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Nilotinib treatment induces cognitive impairment by elevating hippocampal oxidative stress in rats
S H Alharbi1, A H Alhowail, M A Aldubayan
1Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Qassim, Buraydah, Saudi Arabia. aalhowail@qu.edu.sa.
Objective:
Protein tyrosine kinases (TKs) play a critical role in the regulation of various functions of a cell, including cellular proliferation, differentiation, and growth, and inhibitors of TKs have emerged as next-generation therapeutic agents in various types of cancer. Nilotinib, one of the TK inhibitors used to treat chronic myeloid leukemia, has been poorly investigated for its potential impact on memory function despite its ability to cross the blood-brain barrier (BBB). Thus, in this study, we investigated the effect of nilotinib on hippocampal-dependent cognitive functions and its potential mechanisms.
Materials And Methods:
Wistar albino male rats were divided into three groups of 10 each. The animals of group I (normal control) received drinking water only, while groups II and III were treated with nilotinib at doses of 15 mg/kg and 30 mg/kg, p.o. respectively, once daily for two weeks. The animals were subjected to behavioral tests after completion of drug treatment for the assessment of cognitive function using the Y-maze, novel object recognition (NOR) test, and elevated plus maze (EPM). The animals were euthanized after the estimation of blood glucose, and hippocampal tissues were dissected for the estimation of markers of oxidative stress.
Results:
Nilotinib produced impairment of memory function on the Y-maze, NOR test, and EPM. These results were also supported by a significant increase in glutathione (GSH), malondialdehyde (MDA), Akt, glycogen synthase kinase-3 beta (GSK3β), and total antioxidant capacity (TAC) in hippocampal tissue without altering the blood glucose level.
Conclusions:
Nilotinib treatment produced significant impairment of cognitive function by inducing oxidative stress in the hippocampal tissue of rats.
Insights
Nilotinib, a leukemia drug, impairs memory and cognitive functions in rats by increasing oxidative stress in the hippocampus. Further research is needed to understand its effects on brain function.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Protein tyrosine kinases (TKs) regulate crucial cellular processes.
- TK inhibitors are vital cancer therapeutics.
- Nilotinib, a TK inhibitor, crosses the blood-brain barrier but its cognitive effects are understudied.
Purpose of the Study:
- To investigate the impact of nilotinib on hippocampal-dependent cognitive functions.
- To explore the underlying mechanisms of nilotinib's effects on memory.
Main Methods:
- Wistar albino male rats were administered nilotinib (15 mg/kg and 30 mg/kg) or water for two weeks.
- Cognitive function was assessed using Y-maze, novel object recognition (NOR), and elevated plus maze (EPM) tests.
- Hippocampal oxidative stress markers and blood glucose were measured.
Main Results:
- Nilotinib treatment significantly impaired memory in behavioral tests (Y-maze, NOR, EPM).
- Elevated levels of glutathione (GSH), malondialdehyde (MDA), Akt, glycogen synthase kinase-3 beta (GSK3β), and total antioxidant capacity (TAC) were observed in hippocampal tissue.
- Blood glucose levels remained unchanged.
Conclusions:
- Nilotinib treatment induces cognitive impairment.
- Oxidative stress in hippocampal tissue is a key mechanism underlying nilotinib's negative effects on cognitive function.
