Carveol a Naturally-Derived Potent and Emerging Nrf2 Activator Protects Against Acetaminophen-Induced Hepatotoxicity

Abstract

Acetaminophen (N-acetyl p-aminophenol or APAP) is used worldwide for its antipyretic and anti-inflammatory potential. However, APAP overdose sometimes causes severe liver damage. In this study, we elucidated the protective effects of carveol in liver injury, using molecular and in silico approaches. Male BALB/c mice were divided into two experimental cohorts, to identify the best dose and to further assess the role of carveol in the nuclear factor E2-related factor; nuclear factor erythroid 2; p45-related factor 2 (Nrf2) pathway. The results demonstrated that carveol significantly modulated the detrimental effects of APAP by boosting endogenous antioxidant mechanisms, such as nuclear translocation of Nrf2 gene, a master regulator of the downstream antioxidant machinery. Furthermore, an inhibitor of Nrf2, called all-trans retinoic acid (ATRA), was used, which exaggerated APAP toxicity, in addition to abrogating the protective effects of carveol; this effect was accompanied by overexpression of inflammatory mediators and liver = 2ltoxicity biomarkers. To further support our notion, we performed virtual docking of carveol with Nrf2-keap1 target, and the resultant drug-protein interactions validated the in vivo findings. Together, our findings suggest that carveol could activate the endogenous master antioxidant Nrf2, which further regulates the expression of downstream antioxidants, eventually ameliorating the APAP-induced inflammation and oxidative stress.

Carveol Attenuates Seizure Severity and Neuroinflammation in Pentylenetetrazole‐Kindled Epileptic Rats by Regulating the Nrf2 Signaling Pathway

“…Furthermore, studies have suggested increased COX-2 induction in the mouse brain after electrical kindling of hippocampal pyramidal cells [ 10 ]. Carveol significantly ameliorated the upregulated inflammatory mediators in PTZ-treated animals, which is consistent with recent findings regarding the modulatory effect of carveol on proinflammatory cytokines [ 33 , 59 ]. ATRA treatment further exacerbated the expression of inflammatory markers and abolished the anti-inflammatory potential of carveol, which supports our hypothesis that carveol exerts its anti-inflammatory potential by modulating the Nrf2 pathway.…”

“…For this purpose, extensive research must be conducted on phytochemicals before human clinical trials as neuroprotectants [ 58 ]. Previous studies have shown that carveol is a monoterpene possesses robust antioxidant, anti-inflammatory, and protective properties in various degenerative models [ 33 , 59 ]. However, there have been no direct reports regarding the antiepileptic potential of carveol.…”

“…We previously demonstrated the neuroprotective potential of carveol in ischemic brain injury by attenuating infarction area [ 33 ]. In another study, carveol mitigated hepatocellular necrosis by showing antioxidant, antihyperlipidemic, and anti-inflammatory activities [ 41 ]. Furthermore, carveol exhibited promising results in the management of diabetes [ 42 ].…”

Natural Dietary Supplement, Carvacrol, Alleviates LPS-Induced Oxidative Stress, Neurodegeneration, and Depressive-Like Behaviors via the Nrf2/HO-1 Pathway

“…GST activity was measured using CDNB as a substrate, as described previously with a slight modification. 41 Each well was filled with 10 μL of 1 mM CDNB, 10 μL of 5 mM reduced glutathione, 270 μL of buffer solution, and 10 μL of the sample. The absorbance was read at 340 nm using a plate reader.…”

Potential Neuroprotective Activity of Essential Oils in Memory and Learning Impairment

“…8 Carveol could be a powerful antioxidant and anti-inflammatory agent, activating the master endogenous protein Nrf2 which is an integral part of the cellular defense mechanism against oxidative stress and electrophilic aggression. Nrf2 joins the antioxidant response elements at the promoter site, which in turn encodes various phase II detoxifying and antioxidant enzymes and other important stress response factors, [80][81] and may be associated with negative modulation of p-JNK and other neuroinflammatory mediators. Therefore, it may offer a new therapeutic option to prevent and control oxidative stress and inflammation in degenerative disorders.…”