pain in Mice

Tsubota

Matsui

Fukushi

et al. 2021

Biological & Pharmaceutical Bulletin

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T-Type Ca 2 channels (T-channels), particularly Ca v 3.2, are now considered as therapeutic targets for treatment of intractable pain including visceral pain. Among existing medicines, bepridil, a multi-channel blocker, used for treatment of arrhythmia and angina, and pimozide, a dopamine D 2 receptor antagonist, known as a typical antipsychotic, have potent T-channel blocking activity. We thus tested whether bepridil and pimozide could suppress visceral pain in mice. Colonic and bladder pain were induced by intracolonic administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) and systemic administration of cyclophosphamide (CPA), respectively. Referred hyperalgesia was assessed by von Frey test, and colonic hypersensitivity to distension by a volume load with intracolonic water injection and spontaneous bladder pain were evaluated by observing nociceptive behaviors in conscious mice. The mice exhibited referred hyperalgesia and colonic hypersensitivity to distension on day 6 after TNBS treatment. Systemic administration of bepridil at 10-20 mg/kg or pimozide at 0.1-0.5 mg/kg strongly reduced the referred hyperalgesia on the TNBS-induced referred hyperalgesia and colonic hypersensitivity to distension. CPA treatment caused bladder pain-like nociceptive behavior and referred hyperalgesia, which were reversed by bepridil at 10-20 mg/kg or pimozide at 0.5-1 mg/kg. Our data thus suggest that bepridil and pimozide, existing medicines capable of blocking Tchannels, are useful for treatment of colonic and bladder pain, and serve as seeds for the development of new medicines for visceral pain treatment.

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“…Nevertheless, lack of pain-reducing effects has also been reported for non-selective blockers gabapentin and pregabalin (de Andrade et al, 2017;Wiffen et al, 2017). In rodent models of oxaliplatin, T-type, L-type, and non-selective blockers reduce mechanical and/or cold hyperalgesia (Ling et al, 2008;Gauchan et al, 2009;Kawashiri et al, 2012;Aoki et al, 2014;Ohsawa et al, 2014;Ruyang et al, 2015;Di Cesare Mannelli et al, 2017;Sekiguchi et al, 2018). Moreover, in vitro pre-treatment of oxaliplatin for 24 h selectively up-regulates T-and L-type calcium channels in DRG neurons (Schmitt et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Effects of Columbianadin on Nociceptive Behaviors in a Neuropathic Pain Model, and on Voltage-Gated Calcium Currents in Dorsal Root Ganglion Neurons in Mice

Zhang

et al. 2020

Front. Pharmacol.

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Radix angelicae pubescentis (RAP) has been used in Chinese traditional medicine to treat painful diseases such as rheumatism and headache. A previous study has reported that columbianadin (CBN), a major coumarin in RAP inhibits acute and inflammatory pain behaviors. However, the effects of CBN on neuropathic pain behaviors, and the potential underlying mechanism have not been reported. In the present study, the effects of CBN, compared to another major coumarin of RAP osthole (OST), on oxaliplatin-induced neuropathic pain behaviors and on the voltage-gated calcium currents in small dorsal root ganglion (DRG) neurons were studied in mice. It was found that CBN and OST inhibited both mechanical and cold hypersensitivity induced by oxaliplatin. Moreover, CBN and OST might preferentially inhibit T-and L-type calcium currents (Ica). The inhibitory effects of CBN and OST on the oxaliplatin-induced mechanical allodynia were prevented by gabapentin. These results suggest that CBN, as well as OST might inhibit neuropathic pain behaviors through an inhibition of T-and L-type calcium currents in nociceptive DRG neurons.

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Blockade of T-type calcium channels by 6-prenylnaringenin, a hop component, alleviates neuropathic and visceral pain in mice

Cited by 24 publications

References 54 publications

Calcium channelopathies and intellectual disability: a systematic review

Calcium channelopathies and intellectual disability: a systematic review

Effects of Bepridil and Pimozide, Existing Medicines Capable of Blocking T-Type Ca<sup>2+</sup> Channels, on Visceral Pain in Mice

Inhibitory Effects of Columbianadin on Nociceptive Behaviors in a Neuropathic Pain Model, and on Voltage-Gated Calcium Currents in Dorsal Root Ganglion Neurons in Mice

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