Capsaicin Protects Against Cisplatin Ototoxicity by Changing the STAT3/STAT1 Ratio and Activating Cannabinoid (CB2) Receptors in the Cochlea.

Autor: Bhatta P; Departments of Pharmacology, Internal Medicine and Surgery, SIU School of Medicine, PO Box 19629, Springfield, IL, 62794, USA., Dhukhwa A; Departments of Pharmacology, Internal Medicine and Surgery, SIU School of Medicine, PO Box 19629, Springfield, IL, 62794, USA., Sheehan K; Departments of Pharmacology, Internal Medicine and Surgery, SIU School of Medicine, PO Box 19629, Springfield, IL, 62794, USA., Al Aameri RFH; Departments of Pharmacology, Internal Medicine and Surgery, SIU School of Medicine, PO Box 19629, Springfield, IL, 62794, USA., Borse V; Departments of Pharmacology, Internal Medicine and Surgery, SIU School of Medicine, PO Box 19629, Springfield, IL, 62794, USA., Ghosh S; Departments of Pharmacology, Internal Medicine and Surgery, SIU School of Medicine, PO Box 19629, Springfield, IL, 62794, USA., Sheth S; Departments of Pharmacology, Internal Medicine and Surgery, SIU School of Medicine, PO Box 19629, Springfield, IL, 62794, USA., Mamillapalli C; Departments of Pharmacology, Internal Medicine and Surgery, SIU School of Medicine, PO Box 19629, Springfield, IL, 62794, USA., Rybak L; Departments of Pharmacology, Internal Medicine and Surgery, SIU School of Medicine, PO Box 19629, Springfield, IL, 62794, USA., Ramkumar V; Departments of Pharmacology, Internal Medicine and Surgery, SIU School of Medicine, PO Box 19629, Springfield, IL, 62794, USA., Mukherjea D; Departments of Pharmacology, Internal Medicine and Surgery, SIU School of Medicine, PO Box 19629, Springfield, IL, 62794, USA. dmukherjea@siumed.edu.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2019 Mar 11; Vol. 9 (1), pp. 4131. Date of Electronic Publication: 2019 Mar 11.
DOI: 10.1038/s41598-019-40425-9
Abstrakt: Capsaicin, the spicy component of hot chili peppers activates the TRPV1 pain receptors, and causes rapid desensitization. Capsaicin also ameliorates cisplatin-induced nephrotoxicity. Cisplatin, a commonly used anti-neoplastic agent for solid tumors causes significant hearing loss, nephrotoxicity and peripheral neuropathy. Upregulation of cochlear TRPV1 expression is related to cisplatin-mediated ototoxicity. Here we report that direct TRPV1 activation by localized trans-tympanic (TT) or oral administration of capsaicin (TRPV1 agonist) prevents cisplatin ototoxicity by sustained increased activation of pro-survival transcription factor signal transducer and activator of transcription (STAT3) in the Wistar rat. Cisplatin treatment produced prolonged activation of pro-apoptotic Ser 727 p-STAT1 and suppressed Tyr 705 -p-STAT3 for up to 72 h in the rat cochlea. Our data indicate that capsaicin causes a transient STAT1 activation via TRPV1 activation, responsible for the previously reported temporary threshold shift. Additionally, we found that capsaicin increased cannabinoid receptor (CB2) in the cochlea, which leads to pro-survival Tyr 705 -p-STAT3 activation. This tilts the delicate balance of p-STAT3/p-STAT1 towards survival. Furthermore, capsaicin mediated protection is lost when CB2 antagonist AM630 is administered prior to capsaicin treatment. In conclusion, capsaicin otoprotection appears to be mediated by activation of CB2 receptors in the cochlea which are coupled to both STAT1 and STAT3 activation.
Databáze: MEDLINE
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