Agomelatine attenuates cisplatin-induced cognitive impairment via modulation of BDNF/TrkB signaling in rat hippocampus

• Published in: Journal of chemical neuroanatomy Vol. 130; p. 102269
• Main Authors: Saral, Sinan, Topçu, Atilla, Alkanat, Mehmet, Mercantepe, Tolga, Şahin, Zafer, Akyıldız, Kerimali, Karataş, Kader Semra, Yıldız, Lamiye, Tümkaya, Levent, Yazıcı, Zihni Açar
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.07.2023
• Subjects: Agomelatine; Animals; BDNF; Brain-Derived Neurotrophic Factor - metabolism; Cisplatin; Cisplatin - toxicity; Cognitive Dysfunction - chemically induced; Cognitive Dysfunction - drug therapy; Cognitive Dysfunction - metabolism; Hippocampus - metabolism; Male; Memory; nNOS; Rats; Receptor, trkB - metabolism; Receptor, trkB - pharmacology; Receptor, trkB - therapeutic use; Spatial Memory; Agomelatine; BDNF; Memory; Cisplatin; nNOS
• ISSN: 0891-0618; 1873-6300
• DOI: 10.1016/j.jchemneu.2023.102269

Cisplatin is a drug used effectively in the treatment of malignant tumors. However, cisplatin has many side effects, including cognitive impairment. Agomelatine, a synthetic melatonin analogue, is an important antidepressant. Increasing evidence has shown that agomelatine may be a potential neuroprotective agent. The aim of this study was to investigate the effect of agomelatine on learning and memory functions in cisplatin-induced cognitive impairment in a rat model. Male rats were administered agomelatine and cisplatin for 4 weeks. Neurobehavioral tests were performed at the end of the 4th week. After behavioral tests, rats were euthanized and BDNF, TNF, IL-1β, MDA and GSH levels were measured in hippocampal homegenates by ELISA. In addition, nNOS and TrkB receptor activity were measured immunohistochemically. The results showed that agomelatine significantly improved cognitive functions in spatial memory tests in rats with cisplatin-induced cognitive impairment. In addition, agomelatine treatment positively affected the discrimination index (DI). On the other hand, agomelatine treatment elevated cisplatin-suppressed hippocampal BDNF levels. Agomelatine treatment reduced cisplatin-induced neuroinflammation by suppressing TNF and IL-1β levels. Similarly, agomelatine reduced oxidative stress in the hippocampus. Histological findings showed that agomelatine treatment reduced pyramidal neuron damage in hippocampal DG, CA1 and CA3. Cisplatin increased nNOS and TrkB positivity in DG, CA1 and CA3 neurons compared to control. In contrast, agomelatine treatment decreased both nNOS and TrkB positive scores. These findings indicate that agomelatine reduces cisplatin-related cognitive impairment by exerting anti-inflammatory action and possibly by the modulation of the BDNF/TrkB/nNOS pathways in the hippocampus. [Display omitted] •Chemotherapeutic cisplatin causes memory impairment in rats.•Cisplatin increases neuroinflammation while decreasing BDNF level in hippocampus.•Cisplatin increases TrkB and nNOS positivity in the hippocampus.•Agomelatine improves memory functions by restoring BDNF level and suppressing neuroinflammation and oxidative stress.