Daidzein improves neuronal health and alleviates inflammation and apoptosis through BDNF and estrogen receptors in the hippocampus of ovariectomized rats

Document Type : Original Article

Authors

1 Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

2 Research committee, endocrine and metabolism research center, Shiraz University of Medical Sciences, Shiraz, Iran

3 Reproductive Biology Department, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran

4 Autophagy Research Center, Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

5 School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia

6 Infertility Research Centre, Shiraz University of Medical Sciences, Shiraz, Iran

10.22038/ijbms.2025.82074.17758

Abstract

Objective(s): Isoflavone Daidzein (DDZ) has emerged as a promising alternative to hormone replacement therapy (HRT) for ameliorating estrogen deficiency (ED). However, the stereological and molecular mechanism of its effects in the OVX-hippocampus are unclear. We studied the impact of DDZ on stereological changes, estrogen receptor (ERs) expression, BDNF, GSK-3β, and inflammatory and apoptosis-related genes in the hippocampus of ovariectomized rats, compared to 17β-estradiol (E2).
Materials and Methods: OVX rats were treated with DDZ or E2. The stereological analysis assessed the total volume and number of pyramidal and granular neurons in the hippocampus CA1 and DG subregions. Expression of proinflammatory cytokines, apoptotic-related genes, ERs, and BDNF genes was evaluated using Real-Time PCR, and the GSK-3β phosphorylation level was measured by western blot analysis.
Results: DDZ has effectively increased the volume and total number of pyramidal neurons in the CA1 region, the expression of ERα, ERβ, BDNF, and Bcl-2 genes, and the phosphorylation rate of GSK-3β protein. However, the effect of DDZ on the DG region, ERα, and BDNF genes was not significant in comparison with E2; DDZ significantly suppressed the expression of TNF-α, IL-6, and the Bax/Bcl2 ratio compared with OVX rats.
Conclusion: DDZ effectively reversed the stereological changes in the CA1 region by stimulating BDNF gene expression, increasing the phosphorylation ratio of the GSK-3β protein, and modulating inflammatory and apoptotic pathways. Although its effects on the DG region, BDNF, and ERα molecules were less significant than E2, DDZ could still be a promising candidate for ameliorating ED.

Keywords

Main Subjects

References

1. Torromino G, Maggi A, De Leonibus E. Estrogen-dependent hippocampal wiring as a risk factor for age-related dementia in women. Prog Neurobiol 2021; 197:101895.
2. Alkadhi KA. Cellular and molecular differences between area CA1 and the dentate gyrus of the hippocampus. Mol Neurobiol 2019; 56: 6566-6580.
3. Iqbal J, Tan Z-N, Li M-X, Chen H-B, Ma B, Zhou X, et al. Estradiol alters hippocampal gene expression during the estrous cycle. Endocr Res 2020; 45: 84-101.
4. Duff MC, Covington NV, Hilverman C, Cohen NJ. Semantic memory and the hippocampus: Revisiting, reaffirming, and extending the reach of their critical relationship. Front Neurol 2020; 13: 471-488.
5. Banker SM, Gu X, Schiller D, Foss-Feig JH. Hippocampal contributions to social and cognitive deficits in autism spectrum disorder. Trends Neurosci 2021; 44: 793-807.
6. Tanapat P, Hastings NB, Reeves AJ, Gould E. Estrogen stimulates a transient increase in the number of new neurons in the dentate gyrus of the adult female rat. Neurosci J 1999; 19: 5792-5801.
7. Jover T, Tanaka H, Calderone A, Oguro K, Bennett MV, Etgen AM, et al. Estrogen protects against global ischemia-induced neuronal death and prevents activation of apoptotic signaling cascades in the hippocampal CA1. Neurosci J 2002; 22: 2115-2124.
8. Woolley CS, McEwen BS. Estradiol mediates fluctuation in hippocampal synapse density during the estrous cycle in the adult rat. J Neurosci 1992; 12: 2549-2554.
9. Luine V, Frankfurt M. Interactions between estradiol, BDNF and dendritic spines in promoting memory. Neuroscience 2013; 239: 34-45.
10. Hattiangady B, Rao MS, Shetty GA, Shetty AK. Brain-derived neurotrophic factor, phosphorylated cyclic AMP response element binding protein, and neuropeptide Y decline as early as middle age in the dentate gyrus and CA1 and CA3 subfields of the hippocampus. Exp Neurol 2005; 195: 353-371.
11. Sohrabji F, Lewis DK. Estrogen-BDNF interactions: Implications for neurodegenerative diseases. Front Neurol 2006; 27: 404-414.
12. Stambolic V, Ruel L, Woodgett JR. Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells. Curr Biol 1996; 6: 1664-1669.
13. Yu Y, Feng L, Li J, Lan X, A L, Lv X, et al. The alteration of autophagy and apoptosis in the hippocampus of rats with natural aging-dependent cognitive deficits. Behav Brain Res 2017; 334: 155-162.
14. Park JH, Lee JE, Shin IC, Koh HC. Autophagy regulates chlorpyrifos-induced apoptosis in SH-SY5Y cells. Toxicol Appl Pharmacol 2013; 268: 55-67.
15. Hidalgo RB, Barnett SD, Davidson JR. Social anxiety disorder in review: two decades of progress. Int J Neuropsychopharmacol 2001; 4: 279-298.
16. Fang YY, Zeng P, Qu N, Ning LN, Chu J, Zhang T, et al. Evidence of altered depression and dementia‐related proteins in the brains of young rats after ovariectomy. J Neurochem 2018; 146: 703-721.
17. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results From the Women’s Health initiative randomized controlled trial. JAMA 2002; 288: 321-333.
18. Sjögren LL, Mørch LS, Løkkegaard E. Hormone replacement therapy and the risk of endometrial cancer: A systematic review. Maturitas 2016; 91: 25-35.
19. Luo D, Kang L, Ma Y, Chen H, Kuang H, Huang Q, et al. Effects and mechanisms of 8-prenylnaringenin on osteoblast MC3T3-E1 and osteoclast-like cells RAW264.7. Food Sci Nutr 2014; 2: 341-350.
20. Cao YK, Zhang SF, Zou SE, Xia X. Daidzein improves insulin resistance in ovariectomized rats. Climacteric 2012; 16: 111-116.
21. Anupongsanugool E, Teekachunhatean S, Rojanasthien N, Pongsatha S, Sangdee C. Pharmacokinetics of isoflavones, daidzein and genistein, after ingestion of soy beverage compared with soy extract capsules in postmenopausal Thai women. BMC Clin Pharmacol 2005; 5: 2-12.
22. Zhao L, Mao Z, Brinton RD. A select combination of clinically relevant phytoestrogens enhances estrogen receptor β-binding selectivity and neuroprotective activities in vitro and in vivo. Endocrinology 2009; 150: 770-783.
23. Wang P, Jeng C-J, Chien C-L, Wang S-M. Signaling mechanisms of daidzein-induced axonal outgrowth in hippocampal neurons. Biochem Biophys Res Commun 2008; 366: 393-400.
24. Wei J, Yang F, Gong C, Shi X, Wang G. Protective effect of daidzein against streptozotocin‐induced Alzheimer’s disease via improving cognitive dysfunction and oxidative stress in rat model. J Biochem Mol Toxicol 2019; 33: e22319.
25. Martínez-Montemayor MM, Otero-Franqui E, Martinez J, De La Mota-Peynado A, Cubano LA, Dharmawardhane S. Individual and combined soy isoflavones exert differential effects on metastatic cancer progression. Clin Exp Metastasis 2010; 27: 465-480.
26. Mohammad-Shahi M, Haidari F, Rashidi B, Saei AA, Mahboob S, Rashidi MR. Comparison of the effects of genistein and daidzein with dexamethasone and soy protein on rheumatoid arthritis in rats. Bioimpacts 2011; 1: 161-170.
27. Vakili S, Zal F, Mostafavi-Pour Z, Savardashtaki A, Koohpeyma F. Quercetin and vitamin E alleviate ovariectomy-induced osteoporosis by modulating autophagy and apoptosis in rat bone cells. J Cell Physiol 2021; 236: 3495-3509.
28. Yang Y, Zheng X, Li B, Jiang S, Jiang L. Increased activity of osteocyte autophagy in ovariectomized rats and its correlation with oxidative stress status and bone loss. Biochem Biophys Res Commun 2014; 451: 86-92.
29. Mohammadshahi M, Haidari F, Saei AA, Rashidi B, Mahboob S, Rashidi M-R. Soy protein, genistein, and daidzein improve serum paraoxonase activity and lipid profiles in rheumatoid arthritis in rats. J Med Food 2013; 16: 147-154.
30. Maghool F, Khaksari M. Differences in brain edema and intracranial pressure following traumatic brain injury across the estrous cycle: Involvement of female sex steroid hormones. Brain Res 2013; 1497: 61-72.
31. Neisy A, Zal F, Seghatoleslam A, Alaee S. Amelioration by quercetin of insulin resistance and uterine GLUT4 and ERα gene expression in rats with polycystic ovary syndrome (PCOS). Reprod Fertil Dev 2019; 31: 315-323.
32. Kim YH, Lee YJ. TRAIL apoptosis is enhanced by quercetin through Akt dephosphorylation. J Cell Biochem 2007; 100: 998-1009.
33. Neisy A, Koohpeyma F, Khorchani MJ, Karimi F, Zal F. Quercetin modulates ovarian autophagy–related molecules and stereological parameters in a rat model of PCOS. Asian Pac J Trop Biomed 2023; 13: 9-16.
34. Bas O, Odaci E, Mollaoglu H, Ucok K, Kaplan S. Chronic prenatal exposure to the 900 megahertz electromagnetic field induces pyramidal cell loss in the hippocampus of newborn rats. Toxicol Ind Health 2009; 25: 377-384.
35. Noorafshan A, Karimi F, Kamali A-M, Karbalay-Doust S, Nami M. Restorative effects of curcumin on sleep-deprivation induced memory impairments and structural changes of the hippocampus in a rat model. Life Sci 2017; 189: 63-70.
36. Hall JM, Couse JF, Korach KS. The multifaceted mechanisms of estradiol and estrogen receptor signaling. J Biol Chem 2001; 276: 36869-36872.
37. Jefferson WN, Couse JF, Padilla-Banks E, Korach KS, Newbold RR. Neonatal exposure to genistein induces estrogen receptor (ER) α expression and multioocyte follicles in the maturing mouse ovary: Evidence for ERβ-mediated and nonestrogenic actions. Biol Reprod 2002; 67: 1285-1296.
38. Takashima-Sasaki K, Komiyama M, Adachi T, Sakurai K, Kato H, Iguchi T, et al. Effect of exposure to high isoflavone-containing diets on prenatal and postnatal offspring mice. Biosci Biotechnol Biochem 2006; 70: 2874-2882.
39. MacLusky NJ, Thomas G, Leranth C. Low dietary soy isoflavonoids increase hippocampal spine synapse density in ovariectomized rats. Brain Res 2017; 1657: 361-367.
40. Luine V, Attalla S, Mohan G, Costa A, Frankfurt M. Dietary phytoestrogens enhance spatial memory and spine density in the hippocampus and prefrontal cortex of ovariectomized rats. Brain Res 2006; 1126: 183-187.
41. Abd Ellatif RA. The effect of Panax Ginseng on dentate gyrus of ovariectomized albino rats. Histological and Immunohistochemical study. Zagazig Univ Med J 2024; 30: 163-175.
42. Dudek SM, Alexander GM, Farris S. Rediscovering area CA2: Unique properties and functions. Nat Rev Neurosci 2016; 17: 89-102.
43. Blurton‐Jones M, Kuan P, Tuszynski M. Anatomical evidence for transsynaptic influences of estrogen on brain‐derived neurotrophic factor expression. J Comp Neurol 2004; 468: 347-360.
44. Shughrue PJ, Lane MV, Merchenthaler I. Comparative distribution of estrogen receptor-α and -β mRNA in the rat central nervous system. J Comp Neurol 1997; 388: 507-525.
45. Yang L-c, Zhang Q-G, Zhou C-f, Yang F, Zhang Y-d, Wang R-m, et al. Extranuclear estrogen receptors mediate the neuroprotective effects of estrogen in the rat hippocampus. PloS One 2010; 5: e9851-9864.
46. Erickson KI, Miller DL, Roecklein KA. The aging hippocampus: Interactions between exercise, depression, and BDNF. Neuroscientist 2012; 18: 82-97.
47. Tolwani RJ, Buckmaster PS, Varma S, Cosgaya JM, Wu Y, Suri C, et al. BDNF overexpression increases dendrite complexity in hippocampal dentate gyrus. Neuroscience 2002; 114: 795-805.
48. Pan M, Han H, Zhong C, Geng Q. Effects of genistein and daidzein on hippocampus neuronal cell proliferation and BDNF expression in H19-7 neural cell line. J Nutr Health Aging 2012; 16: 389-394.
49. Pan M, Li Z, Yeung V, Xu R-J. Dietary supplementation of soy germ phytoestrogens or estradiol improves spatial memory performance and increases gene expression of BDNF, TrkB receptor and synaptic factors in ovariectomized rats. Nutr Metab 2010; 7: 1-11.
50. Colucci-D’Amato L, Speranza L, Volpicelli F. Neurotrophic factor BDNF, physiological functions and therapeutic potential in depression, neurodegeneration and brain cancer. Int J Mol Sci 2020; 21: 7777-7806.
51. Laddha AP, Kulkarni YA. Daidzein attenuates kidney damage in diabetic rats. FASEB J 2020; 34: 1-1.
52. Wine RN, McPherson CA, Harry GJ. IGF-1 and pAKT signaling promote hippocampal CA1 neuronal survival following injury to dentate granule cells. Neurotox Res 2009; 16: 280-292.
53. Semmler A, Okulla T, Sastre M, Dumitrescu-Ozimek L, Heneka MT. Systemic inflammation induces apoptosis with variable vulnerability of different brain regions. J Chem Neuroanat 2005; 30: 144-157.
54. Benedusi V, Meda C, Della Torre S, Monteleone G, Vegeto E, Maggi A. A lack of ovarian function increases neuroinflammation in aged mice. Endocrinology 2012; 153: 2777-2788.
55. Mao Z, Zheng Y-l, Zhang Y-q, Han B-p, Zhu X-w, Chang Q, et al. The anti-apoptosis effects of daidzein in the brain of D-galactose treated mice. Molecules 2007; 12: 1455-1470.
56. Besing RC, Paul JR, Hablitz LM, Rogers CO, Johnson RL, Young ME, et al. Circadian rhythmicity of active GSK3 isoforms modulates molecular clock gene rhythms in the suprachiasmatic nucleus. J Biol Rhythms 2015; 30: 155-160.
57. Liu H, Yang L, Zhao Y, Zeng G, Wu Y, Chen Y, et al. Estrogen is a novel regulator of Tnfaip1 in mouse hippocampus. Int J Mol Med 2014; 34: 219-227.
58. Napolitano M, Costa L, Piacentini R, Grassi C, Lanzone A, Gulino A. 17β-estradiol protects cerebellar granule cells against β-amyloid-induced toxicity via the apoptotic mitochondrial pathway. Neurosci Lett 2014; 561: 134-139.
59. Cheema ZF, Santillano DR, Wade SB, Newman JM, Miranda RC. The extracellular matrix, p53, and estrogen compete to regulate cell-surface Fas/Apo-1 suicide receptor expression in proliferating embryonic cerebral cortical precursors, and reciprocally, Fas-ligand modifies estrogen control of cell-cycle proteins. BMC Neurosci 2004; 5: 1-21.
60. Litwa E, Rzemieniec J, Wnuk A, Lason W, Krzeptowski W, Kajta M. Apoptotic and neurotoxic actions of 4-para-nonylphenol are accompanied by activation of retinoid X receptor and impairment of classical estrogen receptor signaling. J Steroid Biochem Mol Biol 2014; 144: 334-347.
Iranian Journal of Basic Medical Sciences
Volume 28, Issue 7
July 2025
Pages 888-898

Files

Share

How to cite

Statistics