Nerolidol, a Sesquiterpene from the Essential Oils of Aromatic Plants, Attenuates Doxorubicin-Induced Chronic Cardiotoxicity in Rats

Abstract

The clinical usage of doxorubicin (DOX), a potent anthracycline antineoplastic drug, is limited due to its cardiotoxicity. The aim of this study was to assess the possible cardioprotective effects of nerolidol (NERO) in a rat model of DOXinduced chronic cardiotoxicity and the underlying molecular mechanisms. DOX (2.5 mg/kg) was injected intraperitoneally once in a week for 5 weeks to induce chronic cardiotoxicity in male albino Wistar rats. The rats were treated with NERO (50 mg/kg, orally) 6 days a week for a duration of 5 weeks. DOX-injected rats showed a significant decline in cardiac function, elevated levels of serum cardiac marker enzymes, and enhanced oxidative stress markers along with altered PI3K/Akt and Nrf2/Keap1/HO-1 signaling pathways. DOX also triggered the activation of NF-κB/MAPK signaling and increased the levels/expression of proinflammatory cytokines (TNF-α, IL-6, and IL-1β) and expression of inflammatory mediators (iNOS and COX-2) in the heart. DOX activated NLRP3 inflammasome-mediated pyroptotic cell death along with fibrosis, mitochondrial dysfunction, DNA damage, and apoptosis in the myocardium. Additionally, histological studies, TUNEL staining, and myocardial lesions revealed structural alterations of the myocardium. NERO treatment showed considerable protective effects on the biochemical and molecular parameters studied. The findings demonstrate that NERO protects against DOX-induced chronic cardiotoxicity and the observed cardioprotective effects are attributed to its potent antioxidant and free radical scavenging properties.

Lycopene regulates the mitochondrial unfolded protein response to prevent DEHP-induced cardiac mitochondrial damage in mice

“…61 Some studies have proved that Nrf2 can improve cardiac function injury and structural changes in mice by regulating oxidative stress. 62,63 CAT, MDA and T-SOD are important indicators of oxidative stress. 64,65 NQO1, SOD2, SOD3 and CAT serve as markers for antioxidant capacity and catalytic removal of peroxides.…”

Cardiomyocyte Atrophy, an Underestimated Contributor in Doxorubicin-Induced Cardiotoxicity

“…The PI3K-AKT signaling pathway plays a vital role in regulating the muscle hypertrophy and atrophy response (77). Studies have revealed that DOX inhibited PI3K-AKT activity both in vivo and in vitro (79,(88)(89)(90). PI3K, a lipid kinase family transducing receptor tyrosine kinase signaling, is aberrantly upregulated in human cancers frequently (91).…”

“…For example, Chen et al found that total flavonoids stimulated PI3K-AKT and attenuated DOX-induced HW loss, while inhibition of PI3K-AKT abrogated the protection of total flavonoids against DIC (97). Meeran et al revealed that nerolidol, a sesquiterpene from the essential oils of aromatic plants, alleviated DOX-induced cardiac atrophy possibly via the PI3K-AKT pathway (88). Intriguingly, both upregulation and downregulation of PI3K-AKT triggered by DOX has been reported (98,99).…”

Doxycycline Attenuates Doxorubicin-Induced Cardiotoxicity by Improving Myocardial Energy Metabolism in Rats

“…The most accepted mechanism includes increased oxidative stress due to an excessive formation of reactive oxygen species (ROS). ROS generation in Dox-induced cardiotoxicity is related to changes in myocardial energy metabolism and mitochondrial dysfunction, impairment in iron handling, and the presence of nitric oxide synthase [ 6 , 7 ]. Moreover, Dox deactivates antioxidant substances such as glutathione peroxidase, superoxide dismutase, and catalase [ 1 ].…”