Agomelatine ameliorates doxorubicin-induced cortical and hippocampal brain injury via inhibition of TNF-alpha/NF-kB pathway

Abstract

Side effects of doxorubicin (DOX) are mainly due to oxidative stress, with the involvement of inflammatory and apoptotic mechanisms. Agomelatine (AGO) is a melatonin receptor agonist with antioxidant, anti-inflammatory, and anti-apoptotic features. This study aimed to evaluate the effects of AGO with different doses on DOX-induced neurotoxicity. Rats were divided into four groups as control, DOX (40 mg/kg, intraperitoneal single dose), DOX + AGO20 (20 mg/kg AGO oral gavage for 14 days), and DOX + AGO40 (40 mg/kg AGO oral gavage for 14 days). On day 14, brain tissues were collected for biochemical, histopathological, and genetic examinations. DOX significantly increased malondialdehyde and decreased superoxide dismutase and catalase (CAT) levels. CAT levels were significantly increased only in the DOX + AGO40 group compared to the DOX group (p = 0.040) while other changes in oxidant and antioxidant indicators were insignificant. DOX-induced significant increases in TNF-alpha and NF-κB were reversed following both low and high-dose AGO administration in a dose-dependent manner (p < 0.001 for both doses). Cellular shrinkage, pycnotic change, and vacuolization in apoptotic bodies were apparent in the cortical and hippocampal areas of DOX-treated samples. Both doses of AGO alleviated these histopathological changes (p = 0.01 for AGO20 and p = 0.05 for AGO40). Significantly increased apoptosis shown with caspase-3 immunostaining in the DOX group was alleviated following AGO administration, with additional improvement after high-dose treatment (p < 0.01 for DOX compared to both AGO groups and p < 0.05 for AGO40 compared to AGO20). AGO can be protective against DOX-induced neurotoxicity by antioxidant, anti-inflammatory, and anti-apoptotic mechanisms in a dose-dependent manner.

Keywords:

• Agomelatine
• doxorubicin
• inflammation
• neurotoxicity
• oxidative stress

Acknowledgement

We thank Mekin Sezik, MD, (Suleyman Demirel University Faculty of Medicine Department of Obstetrics and Gynecology) for comments on the manuscript.

Author contributions

MS and SA conceived and designed research. MS, HA, MK, and NFK conducted experiments. YE, KG, and RA contributed analytical tools. MS and MK analyzed data. MS wrote the manuscript. All authors read and approved the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data supporting this study’s findings are available on request from the corresponding author.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.