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Antioxidative and Anti-inflammatory Effects of Kojic Acid in Aβ-Induced Mouse Model of Alzheimer’s Disease

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Abstract

Alzheimer’s disease (AD) is a common cause of dementia that is clinically characterized by the loss of memory and cognitive functions. Currently, there is no specific cure for the management of AD, although natural compounds are showing promising therapeutic potentials because of their safety and easy availability. Herein, we evaluated the neuroprotective properties of kojic acid (KA) in an AD mouse model. Intracerebroventricular injection (i.c.v) of Aβ1-42 (5 μL/5 min/mouse) into wild-type adult mice induced AD-like pathological changes in the mouse hippocampus by increasing oxidative stress and neuroinflammation, affecting memory and cognitive functions. Interestingly, oral treatment of kojic acid (50 mg/kg/mouse for 3 weeks) reversed the AD pathology by reducing the expression of amyloid-beta (Aβ) and beta-site amyloid precursor protein cleaving enzyme1 (BACE-1). Moreover, kojic acid reduced oxidative stress by enhancing the expression of nuclear factor erythroid-related factor 2 (Nrf2) and heme oxygenase 1 (HO1). Also, kojic acid reduced the lipid peroxidation and reactive oxygen species in the Aβ + kojic acid co-treated mice brains. Moreover, kojic acid decreased neuroinflammation by inhibiting Toll-like receptor 4, phosphorylated nuclear factor-κB, tumor necrosis factor-alpha, interleukin 1-beta (TLR-4, p-NFκB, TNFα, and IL-1β, respectively), and glial cells. Furthermore, kojic acid enhanced synaptic markers (SNAP-23, SYN, and PSD-95) and memory functions in AD model mice. Additionally, kojic acid treatment also decreased Aβ expression, oxidative stress, and neuroinflammation in vitro in HT-22 mouse hippocampal cells. To the best of our knowledge, this is the first study to show the neuroprotective effects of kojic acid against an AD mouse model. Our findings could serve as a favorable and alternative strategy for the discovery of novel drugs to treat AD-related neurodegenerative conditions.

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Data Availability

The authors hereby declare that the generated datasets in this study will be presented upon request from the corresponding author.

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Funding

This research was supported by the Neurological Disorder Research Program of the National Research Foundation (NRF) funded by the Korean Government (MSIT) (2020M3E5D9080660).

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Authors and Affiliations

  1. Division of Applied Life Science (BK 21 Four), College of Natural Sciences, Gyeongsang National University, Jinju, 52828, Republic of Korea

    Amjad Khan, Muhammad Ikram, Sareer Ahmad, Riaz Ahmad, Min Gi Jo & Myeong Ok Kim

  2. Haemato-Oncology/Systems Medicine Group, Paul O’Gorman Leukaemia Research Centre, Institute of Cancer Sciences, MVLS, University of Glasgow, Glasgow, UK

    Tae Ju Park

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  1. Amjad Khan
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Contributions

A.K, T.J.P, I.K, S.A, R.A, and M.G. J designed and conducted the experiments, wrote the manuscript, and performed the statistical analysis. M.O.K. supplied all of the chemicals and supervised and approved the final version of the manuscript. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Myeong Ok Kim.

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All the experiments with animal and other experimental protocols and procedures were approved (Approval ID: 125) by the Ethics Review Committee of the Gyeongsang National University, Republic of Korea.

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Khan, A., Park, T.J., Ikram, M. et al. Antioxidative and Anti-inflammatory Effects of Kojic Acid in Aβ-Induced Mouse Model of Alzheimer’s Disease. Mol Neurobiol 58, 5127–5140 (2021). https://doi.org/10.1007/s12035-021-02460-4

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