β-caryophyllene ameliorates hepatic ischemia reperfusion-induced injury: the involvement of Keap1/Nrf2/HO 1/NQO 1 and TLR4/NF-κB/NLRP3 signaling pathways

M.E. Mohamed, R.M. Abdelnaby, N.S. Younis

Al Bilad Bank Scholarly Chair for Food Security, the Deanship of Scientific Research, the Vice Presidency for Graduate Studies and Scientific Research, Al Ahsa, Saudi Arabia. memohamed@kfu.edu.sa

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• Gastroenterology
• Pharmacology

OBJECTIVE: Hepatic ischemia-reperfusion (H I/R) injury is a frequent clinical event during which the leading contributing players are inflammation and oxidative stress responses. β-caryophyllene (BCP), a natural bicyclic sesquiterpene, is an essential oil component of different plant species and edibles. This study aims to identify whether BCP pretreatment could avert H I/R injury with inspections of the underlying mechanisms.

MATERIALS AND METHODS: Animals were devised into five groups; Sham and BCP + Sham; the animals were administered saline or BCP (200 mg/kg, orally) respectively; H I/R group, the animals were administered saline orally for 14 days before induction of H I/R; BCP100 and BCP200, the animals were administered BCP (100 and 200 mg/kg, respectively) for 14 days, followed by induction of H I/R.

RESULTS: H I/R showed markedly increased ALT, AST, MDA, and lowered antioxidant enzyme activities, while the Nrf2/HO1/NQO1 pathway components were significantly augmented. The TLR4/NF-κB/NLRP3 elements were deterred, and subsequently, escalations in the inflammatory mediators (IL-1β, IL-6, and TNF-α), adhesion molecule ICAM-1, neutrophils infiltration (MPO), and apoptotic markers were observed. Pretreatment with BCP amplified the antioxidant enzyme activities and Keap1/Nrf2/HO1/NQO1 pathway components. BCP pretreatment lowered TLR4/NF-κB/NLRP3 pathway elements, which mitigated inflammatory mediators, ICAM-1, MPO, and apoptotic markers.

CONCLUSIONS: The protective effect of BCP against hepatic I/R induced injury might be accomplished via mitigation of oxidative stress by regulating the Keap1/Nrf2/HO1/NQO1 pathway and inhibition of the inflammatory process via manipulating the TLR4/ NF-κB/ NLRP3, reflected by inflammatory markers, neutrophils recruitment, and adhesion molecules reduction. BCP might be a potential therapeutic agent for alleviating hepatic I/R-induced injury.

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