Novel charged sodium and calcium channel inhibitor active against neurogenic inflammation
| Autor: | Thomas Jacquemont, Masakazu Kotoda, Clifford J. Woolf, Laurel M. Heckman, Nick Andrews, Bruce P. Bean, Seungkyu Lee, Han-Xiong Bear Zhang, Michelino Puopolo, Sooyeon Jo, Sébastien Talbot, Maud Pascal, Aakanksha Jain, Jinbo Lee, Pin W. Liu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Mouse Pharmacology calcitonin gene-related peptide Sodium Channels Mice Calcium Channels N-Type 0302 clinical medicine Sodium channel blocker Ganglia Spinal Biology (General) Nav1.7 Neurogenic inflammation Voltage-dependent calcium channel Chemistry General Neuroscience Nociceptors General Medicine Calcium Channel Blockers Bupivacaine Medicine Neurogenic Inflammation Cav2.2 Sodium Channel Blockers Research Article dorsal root ganglion QH301-705.5 Sodium Science Pain chemistry.chemical_element Calcium Calcitonin gene-related peptide General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Animals Humans Calcium Signaling General Immunology and Microbiology Calcium channel Sodium channel Lidocaine asthma Disease Models Animal 030104 developmental biology inflammatory peptide 030217 neurology & neurosurgery Neuroscience |
| Zdroj: | eLife, Vol 8 (2019) eLife |
| 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: | OpenAIRE |
| Externí odkaz: |
|