Identification and characterization of saikosaponins as antagonists of transient receptor potential A1 channel
| Autor: | Jong Suk Lee, Songmi Kim, Myung-Jin Song, Yongmun Choi, Yeon Ju Nam, Woo Jung Kim, Jin Koo Lee, Ji Hyun Lee, Jin Kyu Kim, Kyoung Tai No, Gyeongbeen Lee, Jiwon Choi, Kim Pan Soo |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Drug media_common.quotation_subject Drug Evaluation Preclinical Mutagenesis (molecular biology technique) Pharmacology Mice 03 medical and health sciences Transient receptor potential channel 0302 clinical medicine Animals Humans Medicine Pain perception Oleanolic Acid Adverse effect TRPA1 Cation Channel Pain Measurement media_common Mice Inbred ICR 0303 health sciences business.industry 030302 biochemistry & molecular biology Saponins Molecular Docking Simulation HEK293 Cells Nociception Hyperalgesia 030220 oncology & carcinogenesis Saikosaponin D Neuropathic pain Neuralgia business |
| Zdroj: | Phytotherapy Research. 34:788-795 |
| ISSN: | 1099-1573 0951-418X |
| DOI: | 10.1002/ptr.6559 |
| Popis: | Neuropathic pain is associated with an increased sensitivity to painful stimuli or abnormal sensitivity to otherwise innocuous stimuli. However, in addition to adverse effects, currently available drugs have shown limited response in patients with neuropathic pain, which provides a rationale to explore new drug classes acting on novel targets and with better efficacy and safety profiles. Here, we found that saikosaponins potently inhibit agonist-induced activation of the transient receptor potential A1 (TRPA1) channel, which has been reported to mediate neuropathic pain by sensing a variety of chemical irritants. Molecular docking and site-directed mutagenesis analyses suggested that saikosaponins bind to the hydrophobic pocket in TRPA1 near the Asn855 residue, which, when mutated to Ser, was previously associated with enhanced pain perception in humans. In support of these findings, saikosaponin D significantly attenuated agonist-induced nociceptive responses and vincristine-induced mechanical hypersensitivity in mice. These results indicate that saikosaponins are TRPA1 antagonists and provide a basis for further elaboration of saikosaponin derivatives for the development of new therapeutics for neuropathic pain. |
| Databáze: | OpenAIRE |
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