Effect of thymol on oxidative stress and reelin signaling pathway in Alzheimer's disease model

Alzheimer's disease (AD), the primary cause of dementia and the fifth leading cause of global mortality, affects 45 million people worldwide.Neurodegeneration in AD is characterized by abnormal accumulation of Aβ plaques, neuritic plaques, neurofibrillary tangles, and synaptic abnormalities (Hampel et al., 2021;Peng et al., 2022).D-galactose (D-gal), a six-carbon monosaccharide found in hemicellulose, pectins, and gums, is often used as a model for studying AD mechanisms and potential treatments (Gao et al., 2016;Chroumpi et al., 2022).Abnormal D-gal metabolism leads to reactive oxygen species (ROS) production and oxidative stress, causing inflammatory aging (Gao et al., 2016).Aluminum, a heavy metal with cholinotoxic properties, contributes to neurodegenerative disorders, including cognitive dysfunction, neurodegeneration, and apoptotic neuronal loss (Huat et al., 2019).Prolonged exposure to aluminum impairs learning ability in mice and causes neurodegenerative changes in the hippocampus, spinal cord, and cerebral cortex (Liaquat et al., 2019;Chen et al., 2021).ApoE is responsible for cholesterol transport in the brain.There are three common isoforms in humans, ApoE2, ApoE3, and ApoE4 (Knopman et al., 2021).Heterozygous carriers of the ε4 allele of the gene encoding ApoE are four times more likely to develop Alzheimer's disease (Vecchio et al., 2022).ApoE4 increases betaamyloid aggregation, contributing to neurofibrillary tangle formation and the pathogenesis of AD through processes such as neuroinflammation and synaptic loss (Mamun et al., 2020).Reelin, a 450 kDa extracellular glycoprotein, is crucial for brain development and maturation.It is produced by Cajal-Retzius neurons and regulates neuronal migration.In adult neurons, it controls synaptic activity, improves memory and learning abilities, and exhibits Background/aim: The purpose of this study was to investigate how thymol affects cognitive functions and the levels of MDA, GSH, Aβ 1-42 , ApoE, reelin, and LRP8 in an AD model induced in male Wistar albino rats with the application of D-galactose (D-gal) and aluminum chloride (AlCl 3 ).Materials and methods: In this work, 3-month-old male Wistar albino rats were used.Group 1 served as the Control, Group 2 received 0.5 mL/day saline + 0.5 mL/day sunflower oil, Group 3 was administered 200 mg/kg/day AlCl 3 + 60 mg/kg/day D-gal, Group 4 received 30 mg/kg/day thymol, and Group 5 was administered 200 mg/kg/day AlCl 3 + 60 mg/kg/day D-gal + 30 mg/kg/day thymol.At the end of the 10-week experimental period, behavioral and memory tests were performed.GSH and MDA levels were measured in the obtained serum and brain tissue samples, while Aβ 1-42 , ApoE, reelin, and LRP8 levels were measured in brain tissue samples.Statistical analyses were performed using ANOVA test in Graphpad Prism V8.3 program.A p-value <0.05 was considered significant in intergroup analyses.Results: When the novel object recognition test (NORT) results were evaluated, the Alzheimer + thymol (ALZ+TYM) group showed a significant increase in the recognition index (RI) and discrimination index (DI) compared to the Alzheimer (ALZ) group at the 24th hour.Thymol reduced working memory errors (WME), reference memory errors (RME), and maze completion time at 48, 72, and 96 hours when evaluated in terms of spatial memory in rats with Alzheimer's disease.Furthermore, Aβ 1-42 and ApoE levels were increased in the ALZ group compared to the control (C), while reelin and LRP8 levels were decreased in the ALZ group compared to the C group. Conclusion:The data we obtained suggest that thymol may play an effective role in cognitive processes against AD and have an anti-Alzheimer's disease effect.