Effects of Exogenous Estrogen Treatment on Hippocampal Neurogenesis of Diabetic Ovariectomized Rats
International Clinical Neuroscience Journal,
Vol. 3 No. 2 (2016),
22 September 2016
Background: Mellitus Diabetes (DM) is the most important metabolic diseases. The incidence of DM is prone to increase. Vasculopathy, retinopathy, central and peripheral neuropathy are the most important reported side effects of DM. Cognitive dysfunction following DM reported in both sexes. Hippocampus is a major part of brain involving in cognitive function, its cells are able to neurogenesis, so it is possible that DM affects the hippocampus. In addition, neuroprotective effects of female sex steroids are reported elsewhere. In order to answer the question of whether female sex steroid are able to suppress the effects of DM on neurogenesis of dentate gyrus (DG) in diabetic ovariectomized rat the present study designed.
Methods: Sprague-Dawley adult female rats were used in this study. The animals randomly divided in 8 groups including; control, diabetic (Diab), ovariectomy (OVX), Diab+OVX, estrogen treated (E2; Diab+OVX+E2), surgical and vehicle sham. Intrapritoneal injection of STZ, subcutaneous injection of E2 and routine bilateral surgery were used respectively to induce diabetes, estrogen treatment and OVX. Nissl staining, Brdu immunohistochemistry (IHC) and western blotting were used in this study. Statistical analysis was done and the results presented in mean ± SD, Pv < 0.05 considered significant.
Results: Brdu IHC showed that the neurogenesis significantly decreased in OVX, Diab and OVX-Diab groups (Pv < 0.05) in comparison with control and sham groups. Western blotting showed significant increase of Bax and decrease of Bcl2 proteins of trial groups comparing to control. Estrogen treatment significantly improved neurogenesis in animals of Diab+OVX+E2 group. The neurogenesis impairment was more sever in OVX + Diab animals than OVX and Diab ones merely.
Conclusion: Based on our data, cognitive dysfunction caused by DM is related to hippocampal neurogenesis reduction and might improve under the influence of ovarian steroidal hormone therapy.
- Mellitus Diabetes
- Ovarian hormones
- Cognitive function
How to Cite
Biessels GJ, van der Heide LP, Kamal A, Bleys RL, Gispen WH. Ageing and diabetes: implications for brain function. European Journal of Pharmacology. 2002. 441(1): 1-14.
Vinik AI, Park TS, Stansberry KB, Pittenger GL. Diabetic neuropathies. Diabetologia. 2000. 43(8): 957-973.
Artola A, Kamal A, Ramakers GM, Gardoni F, Di Luca M, Biessels GJ, et al. Synaptic plasticity in the diabetic brain: advanced aging Progress in Brain Research. 2002. 138: 305-314.
Gispen WH, Biessels GJ. Biessels, Cognition and synaptic plasticity in diabetes mellitus. Trends in Neurosciences. 2000. 23(11): 542-549.
Biessels GJ, Kappelle AC, Bravenboer B, Erkelens DW, Gispen WH. Cerebral function in diabetes mellitus. Diabetologia. 1994. 37(7): 643-650.
Klein JP, Waxman SG. The brain in diabetes: molecular changes in neurons and their implications for end-organ damage. The Lancet Neurology. 2003. 2(9): 548-554.
Taupin P, Gage FH. Adult neurogenesis and neural stem cells of the central nervous system in mammals. Journal of Neuroscience Research. 2002. 69(6): 745-749.
Hastings NB, Gould E. Rapid extension of axons into the CA3 region by adult‐generated granule cells. Journal of Comparative Neurology. 1999. 413(1): 146-154.
Bédard A, Parent A. Evidence of newly generated neurons in the human olfactory bulb. Developmental Brain Research. 2004. 151(1): 159-168.
Seaberg RM, van der Kooy D. Stem and progenitor cells: the premature desertion of rigorous definitions. Trends in Neurosciences. 2003. 26(3): 125-131.
van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH. Functional neurogenesis in the adult hippocampus. Nature. 2002. 415(6875): 1030-1034.
Leuner B, Gould E, Shors TJ. Is there a link between adult neurogenesis and learning Hippocampus. 2006. 16(3): 216-224.
Behl C. Oestrogen as a neuroprotective hormone. Nature Reviews Neuroscience. 2002. 3(6): 433-442.
Galanopoulou AS, Alm EM, Velı́šková J. Estradiol reduces seizure-induced hippocampal injury in ovariectomized female but not in male rats. Neuroscience letters. 2003. 342(3): 201-205.
Jameie SB, Shahnam F, Kelarestaghy H, Mehdinejadian Sh, Kerdari M, Kouchmeshky A, et al. Median Raphe Nucleus of Adult Rat: Sexual Dimorphism and effects of femal gonadal steroid deprivation. Iranian Journal of Neurology. 2010; 9(29-30): 732-74416.
Jameie SB, Noyan MH, Behzadi,G. Ovariectomy reduces the spine density of the dorsal raphe neurons in adult rat. Archives of Iranian Medicine. 2004; 7 (2) 122 –127
Cosimo Melcangi R, Garcia-Segura LM. Sex-specific therapeutic strategies based on neuroactive steroids: in search for innovative tools for neuroprotection. Hormones and Behavior. 2010. 57(1): 2-11.
Cameron HA, McKay RD. Restoring production of hippocampal neurons in old age. Nature Neuroscience. 1999. 2(10): 894-897.
Brännvall K, Korhonen L, Lindholm D. Estrogen-receptor-dependent regulation of neural stem cell proliferation and differentiation. Molecular and Cellular Neuroscience. 2002. 21(3): 512-520.
Cardona-Gómez GP, Mendez P, DonCarlos LL, Azcoitia I, Garcia-Segura LM. Interactions of estrogens and insulin-like growth factor-I in the brain: implications for neuroprotection. Brain Research Reviews. 2001. 37(1): 320-334.
Gould E, Tanapat P, Hastings NB, Shors TJ. Neurogenesis in adulthood: a possible role in learning. Trends in Cognitive Sciences. 1999;3(5): 186-191.
Reagan LP, MAGARIÑOS A, McEWEN BS. Neurological changes induced by stress in treptozotocin diabetic rats. Annals of the New York Academy of Sciences. 1999. 893(1): 126-137.
Ristow M. Neurodegenerative disorders associated with diabetes mellitus. J. Mol Med. 2004; 82:510–529.
Mäkimattila S, Malmberg-Cèder K, Häkkinen AM, Vuori K, Salonen O, Summanen P, et al. Brain metabolic alterations in patients with type1 diabetes-hyperglycemia-induced injury. J Cereb. Blood Flow Metab. 2004:1393–1399.
Saravia FE, Revsin Y, Gonzalez Deniselle MC, Gonzalez SL, Roig P, Lima A,et al. Increased astrocyte reactivity in the hippocampus of murine models of type I diabetes: The nonobese diabetic (NOD) and streptozotocin-treated mice. Brain Res. 2002;957:345–353.
Ignatius MJ, Gebicke-Härter PJ, Skene JH, Schilling JW, Weisgraber KH, Mahley RW, et al. Expression of apolipoprotein E during nerve degeneration and regeneration. Proc Natl Acad Sci USA. 1986;Feb;83(4):1125-9.
Boschert U, Merlo-Pich E, Higgins G, Roses AD, Catsicas S. Apolipoprotein E expression by neurons surviving excitotoxic stress. Neurobiol Dis. 1999 Dec;6(6):508-14.
Couch R. Dissociation of cortisol and adrenal androgen secretion in poorly controlled insulin-dependent diabetes mellitus. Acta Endocrinologica. 1992; 127(2): 115-117.
McEwen BS, Sapolsky RM. Stress and cognitive function. Current Opinion in Neurobiology. 1995; 5(2): 205-216.
O'Kusky JR, Ye P, D'Ercole AJ. Insulin-like growth factor-I promotes neurogenesis and synaptogenesis in the hippocampal dentate gyrus during postnatal development. The Journal of Neuroscience. 2000;20(22): 8435-8442.
Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocrine Reviews. 1995; 16(1): 3-34.
Carro E, Trejo JL, Busiguina S, Torres-Aleman I. Circulating insulin-like growth factor I mediates the protective effects of physical exercise against brain insults of different etiology and anatomy. J Neurosci. 2001 Aug 1;21(15):5678-84.
Zhang WJ, Tan YF, Yue JT, Vranic M, Wojtowicz JM. Impairment of hippocampal neurogenesis in streptozotocin-treated diabetic rats. Acta Neurol Scand. 2008 Mar;117(3):205-10.
Li ZG, Zhang W, Grunberger G, Sima AA. Hippocampal neuronal apoptosis in type 1 diabetes. Brain Res. 2002 Aug 16;946(2):221-31.
Biessels GJ, Kamal A, Urban IJ, Spruijt BM, Erkelens DW, Gispen WH. Water maze learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: effects of insulin treatment. Brain Res. 1998 Jul 27;800(1):125-35.
Azcoitia I, Sierra A, Garcia-SeguraLM. Neuroprotective effects of estradiol in the adult rat hippocampus: interaction with insulin-like growth factor-I signalling. J Neurosci Res. 1999;58: 815–822.
Harms C, Lautenschlager M, Bergk A, Katchanov J, Freyer D, Kapinaya K, et al. Differential mechanisms of neuroprotection by 17 beta-estradiol in apoptotic versus necrotic neurodegeneration. J Neurosci. 2001; 21:2600–2609.
Yi KD, Cai ZY, Covey DF, Simpkins JW. Estrogen receptor independent neuroprotection via proteinphosphatase preservation and attenuation of persistent extracellular signal-regulated
kinase1/2 activation. J Pharmacol Exp Ther. 2008;324:1188–1195.
Behl C. Estrogen can protect neurons: modes of action. J Steroid Biochem Mol Biol. 2002; 83: 195–197.
Reyes MR, Sifuentes-Alvarez A, Lazalde B. Estrogens are potentially the only steroids with an antioxidant role in pregnancy: invitro evidence. Acta Obstet Gynecol Scand. 2006;85:1090–1093.
Perez-Martin M, Azcoitia I, Trejo JL, Sierra A, Garcia-Segura LM. An antagonist of estrogen receptors blocks the induction of adult neurogenesis by insulin-like growth factor-I in the dentate gyrus of adult female rat. Eur J Neurosci. 2003 Aug;18(4):923-30.
Picazo O, Becerril-Montes A, Huidobro-Perez D, Garcia-Segura LM. Neuroprotective Actions of the Synthetic Estrogen 17a-Ethynylestradiol in the Hippocampus. Cell Mol Neurobiol. 2010; 30:675–682.
Ormerod B, Lee T, Galea L. Estradiol initially enhances but subsequently suppresses (via adrenal steroids) granule cell proliferation in the dentate gyrus of adult female rats. Journal of Neurobiology. 2003; 55(2): 247-260.
Saravia F, Revsin Y, Lux-Lantos V, Beauquis J, Homo-Delarche F, De Nicola AF. Oestradiol restores cell proliferation in dentate gyrus and subventricular zone of streptozotocin-diabetic mice. J Neuroendocrinol. 2004 Aug;16(8):704-10.
Gispen WH, Biessels GJ. Cognition and synaptic plasticity in diabetes mellitus. TINS. 2000; 23: 542–549
Flood JF, Mooradian AD, Morley JE. Characteristics of learning and memory in streptozocin-induced diabetic mice. Diabetes. 1990;39: 1391–1398.
Gundlah C, Kohama SG, Mirkes SJ, Garyfallou VT, Urbanski HF, Bethea CL. Distribution of strogen receptor beta (Erbeta) mRNA in hypothalamus, midbrain and temporal lobe of spayed acaques: continued expression with hormone replacement. Brain Res Mol Brain Res. 2000;76: 191–204.
Kempermann G, Kuhn HG, Gage FH. More hippocampal neurons in adult mice living in an enriched environment. Nature. 1997;386:493–495.
van Praag H, Kempermann G, Gage FH. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci. 1999;2:266–270.
McEwen BS, Alves SE, Bulloch K, Weiland NG. Ovarian steroids and the brain: Implications for cognition and aging. Neurology. 1997;48:S8–S15.
Bodnoff SR, Humphreys AG, Lehman JC, Diamond DM, Rose GM, Meaney MJ. Enduring effects of chroniccorticosterone treatment on spatial learning, synaptic plasticity, and hippocampal neuropathology in young and mid-aged rats. J Neurosci. 1995;15:61–69.
Endo Y, Nishimura JI, Kimura F. Impairment of maze learning in rats following long-term glucocorticoid treatments. Neurosci Lett. 1996;203:199–202.
Krugers HJ, Douma BR, Andringa G, Bohus B, Korf J, Luiten PG. Exposure to chronic psychosocial stress and corticosterone in the rat: Effects on spatial discrimination learning and hippocampal proteinkinase C gamma immunoreactivity. Hippocampus. 1197;7:427–436.
Liu Zhiping, Gastrad Myriam,Verina Tatyana, Bora Susan, Mounton Peterr R & Koliatsos Vassilis : Estrogens Modulate Experimentally Induced Apoptosis of Granule Cells in the Adult Hippocampus. The Journal of Compartive Neurology. 2001;441: 1–8.
- Abstract Viewed: 495 times
- PDF Downloaded: 340 times