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Hesperetin ameliorates diabetes-associated anxiety and depression-like behaviors in rats via activating Nrf2/ARE pathway

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Abstract

Diabetes-associated affective disorders are of wide concern, and oxidative stress plays a vital role in the pathological process. This study was to investigate the cerebroprotective effects of hesperetin against anxious and depressive disorders caused by diabetes, exploring the potential mechanisms related to activation of Nrf2/ARE pathway. Streptozotocin-induced diabetic rats were intragastrically administrated with hesperetin (0, 50, and 150 mg/kg) for 10 weeks. Forced swimming test, open field test, and elevated plus maze were used to evaluate the anxiety and depression-like behaviors of rats. The brain was collected for assays of Nrf2/ARE pathway. Moreover, high glucose-cultured SH-SY5Y cells were used to further examine the neuroprotective effects of hesperetin and underlying mechanisms. Hesperetin showed anxiolytic and antidepressant effects in diabetic rats according to the behavior tests, and increased p-Nrf2 in cytoplasm and Nrf2 in nucleus followed by elevations in mRNA levels and protein expression of glyoxalase 1 (Glo-1) and γ-glutamylcysteine synthetase (γ-GCS) in brain, known target genes of Nrf2/ARE signaling. Moreover, hesperetin attenuated high glucose-induced neuronal damages through activation of the classical Nrf2/ARE pathway in SH-SY5Y cells. Further study indicated that PKC inhibition or GSK-3β activation pretreatment attenuated even abolished the effect of hesperetin on the protein expression of Glo-1 and γ-GCS in high glucose-cultured SH-SY5Y cells. In summary, hesperetin ameliorated diabetes-associated anxiety and depression-like behaviors in rats, which was achieved through activation of the Nrf2/ARE pathway. Furthermore, an increase in nuclear Nrf2 phosphorylation from PKC activation and GSK-3β inhibition contributed to the activation of Nrf2/ARE pathway by hesperetin.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

AGEs:

Advanced glycation endproducts

ARE:

Antioxidant response element

EPM:

Elevated plus maze

FST:

Forced swimming test

γ-GCS:

γ-Glutamylcysteine synthetase

Glo-1:

Glyoxalase 1

GSK-3β:

Glycogen synthase kinase-3β

HG:

High glucose

HO-1:

Heme oxygenase 1

Hst:

Hesperetin

LDH:

Lactate dehydrogenase

Nrf2:

Nuclear factor erythroid-2-related factor 2

NG:

Normal glucose

OFT:

Open-field test

PKC:

Protein kinase C

qPCR:

Real-time fluorescence quantitative PCR

RAGE:

Receptor for advanced glycation end-products

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Funding

The work was supported through funding from the National Natural Science Foundation of China (81371210), China.

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Authors and Affiliations

Authors

Contributions

Liu YW: Conceptualization, Project administration, Funding acquisition, Writing-Review & Editing. Zhu X: Investigation, Writing-original draft preparation. Zhang YM: Investigation, Methodology, Visualization. Zhang MY: Investigation, Methodology, Visualization, Data curation. Chen YJ: Resources, Data curation.

Corresponding author

Correspondence to Yao-Wu Liu.

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All the authors declare no conflict of interest.

Ethical approval

The animal experiments were obtained the approval from the Animal Ethics Committee of Xuzhou Medical University. Xuzhou Medical University guidelines for the care and use of animals were followed.

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Zhu, X., Zhang, YM., Zhang, MY. et al. Hesperetin ameliorates diabetes-associated anxiety and depression-like behaviors in rats via activating Nrf2/ARE pathway. Metab Brain Dis 36, 1969–1983 (2021). https://doi.org/10.1007/s11011-021-00785-6

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  • DOI: https://doi.org/10.1007/s11011-021-00785-6

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