Major depressive disorder (MDD) is a debilitating human health condition characterized by mood swings and is associated with a high probability of suicide attempts. Several studies have reported a role of neuroinflammation in MMD, yet the efficacy of natural drug substances on neuroinflammation-associated depression has not been wellinvestigated. The present study examined the neuroprotective effects of carvacrol on lipopolysaccharide (LPS)-induced neuroinflammation, depression, and anxiety-like behavior. Methods: Male Sprague Dawley rats were divided into two experimental cohorts to determine the effects and the effective dose of carvacrol (whether 20 mg/kg or 50 mg/kg), and further demonstrate the mechanism of action of nuclear factor E2-related factor (Nrf2) in depression. Results: We found marked neuronal alterations in the cortex and hippocampus of LPSintoxicated animals that were associated with higher inflammatory cytokine expression such as cyclooxygenase (COX2), tumor necrosis factor-alpha (TNF-α), and c-Jun N-terminal kinase (p-JNK). These detrimental effects exacerbated oxidative stress, as documented by a compromised antioxidant system due to high lipid peroxidase (LPO). Carvacrol (20 mg/kg) significantly reverted these changes by positively modulating the antioxidant gene Nrf2, a master regulator of the downstream antioxidant pathway. To further investigate the role of Nrf2, an inhibitor of Nrf2 called all-trans retinoic acid (ATRA) was used, which further exacerbated LPS toxicity with a higher oxidative and inflammatory cytokine level. To further support our notion, we performed virtual docking of carvacrol with the Nrf2-Keap1 target and the resultant drug-protein interactions validated the in vivo findings. Conclusion: Collectively, our findings suggest that carvacrol (20 mg/kg) could activate the endogenous master antioxidant Nrf2, which further regulates the expression of downstream antioxidants, eventually ameliorating LPS-induced neuroinflammation and neurodegeneration.
The authors became aware of suspected duplicated images in Figures 4 and 5 and requested for the article to be retracted. Specifically,• Figure 4B, Bcl-2, Hippocampus, FLX+LPS appears to have been duplicated with the same image for Figure 4C, Caspase-3, Hippocampus, CAR 20+LPS. • Figure 5D, TNF-α, Cortex, LPS appears to have been duplicated with the same image for Figure 5D, TNF-α, Cortex, CAR 20+ATRA+LPS. • Figure 5D, TNF-α, Cortex, ATRA+LPS appears to have been duplicated with the same image for Figure 5E, p-NFκB, Cortex, ATRA+LPS (which has been flipped).The Editor agreed with the authors retraction request and the authors were notified of this.Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction.The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as "Retracted".
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