Novel charged sodium and calcium channel inhibitor active against neurogenic inflammation
| Autor: | Seungkyu Lee, Sooyeon Jo, Sébastien Talbot, Han-Xiong Bear Zhang, Masakazu Kotoda, Nick A Andrews, Michelino Puopolo, Pin W Liu, Thomas Jacquemont, Maud Pascal, Laurel M Heckman, Aakanksha Jain, Jinbo Lee, Clifford J Woolf, Bruce P Bean |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: | |
| Zdroj: | eLife, Vol 8 (2019) |
| Druh dokumentu: | article |
| ISSN: | 2050-084X 25275445 |
| DOI: | 10.7554/eLife.48118 |
| Popis: | Voltage-dependent sodium and calcium channels in pain-initiating nociceptor neurons are attractive targets for new analgesics. We made a permanently charged cationic derivative of an N-type calcium channel-inhibitor. Unlike cationic derivatives of local anesthetic sodium channel blockers like QX-314, this cationic compound inhibited N-type calcium channels more effectively with extracellular than intracellular application. Surprisingly, the compound is also a highly effective sodium channel inhibitor when applied extracellularly, producing more potent inhibition than lidocaine or bupivacaine. The charged inhibitor produced potent and long-lasting analgesia in mouse models of incisional wound and inflammatory pain, inhibited release of the neuropeptide calcitonin gene-related peptide (CGRP) from dorsal root ganglion neurons, and reduced inflammation in a mouse model of allergic asthma, which has a strong neurogenic component. The results show that some cationic molecules applied extracellularly can powerfully inhibit both sodium channels and calcium channels, thereby blocking both nociceptor excitability and pro-inflammatory peptide release. |
| Databáze: | Directory of Open Access Journals |
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