Naringin Abrogates Cisplatin-Induced Cognitive Deficits and Cholinergic Dysfunction Through the Down-Regulation of AChE Expression and iNOS Signaling Pathways in Hippocampus of Aged Rats

Yassine Chtourou, Brahim Gargouri, Mohammed Kebieche, Hamadi Fetoui

Chemotherapy-related cognitive deficits are a major neurological problem, but the underlying mechanisms are unclear. However, very few studies have looked at the possible ways of preventing this stress-induced deficit. Thus, we investigated the relationship between cisplatin (Cis) exposure to acetylcholinesterase, ATPase, oxidative stress biomarkers, and impaired behavior performance and the possible protecting mechanism of naringin (Nar), a plant-derived flavonoid, in aged rats. The experimental procedures were divided in two sets of experiments. In the first, the animals were divided into four groups: vehicle, Nar 25 mg/kg, Nar 50 mg/kg, and Nar 100 mg/kg. In the second, the animals were divided into four groups: Cis (5 mg kg(-1) week(-1) for five consecutive weeks), Cis plus Nar (25 mg/kg), Cis plus Nar (50 mg/kg), and Cis plus Nar (100 mg/kg). Results showed that Cis exposure leads to the increase in acetylcholinesterase associated with a significant increase in mRNA levels of acetylcholinesterase and the inducible nitric oxide synthase (iNOS) in the hippocampus. Moreover, a decrease in membrane-bound ATPase enzyme activities and enzymatic and nonenzymatic antioxidant activities in the hippocampus and an increase in the levels of malondialdehyde (MDA), protein carbonyls (PCO), nitrite formation (NO), and reactive oxygen species (ROS) levels were found. Further, Cis-induced neuronal alterations were evidenced by impairment behavioral performance. Treatment with Nar significantly and dose-dependently prevented all the behavioral, biochemical, and molecular alterations in aged rats treated with cisplatin. Thus, findings from the current study demonstrate the possible involvement of oxidative-stress-mediated inflammatory signaling in Cis-induced cognitive dysfunction and also suggests the effectiveness of naringin in preventing cognitive deficits in chemotherapy-induced peripheral neuropathy.