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Protective effects of curcumin on desipramine-induced islet β-cell damage via AKAP150/PKA/PP2B complex

Acta Pharmacologica Sinica volume 45, pages 327–338 (2024)Cite this article

Abstract

Tricyclic antidepressants (TCAs) are widely used to treat depression and anxiety-related mood disorders. But evidence shows that TCAs elevate blood glucose levels and inhibit insulin secretion, suggesting that TCAs are a risk factor, particularly for individuals with diabetes. Curcumin is a bioactive molecule from the rhizome of the Curcuma longa plant, which has shown both antidepressant and anti-diabetic activities. In the present study, we investigated the protective effect of curcumin against desipramine-induced apoptosis in β cells and the underlying molecular mechanisms. In the mouse forced swimming test (FST), we found that lower doses of desipramine (5 and 10 mg/kg) or curcumin (2.5 mg/kg) alone did not affect the immobility time, whereas combined treatment with curcumin (2.5 mg/kg) and desipramine (5, 10 mg/kg) significantly decreased the immobility time. Furthermore, desipramine dose-dependently inhibited insulin secretion and elevated blood glucose levels, whereas the combined treatment normalized insulin secretion and blood glucose levels. In RIN-m5F pancreatic β-cells, desipramine (10 μM) significantly reduced the cell viability, whereas desipramine combined with curcumin dose-dependently prevented the desipramine-induced impairment in glucose-induced insulin release, most effectively with curcumin (1 and 10 μM). We demonstrated that desipramine treatment promoted the cleavage and activation of Caspase 3 in RIN-m5F cells. Curcumin treatment inhibited desipramine-induced apoptosis, increased mitochondrial membrane potential and Bcl-2/Bax ratio. Desipramine increased the generation of reactive oxygen species, which was reversed by curcumin treatment. Curcumin also inhibited the translocation of forkhead box protein O1 (FOXO1) from the cytoplasm to the nucleus and suppressed the binding of A-kinase anchor protein 150 (AKAP150) to protein phosphatase 2B (PP2B, known as calcineurin) that was induced by desipramine. These results suggest that curcumin protects RIN-m5F pancreatic β-cells against desipramine-induced apoptosis by inhibiting the phosphoinositide 3-kinase/AKT/FOXO1 pathway and the AKAP150/PKA/PP2B interaction. This study suggests that curcumin may have therapeutic potential as an adjunct to antidepressant treatment.

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Fig. 1: Effects of desipramine and curcumin on immobility time, blood glucose, and serum insulin levels.
Fig. 2: Effects of desipramine and curcumin on cell viability and insulin secretion in RIN-m5F cells.
Fig. 3: Effects of curcumin on desipramine-induced apoptosis in RIN-m5F cells.
Fig. 4: Effects of desipramine and curcumin on PI3K/AKT/ FOXO1 pathway in RIN-m5F cells.
Fig. 5: Effects of desipramine and curcumin on the expression of AKAP150 in RIN-m5F cells.
Fig. 6: Effects of desipramine and curcumin on interaction of AKAP150/PKA/PP2B.
Fig. 7: Schematic illustration of possible mechanisms contributing to curcumin against desipramine-induced apoptosis and insulin secretion impairment.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 92168120, 81974506, 81673486 and 81373405 to Lu Tie, No. 82073878, 81020108031 and 81874318 to Xue-jun Li), and the Beijing Natural Science Foundation (No. Z200019 and 7172119) to Lu Tie.

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  1. These authors contributed equally: Min Hu, Jia-ying Cai, Yao He

Authors and Affiliations

  1. Department of Pharmacology, School of Basic Medical Sciences, Peking University & Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing, 100191, China

    Min Hu, Jia-ying Cai, Yao He, Kui Chen, Feng Hao, Jin-sen Kang, Yan Pan, Lu Tie & Xue-jun Li

  2. Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China

    Jia-ying Cai

  3. Department of Pharmacology, School of Pharmacy, Shihezi University, Shihezi, 832002, China

    Xue-jun Li

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Contributions

The work presented was performed in collaboration by all authors. MH, JYC, and YH designed and performed the experiments, analyzed the data, and wrote the manuscript. KC, FH, JSK, and YP performed the experiments. LT and XJL designed the research and supervised the study. MH, JYC, YH, LT, and XJL revised the concept, designed the research, supervised the study, and wrote the manuscript.

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Correspondence to Lu Tie or Xue-jun Li.

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Hu, M., Cai, Jy., He, Y. et al. Protective effects of curcumin on desipramine-induced islet β-cell damage via AKAP150/PKA/PP2B complex. Acta Pharmacol Sin 45, 327–338 (2024). https://doi.org/10.1038/s41401-023-01176-6

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