Protection against brain tissues oxidative damage as a possible mechanism for improving effects of low doses of estradiol on scopolamine-induced learning and memory impairments in ovariectomized rats


1 Department of Physiology, Shahid Sadoghi University of Medical Sciences, Yazd, Iran

2 Neurocognitive Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

3 Neurogenic Inflammation Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

4 Department of Biochemistry, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran


Background: Regarding the anti-oxidative effects on the central nervous system, the possible protection against brain tissues oxidative damage as a possible mechanism for improving effects of low doses of estradiol on scopolamine-induced learning and memory impairments was investigated in ovariectomized (OVX) rats.
Materials and Methods: The OVX rats treated by (1) vehicle, (2) scopolamine, and (3–4) scopolamine plus estradiol (20 or 20 or 60 μg/kg). Estradiol was administered (20 or 60 μg/kg, intraperitoneally) daily for 6 weeks after ovariectomy. The rats were examined for learning and memory using passive avoidance test. Scopolamine (2 mg/kg) was injected 30 min after training in the test. The brains were then removed to determine malondialdehyde (MDA) and thiol contents.
Results: Scopolamine shortened the time latency to enter the dark compartment in (P < 0.01). Compared to scopolamine, pretreatment by both doses of estradiol prolonged the latency to enter the dark compartment (P < 0.01). The brain tissues MDA concentration as an index of lipid peroxidation was decreased (P < 0.05). Pretreatment by estradiol lowered the concentration of MDA, while it increased thiol content compared to scopolamine (P < 0.05 andP < 0.01).
Conclusions: These results allow us to suggest a protection against brain tissues oxidative damage as a possible mechanism for improving effects of low doses of estradiol on scopolamine-induced learning and memory impairments in OVX rats.


Webber KM, Bowen R, Casadesus G, Perry G, Atwood CS, Smith MA. Gonadotropins and Alzheimer's disease: The link between estrogen replacement therapy and neuroprotection. Acta Neurobiol Exp (Wars) 2004;64:113-8.  Back to cited text no. 1
Shen J, Wu J. Nicotinic cholinergic mechanisms in Alzheimer's disease. Int Rev Neurobiol 2015;124:275-92.  Back to cited text no. 2
Duarte-Guterman P, Yagi S, Chow C, Galea LA. Hippocampal learning, memory, and neurogenesis: Effects of sex and estrogens across the lifespan in adults. Horm Behav 2015;74:37-52.  Back to cited text no. 3
Seshadri S, Wolf PA, Beiser A, Au R, McNulty K, White R, et al. Lifetime risk of dementia and Alzheimer's disease. The impact of mortality on risk estimates in the Framingham Study. Neurology 1997;49:1498-504.  Back to cited text no. 4
Janicki SC, Park N, Cheng R, Lee JH, Schupf N, Clark LN. Estrogen receptor ß variants modify risk for Alzheimer's disease in a multiethnic female cohort. J Alzheimers Dis 2014;40:83-93.  Back to cited text no. 5
Duka T, Tasker R, McGowan JF. The effects of 3-week estrogen hormone replacement on cognition in elderly healthy females. Psychopharmacology (Berl) 2000;149:129-39.  Back to cited text no. 6
Maki PM, Zonderman AB, Resnick SM. Enhanced verbal memory in nondemented elderly women receiving hormone-replacement therapy. Am J Psychiatry 2001;158:227-33.  Back to cited text no. 7
Duff SJ, Hampson E. A beneficial effect of estrogen on working memory in postmenopausal women taking hormone replacement therapy. Horm Behav 2000;38:262-76.  Back to cited text no. 8
Frick KM, Kim J, Tuscher JJ, Fortress AM. Sex steroid hormones matter for learning and memory: Estrogenic regulation of hippocampal function in male and female rodents. Learn Mem 2015;22:472-93.  Back to cited text no. 9
Gresack JE, Frick KM. Environmental enrichment reduces the mnemonic and neural benefits of estrogen. Neuroscience 2004;128:459-71.  Back to cited text no. 10
Heikkinen T, Puoliväli J, Liu L, Rissanen A, Tanila H. Effects of ovariectomy and estrogen treatment on learning and hippocampal neurotransmitters in mice. Horm Behav 2002;41:22-32.  Back to cited text no. 11
Luine V, Rodriguez M. Effects of estradiol on radial arm maze performance of young and aged rats. Behav Neural Biol 1994;62:230-6.  Back to cited text no. 12
Gibbs RB. Long-term treatment with estrogen and progesterone enhances acquisition of a spatial memory task by ovariectomized aged rats. Neurobiol Aging 2000;21:107-16.  Back to cited text no. 13
Fernandez SM, Frick KM. Chronic oral estrogen affects memory and neurochemistry in middle-aged female mice. Behav Neurosci 2004;118:1340-51.  Back to cited text no. 14
Frick KM, Fernandez SM, Bulinski SC. Estrogen replacement improves spatial reference memory and increases hippocampal synaptophysin in aged female mice. Neuroscience 2002;115:547-58.  Back to cited text no. 15
Craig MC, Brammer M, Maki PM, Fletcher PC, Daly EM, Rymer J, et al. The interactive effect of acute ovarian suppression and the cholinergic system on visuospatial working memory in young women. Psychoneuroendocrinology 2010;35:987-1000.  Back to cited text no. 16
Gibbs RB, Aggarwal P. Estrogen and basal forebrain cholinergic neurons: Implications for brain aging and Alzheimer's disease-related cognitive decline. Horm Behav 1998;34:98-111.  Back to cited text no. 17
Gibbs RB. Estrogen therapy and cognition: A review of the cholinergic hypothesis. Endocr Rev 2010;31:224-53.  Back to cited text no. 18
Mennenga SE, Gerson JE, Koebele SV, Kingston ML, Tsang CW, Engler-Chiurazzi EB, et al. Understanding the cognitive impact of the contraceptive estrogen ethinyl estradiol: Tonic and cyclic administration impairs memory, and performance correlates with basal forebrain cholinergic system integrity. Psychoneuroendocrinology 2015;54:1-13.  Back to cited text no. 19
Behl C, Skutella T, Lezoualc'h F, Post A, Widmann M, Newton CJ, et al. Neuroprotection against oxidative stress by estrogens: Structure-activity relationship. Mol Pharmacol 1997;51:535-41.  Back to cited text no. 20
Behl C, Davis JB, Lesley R, Schubert D. Hydrogen peroxide mediates amyloid beta protein toxicity. Cell 1994;77:817-27.  Back to cited text no. 21
Khodabandehloo F, Hosseini M, Rajaei Z, Soukhtanloo M, Farrokhi E, Rezaeipour M. Brain tissue oxidative damage as a possible mechanism for the deleterious effect of a chronic high dose of estradiol on learning and memory in ovariectomized rats. Arq Neuropsiquiatr 2013;71:313-9.  Back to cited text no. 22
Hosseini M, Sadeghnia HR, Salehabadi S, Alavi H, Gorji A. The effect of L-arginine and L-NAME on pentylenetetrazole induced seizures in ovariectomized rats, an in vivo study. Seizure 2009;18:695-8.  Back to cited text no. 23
Zabihi H, Hosseini M, Pourganji M, Oryan S, Soukhtanloo M, Niazmand S. The effects of tamoxifen on learning, memory and brain tissues oxidative damage in ovariectomized and naïve female rats. Adv Biomed Res 2014;3:219.  Back to cited text no. 24
[PUBMED]  Medknow Journal  
Vafaee F, Hosseini M, Hassanzadeh Z, Edalatmanesh MA, Sadeghnia HR, Seghatoleslam M, et al. The effects of Nigella sativa hydro-alcoholic extract on memory and brain tissues oxidative damage after repeated seizures in rats. Iran J Pharm Res 2015;14:547-57.  Back to cited text no. 25
Souza AC, Bruning CA, Acker CI, Neto JS, Nogueira CW. 2-Phenylethynyl-butyltellurium enhances learning and memory impaired by scopolamine in mice. Behav Pharmacol 2013;24:249-54.  Back to cited text no. 26
Karimi S, Hejazian SH, Alikhani V, Hosseini M. The effects of tamoxifen on spatial and nonspatial learning and memory impairments induced by scopolamine and the brain tissues oxidative damage in ovariectomized rats. Adv Biomed Res 2015;4:196.  Back to cited text no. 27
  Medknow Journal  
Mohammadpour T, Hosseini M, Naderi A, Karami R, Sadeghnia HR, Soukhtanloo M, et al. Protection against brain tissues oxidative damage as a possible mechanism for the beneficial effects of Rosa damascena hydroalcoholic extract on scopolamine induced memory impairment in rats. Nutr Neurosci 2015;18:329-36.  Back to cited text no. 28
Hosseini M, Mohammadpour T, Karami R, Rajaei Z, Reza Sadeghnia H, Soukhtanloo M. Effects of the hydro-alcoholic extract of Nigella sativa on scopolamine-induced spatial memory impairment in rats and its possible mechanism. Chin J Integr Med 2015;21:438-44.  Back to cited text no. 29
Jamialahmadi K, Sadeghnia HR, Mohammadi G, Kazemabad AM, Hosseini M. Glucosamine alleviates scopolamine induced spatial learning and memory deficits in rats. Pathophysiology 2013;20:263-7.  Back to cited text no. 30
Lee B, Shim I, Lee H, Hahm DH. Rehmannia glutinosa ameliorates scopolamine-induced learning and memory impairment in rats. J Microbiol Biotechnol 2011;21:874-83.  Back to cited text no. 31
Micheau J, Marighetto A. Acetylcholine and memory: A long, complex and chaotic but still living relationship. Behav Brain Res 2011;221:424-9.  Back to cited text no. 32
Min AY, Doo CN, Son EJ, Sung NY, Lee KJ, Sok DE, Kim MR. N-palmitoyl serotonin alleviates scopolamine-induced memory impairment via regulation of cholinergic and antioxidant systems, and expression of BDNF and p-CREB in mice. Chem Biol Interact. 2015;242:153-62.  Back to cited text no. 33
Melo JB, Agostinho P, Oliveira CR. Involvement of oxidative stress in the enhancement of acetylcholinesterase activity induced by amyloid beta-peptide. Neurosci Res 2003;45:117-27.  Back to cited text no. 34
Ahmed T, Gilani AH. Inhibitory effect of curcuminoids on acetylcholinesterase activity and attenuation of scopolamine-induced amnesia may explain medicinal use of turmeric in Alzheimer's disease. Pharmacol Biochem Behav 2009;91:554-9.  Back to cited text no. 35
Daniel JM. Effects of oestrogen on cognition: What have we learned from basic research? J Neuroendocrinol 2006;18:787-95.  Back to cited text no. 36
Azizi-Malekabadi H, Hosseini M, Soukhtanloo M, Sadeghian R, Fereidoni M, Khodabandehloo F. Different effects of scopolamine on learning, memory, and nitric oxide metabolite levels in hippocampal tissues of ovariectomized and Sham-operated rats. Arq Neuropsiquiatr 2012;70:447-52.  Back to cited text no. 37
Luine VN. Estradiol increases choline acetyltransferase activity in specific basal forebrain nuclei and projection areas of female rats. Exp Neurol 1985;89:484-90.  Back to cited text no. 38
Fader AJ, Hendricson AW, Dohanich GP. Estrogen improves performance of reinforced T-maze alternation and prevents the amnestic effects of scopolamine administered systemically or intrahippocampally. Neurobiol Learn Mem 1998;69:225-40.  Back to cited text no. 39
Packard MG. Posttraining estrogen and memory modulation. Horm Behav 1998;34:126-39.  Back to cited text no. 40
Marriott LK, Korol DL. Short-term estrogen treatment in ovariectomized rats augments hippocampal acetylcholine release during place learning. Neurobiol Learn Mem 2003;80:315-22.  Back to cited text no. 41
Fader AJ, Johnson PE, Dohanich GP. Estrogen improves working but not reference memory and prevents amnestic effects of scopolamine of a radial-arm maze. Pharmacol Biochem Behav 1999;62:711-7.  Back to cited text no. 42
Green PS, Gridley KE, Simpkins JW. Nuclear estrogen receptor-independent neuroprotection by estratrienes: A novel interaction with glutathione. Neuroscience 1998;84:7-10.  Back to cited text no. 43
Culmsee C, Vedder H, Ravati A, Junker V, Otto D, Ahlemeyer B, et al. Neuroprotection by estrogens in a mouse model of focal cerebral ischemia and in cultured neurons: Evidence for a receptor-independent antioxidative mechanism. J Cereb Blood Flow Metab 1999;19:1263-9.  Back to cited text no. 44
Kii N, Adachi N, Liu K, Arai T. Acute effects of 17beta-estradiol on oxidative stress in ischemic rat striatum. J Neurosurg Anesthesiol 2005;17:27-32.  Back to cited text no. 45
Bruce-Keller AJ, Keeling JL, Keller JN, Huang FF, Camondola S, Mattson MP. Antiinflammatory effects of estrogen on microglial activation. Endocrinology 2000;141:3646-56.  Back to cited text no. 46
Gottipati S, Cammarata PR. Mitochondrial superoxide dismutase activation with 17 beta-estradiol-treated human lens epithelial cells. Mol Vis 2008;14:898-905.  Back to cited text no. 47
Wang X, Simpkins JW, Dykens JA, Cammarata PR. Oxidative damage to human lens epithelial cells in culture: Estrogen protection of mitochondrial potential, ATP, and cell viability. Invest Ophthalmol Vis Sci 2003;44:2067-75.  Back to cited text no. 48
Prokai L, Prokai-Tatrai K, Perjesi P, Zharikova AD, Perez EJ, Liu R, et al. Quinol-based cyclic antioxidant mechanism in estrogen neuroprotection. Proc Natl Acad Sci U S A 2003;100:11741-6.  Back to cited text no. 49
Evsen MS, Ozler A, Gocmez C, Varol S, Tunc SY, Akil E, et al. Effects of estrogen, estrogen/progesteron combination and genistein treatments on oxidant/antioxidant status in the brain of ovariectomized rats. Eur Rev Med Pharmacol Sci 2013;17:1869-73.  Back to cited text no. 50
Wang MY, Liehr JG. Induction by estrogens of lipid peroxidation and lipid peroxide-derived malonaldehyde-DNA adducts in male Syrian hamsters: Role of lipid peroxidation in estrogen-induced kidney carcinogenesis. Carcinogenesis 1995;16:1941-5.  Back to cited text no. 51