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In Vitro and In Vivo Supplementation with Curcumin Promotes Hippocampal Neuronal Synapses Development in Rats by Inhibiting GSK-3β and Activating β-catenin

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Abstract

The human fetal thyroid gland is not capable of producing thyroid hormones independently until 20 weeks of gestation, and if maternal thyroid hormone synthesis is inadequate in early pregnancy, fetal brain and nerve development may be affected by maternal hypothyroidism. Curcumin, which is isolated from turmeric (Curcuma longa), has been shown to be effective in repairing neurological disorders and is effective in relieving nerve damage when consumed over a long period of time. In this experiment, we investigated the effect of curcumin supplementation on synaptic development of rat hippocampal neurons. A cell model of oxidative damage and a young rat model of hypothyroidism were constructed, and model cells and rats were treated with triiodothyronine (T3), tetraiodothyronine (T4), and curcumin, respectively. Damage of nerve cells and animal brain tissues was examined, and the effect of curcumin in alleviating the blocked neurodevelopment was investigated. Further modulation of GSK-3β/β-catenin was performed to investigate the mechanism of action of curcumin. Ultimately, we found that T3-, T4-, and curcumin-treated model cells and young rats had increased numbers of synapses and good neurodevelopment. At the same time, we found that curcumin inhibited the production of GSK-3β and Axin to activate β-catenin. The inhibition of β-catenin weakened the therapeutic effect of curcumin, and the differences between the indicators and the model group disappeared. Both cellular and animal experiments supported that curcumin effectively alleviated the oxidative cell damage caused by thyroxine deficiency and activated the synaptogenic ability of nerve synapses by inhibiting GSK-3β and protecting β-catenin activity.

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Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

References

  1. Liu S, Chen Z (2019) Employing endogenous NSCs to promote recovery of spinal cord injury. Stem cells Int 2019:1958631. https://doi.org/10.1155/2019/1958631

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Tiwari SK, Agarwal S, Seth B, Yadav A, Nair S, Bhatnagar P, Karmakar M, Kumari M et al (2014) Curcumin-loaded nanoparticles potently induce adult neurogenesis and reverse cognitive deficits in Alzheimer’s disease model via canonical Wnt/β-catenin pathway. ACS Nano 8(1):76–103. https://doi.org/10.1021/nn405077y

    Article  CAS  PubMed  Google Scholar 

  3. Kempermann G, Song H, Gage FH (2015) Neurogenesis in the adult hippocampus. Cold Spring Harb Perspect Biol 7(9):a018812. https://doi.org/10.1101/cshperspect.a018812

    Article  PubMed  PubMed Central  Google Scholar 

  4. Daynac M, Morizur L, Chicheportiche A, Mouthon MA, Boussin FD (2016) Age-related neurogenesis decline in the subventricular zone is associated with specific cell cycle regulation changes in activated neural stem cells. Sci Rep 6:21505. https://doi.org/10.1038/srep21505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Corenblum MJ, Ray S, Remley QW, Long M, Harder B, Zhang DD, Barnes CA, Madhavan L (2016) Reduced Nrf2 expression mediates the decline in neural stem cell function during a critical middle-age period. Aging Cell 15(4):725–736. https://doi.org/10.1111/acel.12482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Mishra A, Singh S, Tiwari V, Parul SS (2019) Dopamine D1 receptor activation improves adult hippocampal neurogenesis and exerts anxiolytic and antidepressant-like effect via activation of Wnt/β-catenin pathways in rat model of Parkinson’s disease. Neurochem Int 122:170–186. https://doi.org/10.1016/j.neuint.2018.11.020

    Article  CAS  PubMed  Google Scholar 

  7. Zhao F, Siedlak SL, Torres SL, Xu Q, Tang B, Zhu X (2019) Conditional haploinsufficiency of β-catenin aggravates neuronal damage in a paraquat-based mouse model of Parkinson disease. Mol Neurobiol 56(7):5157–5166. https://doi.org/10.1007/s12035-018-1431-z

    Article  CAS  PubMed  Google Scholar 

  8. Marchetti B, Tirolo C, L’Episcopo F, Caniglia S, Testa N, Smith JA, Pluchino S, Serapide MF (2020) Parkinson’s disease, aging and adult neurogenesis: Wnt/β-catenin signalling as the key to unlock the mystery of endogenous brain repair. Aging Cell 19(3):e13101. https://doi.org/10.1111/acel.13101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. L’Episcopo F, Tirolo C, Peruzzotti-Jametti L, Serapide MF, Testa N, Caniglia S, Balzarotti B, Pluchino S et al (2018) Neural stem cell grafts promote astroglia-driven neurorestoration in the aged parkinsonian brain via Wnt/β-catenin signaling. Stem cells (Dayton, Ohio) 36(8):1179–1197. https://doi.org/10.1002/stem.2827

    Article  CAS  PubMed  Google Scholar 

  10. Kalamakis G, Brüne D, Ravichandran S, Bolz J, Fan W, Ziebell F, Stiehl T, Catalá-Martinez F et al (2019) Quiescence modulates stem cell maintenance and regenerative capacity in the aging brain. Cell 176(6):1407-1419.e1414. https://doi.org/10.1016/j.cell.2019.01.040

    Article  CAS  PubMed  Google Scholar 

  11. Austin SHL, Gabarró-Solanas R, Rigo P, Paun O, Harris L, Guillemot F, Urbán N (2021) Wnt/β-catenin signalling is dispensable for adult neural stem cell homeostasis and activation. Dev Camb Engl 148:20. https://doi.org/10.1242/dev.199629

    Article  CAS  Google Scholar 

  12. Lang H, Xiao R, Li Y, Sun J, Chen Y, Lu Y, Cai J (2020) Linc-FOXD3 knockdown enhances hippocampal NSCs activation through upregulation of the Wnt/β-catenin pathway. Neurosci Lett 729:134991. https://doi.org/10.1016/j.neulet.2020.134991

    Article  CAS  PubMed  Google Scholar 

  13. El Nebrisi E, Javed H, Ojha SK, Oz M, Shehab S (2020) Neuroprotective effect of curcumin on the nigrostriatal pathway in a 6-hydroxydopmine-induced rat model of Parkinson’s disease is mediated by α7-nicotinic receptors. Int J Mol Sci 21:19. https://doi.org/10.3390/ijms21197329

    Article  CAS  Google Scholar 

  14. Abdel-Diam MM, Samak DH, El-Sayed YS, Aleya L, Alarifi S, Alkahtani S (2019) Curcumin and quercetin synergistically attenuate subacute diazinon-induced inflammation and oxidative neurohepatic damage, and acetylcholinesterase inhibition in albino rats. Environ Sci Pollut Res Int 26(4):3659–3665. https://doi.org/10.1007/s11356-018-3907-9

    Article  CAS  PubMed  Google Scholar 

  15. Kheirouri S, Alizadeh M (2019) Dietary inflammatory potential and the risk of neurodegenerative diseases in adults. Epidemiol Rev 41(1):109–120. https://doi.org/10.1093/epirev/mxz005

    Article  PubMed  Google Scholar 

  16. Zia A, Farkhondeh T, Pourbagher-Shahri AM, Samarghandian S (2021) The role of curcumin in aging and senescence: molecular mechanisms. Biomed Pharmacother = Biomedecine Pharmacotherapie 134:111119. https://doi.org/10.1016/j.biopha.2020.111119

    Article  CAS  PubMed  Google Scholar 

  17. Islam F, Khadija JF, Harun-Or-Rashid M, Rahaman MS, Nafady MH, Islam MR, Akter A, Emran TB et al (2022) Bioactive compounds and their derivatives: an insight into prospective phytotherapeutic approach against Alzheimer’s disease. Oxid Med Cell Longev 2022:5100904. https://doi.org/10.1155/2022/5100904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ng TP, Chiam PC, Lee T, Chua HC, Lim L, Kua EH (2006) Curry consumption and cognitive function in the elderly. Am J Epidemiol 164(9):898–906. https://doi.org/10.1093/aje/kwj267

    Article  PubMed  Google Scholar 

  19. Ganguli M, Chandra V, Kamboh MI, Johnston JM, Dodge HH, Thelma BK, Juyal RC, Pandav R et al (2000) Apolipoprotein E polymorphism and Alzheimer disease: the Indo-US Cross-National Dementia Study. Arch Neurol 57(6):824–830. https://doi.org/10.1001/archneur.57.6.824

    Article  CAS  PubMed  Google Scholar 

  20. Li H, Dai Y, Wu H, Luo L, Wei L, Zhou L, Lin Y, Wang Q et al (2020) Predictors of early neurologic deterioration in acute pontine infarction. Stroke 51(2):637–640. https://doi.org/10.1161/strokeaha.119.027239

    Article  PubMed  Google Scholar 

  21. Mei X, Zhu L, Zhou Q, Li X, Chen Z (2020) Interplay of curcumin and its liver metabolism on the level of Aβ in the brain of APP(swe)/PS1(dE9) mice before AD onset. Pharm Rep : PR 72(6):1604–1613. https://doi.org/10.1007/s43440-020-00116-z

    Article  CAS  Google Scholar 

  22. Chakrabarti L, Chaerkady R, Wang J, Weng SHS, Wang C, Qian C, Cazares L, Hess S et al (2022) Mitochondrial membrane potential-enriched CHO host: a novel and powerful tool for improving biomanufacturing capability. mAbs 14(1):2020081. https://doi.org/10.1080/19420862.2021.2020081

  23. Coley AA, Gao WJ (2018) PSD95: a synaptic protein implicated in schizophrenia or autism? Prog Neuropsychopharmacol Biol Psychiatry 82:187–194. https://doi.org/10.1016/j.pnpbp.2017.11.016

    Article  CAS  PubMed  Google Scholar 

  24. Eng L, Lam L (2020) Thyroid function during the fetal and neonatal periods. NeoReviews 21(1):e30–e36. https://doi.org/10.1542/neo.21-1-e30

    Article  PubMed  Google Scholar 

  25. Baksi S, Pradhan A (2021) Thyroid hormone: sex-dependent role in nervous system regulation and disease. Biol Sex Differ 12(1):25. https://doi.org/10.1186/s13293-021-00367-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sue LY, Leung AM (2020) Levothyroxine for the treatment of subclinical hypothyroidism and cardiovascular disease. Front Endocrinol 11:591588. https://doi.org/10.3389/fendo.2020.591588

    Article  Google Scholar 

  27. Shakir MKM, Brooks DI, McAninch EA, Fonseca TL, Mai VQ, Bianco AC, Hoang TD (2021) Comparative effectiveness of levothyroxine, desiccated thyroid extract, and levothyroxine+liothyronine in hypothyroidism. J Clin Endocrinol Metab 106(11):e4400–e4413. https://doi.org/10.1210/clinem/dgab478

    Article  PubMed  PubMed Central  Google Scholar 

  28. Ritter MJ, Gupta S, Hennessey JV (2020) Alternative routes of levothyroxine administration for hypothyroidism. Curr Opin Endocrinol Diabetes Obes 27(5):318–322. https://doi.org/10.1097/med.0000000000000558

    Article  CAS  PubMed  Google Scholar 

  29. Woźniak D, Drzymała S, Przysławski J, Drzymała-Czyż S (2021) Dietary supplements in hypothyroidism. Acta Sci Polonorum Technologia Alimentaria 20(4):375–381. https://doi.org/10.17306/j.Afs.0985

  30. Tao YX, Li Q, Li CC, Huo JJ (2023) Efficacy of Chinese medicine in the adjuvant treatment of Hashimoto’s thyroiditis with hypothyroidism: a systematic review and meta-analysis. Biotechnol Genet Eng Rev 1–27. https://doi.org/10.1080/02648725.2023.2184959

  31. Barakat-Walter I, Kraftsik R (2018) Stimulating effect of thyroid hormones in peripheral nerve regeneration: research history and future direction toward clinical therapy. Neural Regen Res 13(4):599–608. https://doi.org/10.4103/1673-5374.230274

  32. Yavarpour-Bali H, Ghasemi-Kasman M, Pirzadeh M (2019) Curcumin-loaded nanoparticles: a novel therapeutic strategy in treatment of central nervous system disorders. Int J Nanomed 14:4449–4460. https://doi.org/10.2147/ijn.S208332

    Article  CAS  Google Scholar 

  33. Mohammadi A, Hosseinzadeh Colagar A, Khorshidian A, Amini SM (2022) The functional roles of curcumin on astrocytes in neurodegenerative diseases. NeuroImmunoModulation 29(1):4–14. https://doi.org/10.1159/000517901

    Article  CAS  PubMed  Google Scholar 

  34. Papiez MA, Kaja M, Gebarowska A (2008) Age-dependent different action of curcumin in thyroid of rat. Folia Histochem Cytobiol 46(2):205–211. https://doi.org/10.2478/v10042-008-0031-6

    Article  CAS  PubMed  Google Scholar 

  35. Jiang Y, Liu Y, Sun Y, Liu Y, Feng L, Duan M, Liu Y, Xu L (2022) Sevoflurane induces microRNA-18a to delay rat neurodevelopment via suppression of the RUNX1/Wnt/β-catenin axis. Cell Death Discov 8(1):404. https://doi.org/10.1038/s41420-022-01179-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Narvaes RF, Furini CRG (2022) Role of Wnt signaling in synaptic plasticity and memory. Neurobiol Learn Mem 187:107558. https://doi.org/10.1016/j.nlm.2021.107558

    Article  CAS  PubMed  Google Scholar 

  37. Nelson KM, Dahlin JL, Bisson J, Graham J, Pauli GF, Walters MA (2017) The essential medicinal chemistry of curcumin. J Med Chem 60(5):1620–1637. https://doi.org/10.1021/acs.jmedchem.6b00975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Jin T, Zhang Y, Botchway BOA, Zhang J, Fan R, Zhang Y, Liu X (2022) Curcumin can improve Parkinson’s disease via activating BDNF/PI3k/Akt signaling pathways. Food Chem Toxicol : Int J Published Br Ind Biol Res Assoc 164:113091. https://doi.org/10.1016/j.fct.2022.113091

    Article  CAS  Google Scholar 

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Funding

This work was supported by the “Famous Doctor” Special Project of the Ten Thousand People Program of Yunnan Province (No. YNWR-MY-2018–016); Co-operation Fund of Kunming Medical University and the Science and Technology Department of Yunnan Province (No. 202101AY070001-262); Open Fund of Yunnan Provincial Key Laboratory for Birth Defects and Genetic Diseases (No. 2020ZDKFKT001); Open Project of Yunnan Provincial Reproductive and Obstetrics and Gynecology Clinical Medicine Center (No. 2022LCZXKF-SZ02); Famous Doctor Project of Xingdian Talent Plan in Yunnan Province (No. XDYC- MY-2022-0005); Co-operation Fund of Kunming Medical University and the Science and Technology Department of Yunnan Province (No. 202201AY070001-232); and Top Experts Training Project for the Academy and Technology in Yunnan Province (No. 202105AC160030).

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Author notes

  1. Yinhong Zhang, Jinghui Yang, and Yanling Gong contributed equally to this work and should be considered equal first coauthors.

Authors and Affiliations

  1. Faculty of Life Science and Biotechnology, Kunming University of Science and Technology, Kunming, 650500, China

    Yinhong Zhang & Li Li

  2. Department of Medical Genetics, NHC Key Laboratory of Preconception Health Birth in Western China, Yunnan Provincial Key Laboratory for Birth Defects and Genetic Diseases, Yunnan Provincial Clinical Research Center for Birth Defects and Rare Diseases, The Affiliated Hospital of Kunming University of Science and Technology, The First People’s Hospital of Yunnan Province, Kunming, 650032, China

    Yinhong Zhang, Jing He & Baosheng Zhu

  3. School of Medicine, Kunming University of Science and Technology, Kunming, 650500, China

    Yinhong Zhang, Yanling Gong & Li Li

  4. Department of Pediatrics, The Affiliated Hospital of Kunming University of Science and Technology, The First People’s Hospital of Yunnan Province, Kunming, 650032, China

    Jinghui Yang, Shan He, Ping Wen & Li Li

  5. Department of Prevention and Healthcare, The Affiliated Hospital of Kunming University of Science and Technology, The First People’s Hospital of Yunnan Province, Kunming, 650032, China

    Yan Jiang

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  1. Yinhong Zhang
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Contributions

All authors contributed to the study conception and design. Material preparation and the first draft of the manuscript were performed by Y. Z., J. Y., and Y. G. Data collection and analysis were performed by S. H. and P. W. The language of the paper was revised by Y. J. and J. H. The manuscript was revised by B. Z. and L. L. All authors approved the final manuscript.

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Correspondence to Baosheng Zhu or Li Li.

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Highlights

• Curcumin repairs nerve damage.

• Inhibition of GSK-3β and Axin production by curcumin leads to activation of β-actin.

• Curcumin alleviates nerve damage caused by thyroxine deficiency.

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Zhang, Y., Yang, J., Gong, Y. et al. In Vitro and In Vivo Supplementation with Curcumin Promotes Hippocampal Neuronal Synapses Development in Rats by Inhibiting GSK-3β and Activating β-catenin. Mol Neurobiol 61, 2390–2410 (2024). https://doi.org/10.1007/s12035-023-03665-5

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