Protective Effects of Nobiletin on Cisplatin-Induced Neurotoxicity in Rats

Abstract

Objectives This study was designed to investigate the possible antioxidant, antiapoptotic and neuroprotective effects of nobiletin on cisplatin-induced neurotoxicity rat model by evaluating neurotrophins, antioxidants and histopathology. Methods Forty male Wistar Albino rats were divided into four groups: control, cisplatin (CIS), cisplatin + nobiletin (CIS + NOB) and nobiletin + cisplatin (NOB + CIS). CIS + NOB was applied nobiletin (10 mg/kg, i.p.) during the last four days whereas NOB + CIS was applied nobiletin during the first four days of the study. Cisplatin (4 mg/kg, i.p. twice a day) was administered to the experimental groups on the 5th day of the study. All rats were sacrificed on the 10th day of the study. BDNF, NGF, G6PD, GPx, tGSH and MDA levels were determined in brain. In addition, routin histolopathological analysis and caspase-3 immunoreactivity assay were conducted. Results BDNF concentrations increased in nobiletin-administered groups, compared to Control and CIS and that the increase was statistically significant in NOB + CIS (p < 0.05). It was also found that G6PD activity increased (p < 0.05) in the nobiletin-administered groups, compared to control and CIS. Histopathologically, neuronal degeneration, oedema and gliosis increased in CIS compared to Control, and nobiletin administration decreased neuronal degeneration and oedema compared to CIS (p < 0.05). Cisplatin increased (p < 0.05) caspase-3 immunoreactivity in cerebrovascular endothelium and neurons compared to Control, while nobiletin administration decreased caspase-3 immunoreactivity in cerebrovascular endothelium. Caspase-3 immunoreactivity in neurons decreased only in NOB + CIS (p < 0.05). Conclusion Nobiletin increased BDNF concentration and G6PD activity in brain and when evaluated together with histopathological and immunohistochemical findings, it may have antioxidant, antiapoptotic and neuroprotective effects against cisplatin.