Effects of genistein and swimming exercise on spatial memory and expression of microRNA 132, BDNF, and IGF-1 genes in the hippocampus of ovariectomized rats

Document Type: Original Article


1 Neuroscience Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

2 Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran


Objective(s): The aim of the present study was to investigate the effects of genistein and exercise on the spatial memory and expression of microRNA-132, BDNF, and IGF-1 in the hippocampus of ovariectomized rats.
Materials and Methods: Sixty animals were divided into six groups of control, sham, ovariectomy (OVX), ovariectomized with 8 weeks of genistein administration (OVX.G), with 8 weeks of swimming training (OVX.E), and with 8 weeks of both of them (OVX.G.E). The effect of genistein and/or exercise was evaluated by measuring microRNA-132, BDNF, and IGF-1 expression levels in the hippocampus tissue. Grafts were analyzed using Real-time polymerase chain reaction for microRNA-132, BDNF, IGF-1, and spatial memory via a Morris water maze (MWM).
 Results: Our findings showed that ovariectomy decreased the expression of microRNA-132, BDNF, and IGF-1 in the hippocampus (P<0.05) in comparison with the sham group as well as performance in the water maze (P<0.05). Also according to results ovariectomized groups that were treated with genistein/exercise or both of them showed significant difference in expression of microRNA-132, BDNF, and IGF-1 in the hippocampus (P<0.05) and decreased latency in MWM (P<0.05) compared with the OVX group but combination treatment was more effective in the OVX.G.E group in comparison with OVX.E and OVX.G groups. 
Conclusion: Overall our results emphasized that combination treatment with genistein and exercise could improve microRNA-132, BDNF, and IGF-1 expression in the hippocampus as well as the spatial memory of ovariectomized rats. These effects may have beneficial impacts on the menopausal period.


1. Henderson VW. Cognitive changes after menopause: influence of estrogen. Clin Obstet Gynecol 2008; 51:618-626.

2. Shuster LT, Rhodes DJ, Gostout BS, Grossardt BR, Rocca WA. Premature menopause or early menopause: long-term health consequences. Maturitas 2010; 65:161-166.

3. Lovekamp-Swan T, Glendenning ML, Schreihofer DA. A high soy diet enhances neurotropin receptor and Bcl-X L gene expression in the brains of ovariectomized female rats. Brain Res 2007; 1159:54-66.

4. Gasbarri A, Tomaz C. Estrogen influences on cognition: INTECH Open Access Publisher; 2012.

5. Park H, Poo MM. Neurotrophin regulation of neural circuit development and function. Nat Rev Neurosci 2013; 14:7-23.

6. Sohrabji F, Lewis DK. Estrogen–BDNF interactions: implications for neurodegenerative diseases. Front Neuroendocrinol 2006; 27:404-414.

7. Scharfman HE, Mercurio TC, Goodman JH, Wilson MA, MacLusky NJ. Hippocampal excitability increases during the estrous cycle in the rat: a potential role for brain-derived neurotrophic factor. J Neurosci 2003; 23:11641-11652.

8. Saadati H, Sheibani V, Esmaeili-Mahani S, Darvishzadeh-Mahani F, Mazhari S. Prior regular exercise reverses the decreased effects of sleep deprivation on brain-derived neurotrophic factor levels in the hippocampus of ovariectomized female rats. Regul Pept 2014;194:11-15.

9. Grönbladh A, Johansson J, Nöstl A, Nyberg F, Hallberg M. GH improves spatial memory and reverses certain anabolic androgenic steroid-induced effects in intact rats. J Endocrinol 2013; 216:31-41.

10. Deak F, Sonntag WE. Aging, synaptic dysfunction, and insulin-like growth factor (IGF)-1.  J Gerontol A Biol Sci Med Sci 2012; 67:611-625.

11. Wang RY, Phang RZ, Hsu PH, Wang WH, Huang HT, Liu IY. In vivo knockdown of hippocampal miR‐132 expression impairs memory acquisition of trace fear conditioning. Hippocampus 2013; 23:625-633.

12. Yi LT, Li J, Liu B-B, Luo L, Liu Q, Geng D. BDNF–ERK–CREB signalling mediates the role of miR-132 in the regulation of the effects of oleanolic acid in male mice. J Psychiatry Neurosci 2014; 39:348.

13. Klinge CM. Estrogen regulation of microRNA expression. Curr Genomics 2009; 10:169-183.

14. Lu J, Xu Y, Hu W, Gao Y, Ni X, Sheng H, et al. Exercise ameliorates depression-like behavior and increases hippocampal BDNF level in ovariectomized rats. Neurosci Lett 2014; 573:13-18.

15. Cetinkaya C, Sisman AR, Kiray M, Camsari UM, Gencoglu C, Baykara B, et al. Positive effects of aerobic exercise on learning and memory functioning, which correlate with hippocampal IGF-1 increase in adolescent rats. Neurosci Lett 2013; 549:177-181.

16. Peng Y, Jiang B, Wu H, Dai R, Tan L. Effects of genistein on neuronal apoptosis, and expression of Bcl-2 and Bax proteins in the hippocampus of ovariectomized rats. Neural Regen Res 2012; 7:2874–2881.

17. Habibi P, Alihemmatti A, Alipour M, Nourazar A, Yousefi H, Andalib S, et al. Effects of exercise on mir-29 and igf-1 expression and lipid profile in the heart of ovariectomized rat. ACTA ENDOCRINOLOGICA-BUCHAREST. 2016; 12:130-136. 

18. DA Silva ND Jr, Fernandes T, Soci U, Monteiro A, Phillips MI, DE Oliveira EM. Swimming training in rats increases cardiac MicroRNA-126 expression and angiogenesis. Med Sci Sports Exerc 2012; 44:1453-1462.

19. Habibi P, Alihemmati A, Nasirzadeh M, Yousefi H, Habibi M, Ahmadiasl N. Involvement of microRNA-133 and-29 in cardiac disturbances in diabetic ovariectomized rats. Iran J Basic Med Sci 2016; 19:1177–1185.

20. Hashemi Nosrat Abadi T, Vaghef L, Babri S, Mahmood-Alilo M, Beirami M. Effects of different exercise protocols on ethanol-induced spatial memory impairment in adult male rats. Alcohol 2013; 47:309-316.

21. M Ardekani A, Moslemi Naeini M. The role of microRNAs in human diseases. Avicenna J Med Biotechnol 2011; 2:161-180.

22. Li Y, Lin L, Jin P. The microRNA pathway and fragile X mental retardation protein. Biochim Biophys Acta  2008; 1779:702-705.

23. Li Y, Kannan G, Pletnikov MV, Yolken RH, Xiao J. Chronic infection of Toxoplasma gondii downregulates miR-132 expression in multiple brain regions in a sex-dependent manner. Parasitology 2015; 142:623-632.

24. Murray PS, Holmes PV. An overview of brain-derived neurotrophic factor and implications for excitotoxic vulnerability in the hippocampus. Int J Pept 2011; 2011:12.

25. MOROVIĆ S, Demarin V. Role of physical activity on human brain functions. Period Biol 2014; 116:219-221.

26. Numakawa T, Yamamoto N, Chiba S, Richards M, Ooshima Y, Kishi S, et al. Growth factors stimulate expression of neuronal and glial miR-132. Neurosci Lett 2011; 505:242-247.

27. Yaffe K, Sawaya G, Lieberburg I, Grady D. Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. JAMA 1998; 279:688-695.

28. Kim TW, Kim CS, Kim JY, Kim CJ, Seo JH. Combined exercise ameliorates ovariectomy-induced cognitive impairment by enhancing cell proliferation and suppressing apoptosis. Menopause 2016; 23:18-26.

29. Cotman CW, Berchtold NC. Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci 2002; 25:295-301.

30. Lee J, Cho HS, Kim DY, Cho JY, Chung JS, Lee HK, et al. Combined effects of exercise and soy isoflavone diet on paraoxonase, nitric oxide and aortic apoptosis in ovariectomized rats. Appetite 2012; 58:462-469.

31. Riesco E, Aubertin-Leheudre M, Maltais ML, Audet M, Dionne IJ. Synergic effect of phytoestrogens and exercise training on cardiovascular risk profile in exercise-responder postmenopausal women: a pilot study. Menopause 2010; 17:1035-1039.