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

Abstract

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.

A novel antagonist of TRPM2 and TRPV4 channels: Carvacrol

“…In the current study, the activation of TRPV4 was caused to the excessive generation of oxidative stress and overload Ca 2+ influx in the SH-SY5Y, BV-2, and HEK293 V4 cells. The modulator role of CARV on several processes such as oxidative stress and Ca 2+ influx in several cells was reported (Chen et al 2015 ; Naeem et al 2021 ). In the current study, the oxidative stress and TRPV4 activation in the SH-SY5Y and HEK293 V4 cells was decreased via the upregulation of GSHPx and GSH, but the downregulation of MDA, cROS, and mROS by the treatment of CARV.…”

“…The decrease of TRPV4 (GSK) and TRPM2 (ADPR and H 2 O 2 ) activators-induced neuronal death in the hippocampus of mice were reported after the administration of antioxidants (Hong et al 2016 ; Kahya et al 2017 ). CARV is a strong antioxidant, and its modulator role on several processes such as free radicals and Ca 2+ influx in several cells was reported (Chen et al 2015 ; Naeem et al 2021 ). At least 11 of 28 subfamilies are activated by oxidative stress (Nazıroğlu et al 2012 ).…”

“…Plant extracts potentially have rich antioxidant contents, and they are potential sources of new drug discoveries. Natural drugs from the plant extracts have modulator potential actions on several processes such as free radicals and Ca 2+ influx (Chen et al 2015 ; Naeem et al 2021 ). Carvacrol (CARV) is extracted as an essential oil from the plants (Thymbra, Origanum, Satureja, and Thymus).…”

“…Carvacrol (CARV) is extracted as an essential oil from the plants (Thymbra, Origanum, Satureja, and Thymus). The CARV has modulator biological property, possibly due to its antioxidant, antiviral, and cation channel modulator properties (Parnas et al 2009 ; Chen et al 2015 ; Naeem et al 2021 ). Hence its protective action against the Covid-19 was recently reported (Javed et al 2021 ).…”

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

“…Moreover, previous studies demonstrated the neuroprotective role of Nrf2 not only in laboratory animals but also in human brain samples [30][31][32]. We have previously shown that activation of Nrf2 signaling attenuated infarction area and inflammatory-related pathologies not only in stroke but also in the depression model [33][34][35]. Therefore, Nrf2 may be a suitable therapeutic target for managing epilepsy and seizures.…”