Inhibition of Hippocampal Microstructural Alterations in Nickel Chloride-Exposed Rats Pretreated with Rutin: Role of NRF-2, Caspase-3, AChE and BDNF

Abstract

Background: Nickel chloride (NiCl₂) induces neurotoxicity by triggering harmful effects in the nervous system, thereby promoting oxidative stress, apoptosis, and ultimately neuronal death. Rutin, a dietary flavonoid, acts as a potent antioxidant, protecting cells from oxidative damage. Accordingly, this study investigated the activity of rutin in the hippocampus of NiCl₂-exposed rats.

Materials and Methods: Forty-eight Wistar rats, randomly distributed into six groups (n=8), were treated for twenty-eight days as follows: Group A – Control; Group B - 5 mg/kg body weight (bw) NiCl₂; Group C - 50 mg/kg bw rutin and 5 mg/kg bw NiCl₂; Group D - 100 mg/kg bw rutin and 5 mg/kg bw NiCl₂; Group E - 50 mg/kg bw rutin; Group F – 100 mg/kg bw rutin. Thereafter, neurobehavioural, antioxidant, lipid peroxidation, histological, gene expression, and in-silico assessments were done.

Results: The findings showed that the NiCl₂ caused a significant decrease (P<0.05) in spontaneous alternation and discrimination index, as well as antioxidant enzymes, following comparison to control. A significant increase (P<0.05) was noticed in lipid peroxidation and microstructural alterations in the hippocampus of NiCl₂-treated rats. Furthermore, a significant downregulation (P<0.05) in NRF-2 expression and a significant upregulation (P<0.05) in Caspase-3 expression were observed following NiCl₂ exposure. However, these effects were inhibited in the NiCl₂-exposed rats pretreated with rutin. Also, in-silico docking results revealed that rutin had a strong binding affinity with AChE and BDNF, thus demonstrating its therapeutic potential against cognitive disorders.

Conclusion: Taken together, these findings demonstrate that rutin attenuated NiCl₂ toxicity in the hippocampus of rats, possibly via its ability to modulate NRF-2, AChE and BDNF activity.