Estrogen agonist genistein differentially influences the cognitive and motor disorders in an ovariectomized animal model of Parkinsonism

Document Type: Original Article

Authors

Physiology Research Center, Kashan University of Medical Sciences, Kashan, Iran

Abstract

Objective(s): Parkinson's disease (PD) is a progressive neurological disorder associated with motor disabilities and cognitive dysfunction as well. Evidence indicates that PD occurs less frequently in women than men, confirming a role for steroid hormones in protection of dopaminergic nigrostriatal neurons. It is reported that soy genistein, an estrogen agonist phytoestrogen, display neuroprotective effects against neuronal death. In this study we evaluated the effect of genistein in animal models of Parkinsonism (P) and Parkinsonism + ovariectomized (OP).
Materials and Methods: The experiments were carried out on the control, P and OP animals. Learning and memory abilities were evaluated using Morris water maze. The latency and speed of locating the platform were measured as cognitive indices. Motor behaviors were assessed by testing the animals in rota rod and the latency to fall from the rod was scored.
Results: We found that Parkinsonism leads to the cognitive and motor disabilities; ovariectomy intensified these disorders. Whereas genistein treatment improved the maze performances in both P and OP animals it failed to influence the kinetic problems. Genistein displayed a neuroprotective effect on dopaminergic neurons.
Conclusion: Positive impact of genistein on the spatial learning and memory may reflect its effects on the nigrostriatal pathway and striatum. Nevertheless, ineffectiveness of genistein on the motor disorders, despite its neuroprotective impacts, led us to conclude that the cognitive improvement by genistein may also contribute to its effects in other areas of brain.

Keywords


1.Galvan A, Wichmann T. Pathophysiology of parkinsonism. Clin Neurophysiol 2008;119: 1459-1474.

2. Skaper SD. The brain as a target for inflammatory processes and neuroprotective strategies. Ann N Y Acad Sci 2007;1122: 23-34.

3.  Lau Y-S, Patki G, Das-Panja K, Le W-D, Ahmad SO. Neuroprotective effects and mechanisms of exercise in a chronic mouse model of Parkinson’s disease with moderate neurodegeneration. ‎Eur J Neurosci 2011; 33: 1264-1274.

4.Helmich RC, Hallett M, Deuschl G, Toni I, Bloem BR. Cerebral causes and consequences of parkinsonian resting tremor: a tale of two circuits? Brain 2012; 135: 3206-3226.

5. Earhart GM. Dance as therapy for individuals with Parkinson disease. Eur J Phys Rehab Med 2009; 45: 231-238.

6.Taylor K, Cook J, Counsell C. Heterogeneity in male to female risk for Parkinson’s disease. J Neurol Neurosurg Psychiatry 2007; 78: 905-906.

7.Aarsland D, Bronnick K, Fladby T. Mild cognitive impairment in Parkinson's disease. Curr Neurol Neurosci Rep 2011; 11: 371-378.

8.Hu LF, Lu M, Tiong CX, Dawe GS, Hu G, Bian JS. Neuroprotective effects of hydrogen sulfide on Parkinson's disease rat models. Aging Cell 2010; 9: 135-146.

9.Vijitruth R, Liu M, Choi DY, Nguyen XV, Hunter RL, Bing G. Cyclooxygenase-2 mediates microglial activation and secondary dopaminergic cell death in the mouse MPTP model of Parkinson's disease. J Neuroinflammation 2006; 3: 1-16.

10.McFarland K, Price DL, Davis CN, Ma JN, Bonhaus DW, Burstein ES, et al. AC-186, a selective nonsteroidal estrogen receptor beta agonist, shows gender specific neuroprotection in a Parkinson's disease rat model. ACS Chem Neurosci 2013; 4: 1249-1255.

11.Rocca WA, Bower JH, Maraganore DM, Ahlskog JE, Grossardt BR, de Andrade M, et al. Increased risk of parkinsonism in women who underwent oophorectomy before menopause. Neurology 2008; 70: 200-209.

12.Datla KP, Murray HE, Pillai AV, Gillies GE, Dexter DT. Differences in dopaminergic neuroprotective effects of estrogen during estrous cycle. Neuroreport 2003; 14: 47-50.

13.Chlebowski RT, Wactawski-Wende J, Ritenbaugh C, Hubbell FA, Ascensao J, Rodabough RJ, et al. Estrogen plus progestin and colorectal cancer in postmenopausal women. N Engl J Med 2004; 350: 991-1004.

14. Bagheri M, Joghataei MT, Mohseni S, Roghani M. Genistein ameliorates learning and memory deficits in amyloid beta(1-40) rat model of Alzheimer's disease. Neurobiol Learn Mem 2011; 95: 270-276.

15.Huang YH, Zhang QH. Genistein reduced the neural apoptosis in the brain of ovariectomised rats by modulating mitochondrial oxidative stress. Br J Nutr 2010; 104: 1297-1303.

16.Bagheri M. Neuroprotective Effect of Genistein: Studies in Rat Models of Parkinson’s and Alzheimer’s Disease 2012.

17.Dexter DT, Holley AE, Flitter WD, Slater TF, Wells FR, Daniel SE, et al. Increased levels of lipid hydroperoxides in the parkinsonian substantia nigra: an HPLC and ESR study. Mov Disorders 1994; 9: 92-97.

18.Marti MJ, Saura J, Burke RE, Jackson-Lewis V, Jimenez A, Bonastre M, et al. Striatal 6-hydroxydopamine induces apoptosis of nigral neurons in the adult rat. Brain Res 2002; 958: 185-191.

19.Windle WF, Rhines R, Rankin J. A Nissl method using buffered solutions of thionin. Biotech Histochem 1943; 18: 77-86.

20.Paxinos GaCW, eds. The rat brain in stereotaxic coordinates. Academic press 2004.

21.Atlante A, Bobba A, Paventi G, Pizzuto R, Passarella S. Genistein and daidzein prevent low potassium-dependent apoptosis of cerebellar granule cells. Biochem Pharmacol 2010; 79: 758-767.

22. Moazedi A, Ghotbeddin Z, Parham G. Comparison of the effects of dose-dependent zinc chloride on short-term and long-term memory in young male rats. Pak J Biol Sci 2007; 10: 2704-2708.

23.Yamada K, Takayanagi M, Kamei H, Nagai T, Dohniwa M, Kobayashi K, et al. Effects of memantine and donepezil on amyloid beta-induced memory impairment in a delayed-matching to position task in rats. Behav Brain Res 2005;162: 191-199.

24.Azami Tameh A, Clarner T, Beyer C, Atlasi MA, Hassanzadeh G, Naderian H. Regional regulation of glutamate signaling during cuprizone-induced demyelination in the brain. Ann Anat 2013; 195:415-423.

25. Zheng H, Kangas L, Harkonen PL. Comparative study of the short-term effects of a novel selective estrogen receptor modulator, ospemifene, and raloxifene and tamoxifen on rat uterus.  Jsteroid Biochem  Mol Biol 2004; 88:143-156.

26.Tamtaji O, Taghizadeh M, Takhtfiroozeh S, Talaei S. The Effect of Elaeagnus Angustifolia Water Extract on Scopolamine-Induced Memory Impairment in Rats. Zanjan Univ Med Sci J 2014; 22: 101-111.

27. Pourganji M, Hosseini M, Soukhtanloo M, Zabihi H, Hadjzadeh MA-r. Protective role of endogenous ovarian hormones against Learning and memory impairments and brain tissues oxidative damage induced by lipopolysaccharide. Iran Red Crescent Med J 2014; 16:13954-13962.

28. Kompoliti K, Comella C, Jaglin J, Leurgans S, Raman R, Goetz C. Menstrual-related changes in motoric function in women with Parkinson’s disease. Neurology 2000; 55:1572-1575.

29.Azizi-Malekabadi H, Hosseini M, Saffarzadeh F, Karami R, Khodabandehloo F. Chronic treatment with the nitric oxide synthase inhibitor, L-NAME, attenuates estradiol-mediated improvement of learning and memory in ovariectomized rats. Clinics 2011; 66: 673-679.

30.Currie LJ, Harrison MB, Trugman JM, Bennett JP, Wooten GF. Postmenopausal estrogen use affects risk for Parkinson disease. Arch Neurol 2004; 61:886-888.

31.Gatto N, Deapen D, Stoyanoff S, Pinder R, Narayan S, Bordelon Y, et al. Lifetime exposure to estrogens and Parkinson's disease in California teachers. Parkinsonism Relat Disord 2014; 20:1149-1156.

32.Rodriguez-Perez AI, Borrajo A, Valenzuela R, Lanciego JL, Labandeira-Garcia JL. Critical period for dopaminergic neuroprotection by hormonal replacement in menopausal rats. Neurobiol Aging 2015; 36:1194-1208.

33.Pan Y, Anthony M, Clarkson TB. Effect of estradiol and soy phytoestrogens on choline acetyltransferase and nerve growth factor mRNAs in the frontal cortex and hippocampus of female rats. Exp Biol Med 1999; 221:118-125.

34. Sarkaki A, Amani R, Badavi M, Moghaddam AZ, Aligholi H, Safahani M, et al. Pre-treatment effect of different doses of soy isoflavones on spatial learning and memory in an ovariectomized animal model of Alzheimer's disease. Pak J Biol Sci 2008; 11:1114-1119.

35. Lund TD, Lephart ED. Dietary soy phytoestrogens produce anxiolytic effects in the elevated plus-maze. Brain Res 2001; 913:180-184.

36. Rickard D, Monroe DG, Ruesink T, Khosla S, Riggs B, Spelsberg TC. Phytoestrogen genistein acts as an estrogen agonist on human osteoblastic cells through estrogen receptors α and β. J Cell Biochem 2003; 89: 633-646.

37.Liang HW, Qiu SF, Shen J, Sun LN, Wang JY, Bruce IC, et al. Genistein attenuates oxidative stress and neuronal damage following transient global cerebral ischemia in rat hippocampus. Neurosci Lett 2008; 438: 116-120.

38.Blum-Degen D, Haas M, Pohli S, Harth R, Romer W, Oettel M, etal. Scavestrogens protect IMR 32 cells from oxidative stress-induced cell death. Toxicol Appl Pharmacol 1998; 152: 49-55.

39.Arjmandi BH. The role of phytoestrogens in the prevention and treatment of osteoporosis in ovarian hormone deficiency. J Am Coll Nutr 2001; 20:398-402.

40.Quesada A, Romeo HE, Micevych P. Distribution and localization patterns of estrogen receptor-β and insulin-like growth factor-1 receptors in neurons and glial cells of the female rat substantia nigra: Localization of ERβ and IGF-1R in substantia nigra. J Comp Neurol 2007; 503:198-208.

41.Lee Y-B, Lee HJ, Won MH, Hwang IK, Kang T-C, Lee J-Y, et al. Soy isoflavones improve spatial delayed matching-to-place performance and reduce cholinergic neuron loss in elderly male rats. J Nutr 2004; 134:1827-1831.

42.Sarkaki A, Amani R, Badavi M, Moghaddam AZ, Aligholi H, Safahani M, et al. Pre-treatment effect of different doses of soy isoflavones on spatial learning and memory in an ovariectomized animal model of Alzheimer's disease. Pak J Biol Sci 2008; 11:1114-1119.

43. Tujioka K, Shi X, Ohsumi M, Tuchiya T, Hayase K, Uchida T, et al. Effect of quantity and quality of dietary protein on choline acetyltransferase and nerve growth factor, and their mRNAs in the cerebral cortex and hippocampus of rats. Amino Acids 2009; 36: 13-19.

44.Xu J, Zhu J, Shi C, Guo K, Yew DT. Effects of genistein on hippocampal neurodegeneration of ovariectomized rats. J Mol Neurosci 2007; 31:101-112.

45.Liang HW, Qiu SF, Shen J, Sun LN, Wang JY, Bruce IC, et al. Genistein attenuates oxidative stress and neuronal damage following transient global cerebral ischemia in rat hippocampus. Neurosci Lett 2008; 438:116-120.

46.Ma W, Yuan L, Yu H, Ding B, Xi Y, Feng J, et al. Genistein as a neuroprotective antioxidant attenuates redox imbalance induced by β-amyloid peptides 25–35 in PC12 cells. Int J Dev Neurosci 2010; 28:289-295.

47.Liu LX, Chen WF, Xie JX, Wong MS. Neuroprotective effects of genistein on dopaminergic neurons in the mice model of Parkinson's disease. Neurosci Res 2008; 60:156-161.

48. Koller W, Barr A, Biary N. Estrogen treatment of dyskinetic disorders. Neurology 1982; 32:547-547.

49. Strijks E, Kremer JA, Horstink MW. Effects of female sex steroids on Parkinson's disease in postmenopausal women. Clin Neuropharmacol 1999; 22:93-97.

50. Saunders-Pullman R, Gordon-Elliott J, Parides M, Fahn S, Saunders H, Bressman S. The effect of estrogen replacement on early Parkinson’s disease. Neurology 1999; 52:1417-1417.