6-Shogaol attenuates cisplatin induced emesis by inhibiting the mtDNA-cGAS-STING signaling pathway in a rat pica model

Ethnopharmacological relevance

Ginger (Zingiber officinale Rosc.) is a traditional anti-emetic herb. 6-shogaol, the main active compound of ginger, is reported to possess a variety of bioactivities.

Aims of the study

This study aimed to investigate the anti-emetic effect of 6-shogaol in a cisplatin-induced pica rat model and explore its underlying mechanism.

Materials and methods

The rat pica model was established by intraperitoneal injection of cisplatin. The pathological damage of gastric antrum and ileum were observed by hematoxylin-eosin staining. The levels of serum 8-Hydroxy-desoxyguanosine (8-OHdG) were detected by ELISA. The expression of ZO1 tight junction protein (TJP-1) and occludin in ileum were determined by IHC. The levels of 8-oxo G DNA glycosylase 1 (OGG1), flap endonuclease 1 (FEN1), cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), phospho-STING (p-STING), TANK binding kinase 1 (TBK1), phospho-TBK1 (pTBK1), nuclear factor kappa-B (NF-κB) and phospho-NF-κB (p-NF-κB) in gastric antrum and ileum were assayed by western blotting.

Results

We found that 6-shogaol significantly improved pica behavior in rats by downregulating NF-κB and IL-1β level, and ameliorating inflammatory damage in gastric antrum and ileum. Mechanistically, cGAS-STING axis activated by mtDNA is responsible for the cisplatin-induced gastrointestinal inflammatory responses. 6-Shogaol inhibited the mtDNA-cGAS-STING signaling pathway by increasing the level of base-excision repair enzyme OGG1 and decreasing the level of endonuclease FEN1.

Conclusions

This study indicates that 6-shogaol has a therapeutic effect against chemotherapy-induced nausea and vomiting (CINV), potentially attributable to the suppression of the mtDNA-cGAS-STING signaling pathway.