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Combination of PPT with LiCl Treatment Prevented Bilateral Ovariectomy-Induced Hippocampal-Dependent Cognition Deficit in Rats

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Abstract

Estrogen deprivation is a high risk of cognitive dysfunction in neurodegenerative diseases, and the early used estrogen replacement has been proved effective in many studies. Because of the adverse actions, selective estrogen receptor modulating has been raised to substitute for estrogen replacement. In this study, we observed in hippocampus of bilaterally ovariectomized rats that the level of estrogen receptor α (ERα) was decreased in nuclei with activated glycogen synthase kinase-3β (GSK-3β) in cytoplasm at 8 weeks after operation. The level of nuclear ERα is important for its transcriptional property, and the inhibition of GSK-3β benefits to ERα nuclear translocation. Then, we used 4,4k,4a-(4-propyl-[1H]-pyrazole-1, 3, 5-triyl) trisphenol (PPT) (1 mg/kg/day), an agonist of ERα, combined with LiCl (40 mg/kg/day), an inhibitor of GSK-3β, to treat the ovariectomized rats. After the combination treatment of these two drugs (PPT + LiCl), the improved learning and memory abilities of ovariectomized rats in Morris water maze, increased dendritic spines in CA1 region, and decreased tau phosphorylation at Ser-396 in hippocampus were observed. Furthermore, PPT + LiCl treatment significantly increased ERα level in the nuclear fraction of hippocampus, and in the cytoplasmic fraction, the total level of GSK-3β was declined after treatment with its increased phosphorylation at Ser-9 (inactivation form). This study suggested that PPT + LiCl treatment could inhibit the activation of cytoplasmic GSK-3β and promote the nuclear translocation of ERα, and ERα together with GSK-3β maybe the targets to preserve hippocampus-dependent cognitive ability after long-term ovariectomy.

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References

  1. Foster TC (2012) Role of estrogen receptor alpha and beta expression and signaling on cognitive function during aging. Hippocampus 22:656–669

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  2. Daniel JM, Bohacek J (2010) The critical period hypothesis of estrogen effects on cognition: insights from basic research. Biochim Biophys Acta 1800:1068–1076

    Article  PubMed  CAS  Google Scholar 

  3. Shors TJ, Leuner B (2003) Estrogen-mediated effects on depression and memory formation in females. J Affect Disord 74:85–96

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  4. Foster TC (2005) Interaction of rapid signal transduction cascades and gene expression in mediating estrogen effects on memory over the life span. Front Neuroendocrinol 26:51–64

    Article  PubMed  CAS  Google Scholar 

  5. Barha CK, Dalton GL, Galea LA (2010) Low doses of 17alpha-estradiol and 17beta-estradiol facilitate, whereas higher doses of estrone and 17alpha- and 17beta-estradiol impair, contextual fear conditioning in adult female rats. Neuropsychopharmacology 35:547–559

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  6. Lee JH, Jiang Y, Han DH, Shin SK, Choi WH, Lee MJ (2014) Targeting estrogen receptors for the treatment of Alzheimer’s disease. Mol Neurobiol 49:39–49

    Article  PubMed  CAS  Google Scholar 

  7. Sinopoli KJ, Floresco SB, Galea LA (2006) Systemic and local administration of estradiol into the prefrontal cortex or hippocampus differentially alters working memory. Neurobiol Learn Mem 86:293–304

    Article  PubMed  CAS  Google Scholar 

  8. Ishunina TA, Fischer DF, Swaab DF (2007) Estrogen receptor alpha and its splice variants in the hippocampus in aging and Alzheimer’s disease. Neurobiol Aging 28:1670–1681

    Article  PubMed  CAS  Google Scholar 

  9. Perlman WR, Tomaskovic-Crook E, Montague DM, Webster MJ, Rubinow DR, Kleinman JE, Weickert CS (2005) Alteration in estrogen receptor alpha mRNA levels in frontal cortex and hippocampus of patients with major mental illness. Biol Psychiatry 58:812–824

    Article  PubMed  CAS  Google Scholar 

  10. Savaskan E, Olivieri G, Meier F, Ravid R, Muller-Spahn F (2001) Hippocampal estrogen beta-receptor immunoreactivity is increased in Alzheimer’s disease. Brain Res 908:113–119

    Article  PubMed  CAS  Google Scholar 

  11. Qu N, Wang L, Liu ZC, Tian Q, Zhang Q (2013) Oestrogen receptor alpha agonist improved long-term ovariectomy-induced spatial cognition deficit in young rats. Int J Neuropsychopharmacol 16:1071–1082

    Article  PubMed  CAS  Google Scholar 

  12. Zhang QG, Han D, Wang RM, Dong Y, Yang F, Vadlamudi RK, Brann DW (2011) C terminus of Hsc70-interacting protein (CHIP)-mediated degradation of hippocampal estrogen receptor-alpha and the critical period hypothesis of estrogen neuroprotection. Proc Natl Acad Sci U S A 108:E617–E624

    Article  PubMed Central  PubMed  Google Scholar 

  13. Zhang QG, Raz L, Wang R, Han D, De Sevilla L, Yang F, Vadlamudi RK, Brann DW (2009) Estrogen attenuates ischemic oxidative damage via an estrogen receptor alpha-mediated inhibition of NADPH oxidase activation. J Neurosci 29:13823–13836

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  14. Lannigan DA (2003) Estrogen receptor phosphorylation. Steroids 68:1–9

    Article  PubMed  CAS  Google Scholar 

  15. Grisouard J, Mayer D (2009) Specific involvement of glycogen synthase kinase-3 in the function and activity of sex steroid hormone receptors reveals the complexity of their regulation. J Steroid Biochem Mol Biol 117:87–92

    Article  PubMed  CAS  Google Scholar 

  16. Grisouard J, Medunjanin S, Hermani A, Shukla A, Mayer D (2007) Glycogen synthase kinase-3 protects estrogen receptor alpha from proteasomal degradation and is required for full transcriptional activity of the receptor. Mol Endocrinol 21:2427–2439

    Article  PubMed  CAS  Google Scholar 

  17. Medunjanin S, Hermani A, De Servi B, Grisouard J, Rincke G, Mayer D (2005) Glycogen synthase kinase-3 interacts with and phosphorylates estrogen receptor alpha and is involved in the regulation of receptor activity. J Biol Chem 280:33006–33014

    Article  PubMed  CAS  Google Scholar 

  18. Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI (1986) Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A 83:4913–4917

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  19. Llorens-Martin M, Jurado J, Hernandez F, Avila J (2014) GSK-3beta, a pivotal kinase in Alzheimer disease. Front Mol Neurosci 7:46

    PubMed  Google Scholar 

  20. Medina M, Garrido JJ, Wandosell FG (2011) Modulation of GSK-3 as a therapeutic strategy on tau pathologies. Front Mol Neurosci 4:24

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  21. Wada A (2009) Lithium and neuropsychiatric therapeutics: neuroplasticity via glycogen synthase kinase-3beta, beta-catenin, and neurotrophin cascades. J Pharmacol Sci 110:14–28

    Article  PubMed  CAS  Google Scholar 

  22. Marmol F (2008) Lithium: bipolar disorder and neurodegenerative diseases possible cellular mechanisms of the therapeutic effects of lithium. Prog Neuropsychopharmacol Biol Psychiatry 32:1761–1771

    Article  PubMed  CAS  Google Scholar 

  23. Valdes JJ, Weeks OI (2009) Lithium: a potential estrogen signaling modulator. J Appl Biomech 7:175–188

  24. Wang X, Blanchard J, Kohlbrenner E, Clement N, Linden RM, Radu A, Grundke-Iqbal I, Iqbal K (2010) The carboxy-terminal fragment of inhibitor-2 of protein phosphatase-2A induces Alzheimer disease pathology and cognitive impairment. FASEB J 24:4420–4432

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  25. Alimoradi H, Pourmohammadi N, Mehr SE, Hassanzadeh G, Hadian MR, Sharifzadeh M, Bakhtiarian A, Dehpour AR (2012) Effects of lithium on peripheral neuropathy induced by vincristine in rats. Acta Med Iran 50:373–379

    PubMed  CAS  Google Scholar 

  26. Smith JA, Das A, Ray SK, Banik NL (2012) Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases. Brain Res Bull 87:10–20

    Article  PubMed  CAS  Google Scholar 

  27. Tsien JZ, Huerta PT, Tonegawa S (1996) The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell 87:1327–1338

    Article  PubMed  CAS  Google Scholar 

  28. Anukulthanakorn K, Malaivijitnond S, Kitahashi T, Jaroenporn S, Parhar I (2013) Molecular events during the induction of neurodegeneration and memory loss in estrogen-deficient rats. Gen Comp Endocrinol 181:316–323

    Article  PubMed  CAS  Google Scholar 

  29. Carroll JC, Rosario ER (2012) The potential use of hormone-based therapeutics for the treatment of Alzheimer’s disease. Curr Alzheim Res 9:18–34

    Article  CAS  Google Scholar 

  30. Zhang QG, Wang R, Khan M, Mahesh V, Brann DW (2008) Role of Dickkopf-1, an antagonist of the Wnt/beta-catenin signaling pathway, in estrogen-induced neuroprotection and attenuation of tau phosphorylation. J Neurosci 28:8430–8441

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  31. Correia SC, Santos RX, Cardoso S, Carvalho C, Santos MS, Oliveira CR, Moreira PI (2010) Effects of estrogen in the brain: is it a neuroprotective agent in Alzheimer’s disease? Curr Aging Sci 3:113–126

    Article  PubMed  Google Scholar 

  32. Pompili A, Arnone B, Gasbarri A (2012) Estrogens and memory in physiological and neuropathological conditions. Psychoneuroendocrinology 37:1379–1396

    Article  PubMed  CAS  Google Scholar 

  33. Turgeon JL, Carr MC, Maki PM, Mendelsohn ME, Wise PM (2006) Complex actions of sex steroids in adipose tissue, the cardiovascular system, and brain: Insights from basic science and clinical studies. Endocr Rev 27:575–605

    Article  PubMed  CAS  Google Scholar 

  34. Bonomo SM, Rigamonti AE, Giunta M, Galimberti D, Guaita A, Gagliano MG, Muller EE, Cella SG (2009) Menopausal transition: a possible risk factor for brain pathologic events. Neurobiol Aging 30:71–80

    Article  PubMed  CAS  Google Scholar 

  35. Mitra SW, Hoskin E, Yudkovitz J, Pear L, Wilkinson HA, Hayashi S, Pfaff DW, Ogawa S, Rohrer SP, Schaeffer JM, McEwen BS, Alves SE (2003) Immunolocalization of estrogen receptor beta in the mouse brain: comparison with estrogen receptor alpha. Endocrinology 144:2055–2067

    Article  PubMed  CAS  Google Scholar 

  36. Frye CA, Duffy CK, Walf AA (2007) Estrogens and progestins enhance spatial learning of intact and ovariectomized rats in the object placement task. Neurobiol Learn Mem 88:208–216

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  37. Watanabe T, Inoue S, Hiroi H, Orimo A, Muramatsu M (1999) NMDA receptor type 2D gene as target for estrogen receptor in the brain. Brain Res Mol Brain Res 63:375–379

    Article  PubMed  CAS  Google Scholar 

  38. Leroy K, Boutajangout A, Authelet M, Woodgett JR, Anderton BH, Brion JP (2002) The active form of glycogen synthase kinase-3beta is associated with granulovacuolar degeneration in neurons in Alzheimer’s disease. Acta Neuropathol 103:91–99

    Article  PubMed  CAS  Google Scholar 

  39. Cardona-Gomez P, Perez M, Avila J, Garcia-Segura LM, Wandosell F (2004) Estradiol inhibits GSK3 and regulates interaction of estrogen receptors, GSK3, and beta-catenin in the hippocampus. Mol Cell Neurosci 25:363–373

    Article  PubMed  CAS  Google Scholar 

  40. Manji HK, Moore GJ, Chen G (1999) Lithium at 50: have the neuroprotective effects of this unique cation been overlooked? Biol Psychiatry 46:929–940

    Article  PubMed  CAS  Google Scholar 

  41. Ryves WJ, Harwood AJ (2001) Lithium inhibits glycogen synthase kinase-3 by competition for magnesium. Biochem Biophys Res Commun 280:720–725

    Article  PubMed  CAS  Google Scholar 

  42. Zhang F, Phiel CJ, Spece L, Gurvich N, Klein PS (2003) Inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3) in response to lithium. Evidence for autoregulation of GSK-3. J Biol Chem 278:33067–33077

    Article  PubMed  CAS  Google Scholar 

  43. Valdes JJ, Weeks OI (2009) Estradiol and lithium chloride specifically alter NMDA receptor subunit NR1 mRNA and excitotoxicity in primary cultures. Brain Res 1268:1–12

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  44. Valdes JJ, Ramirez FM, Juarez B, Weeks OI (2010) Lithium enhances cortical mRNA expression in ovariectomized C57BL/6J mice. Acta Neurobiol Exp (Wars) 70:288–296

    Google Scholar 

  45. Verimer T, Arneric SP, Long JP, Walsh BJ, Abou ZM (1981) Effects of ovariectomy, castration, and chronic lithium chloride treatment on stereotyped behavior in rats. Psychopharmacology (Berlin) 75:273–276

    Article  CAS  Google Scholar 

  46. Morissette M, Paolo TD (1996) Acute effect of 17 beta-estradiol and lithium on ovariectomized rat brain biogenic amines metabolism. J Psychiatr Res 30:95–107

    Article  PubMed  CAS  Google Scholar 

  47. Martin L, Latypova X, Wilson CM, Magnaudeix A, Perrin ML, Yardin C, Terro F (2013) Tau protein kinases: involvement in Alzheimer’s disease. Ageing Res Rev 12:289–309

    Article  PubMed  CAS  Google Scholar 

  48. Toledo EM, Inestrosa NC (2010) Activation of Wnt signaling by lithium and rosiglitazone reduced spatial memory impairment and neurodegeneration in brains of an APPswe/PSEN1DeltaE9 mouse model of Alzheimer’s disease. Mol Psychiatry 15(272–85):228

    Article  Google Scholar 

  49. Sharifzadeh M, Aghsami M, Gholizadeh S, Tabrizian K, Soodi M, Khalaj S, Ranjbar A, Hosseini-Sharifabad A, Roghani A, Karimfar MH (2007) Protective effects of chronic lithium treatment against spatial memory retention deficits induced by the protein kinase AII inhibitor H-89 in rats. Pharmacology 80:158–165

    Article  PubMed  CAS  Google Scholar 

  50. Yan XB, Hou HL, Wu LM, Liu J, Zhou JN (2007) Lithium regulates hippocampal neurogenesis by ERK pathway and facilitates recovery of spatial learning and memory in rats after transient global cerebral ischemia. Neuropharmacology 53:487–495

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (30971008, 30971204, 30871035, 81400886) and a grant from Population and Family Planning Commission of Wuhan (WX14B34).

Conflict of Interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Pathology and Pathophysiology, School of Basic Medicine, Institute for Brain Research, Huazhong University of Science and Technology, Hangkong Road 13#, Wuhan, 430030, China

    Na Qu, Xiang-Yu Zhou, Li Han, Lei Wang, Jia-Xin Xu, Teng Zhang, Jiang Chu, Jian-Zhi Wang, Qi Zhang & Qing Tian

  2. Department of Neurology, Liyuan Hospital, Huazhong University of Science and Technology, East Lake Ecological Scenic Lake road 39#, Wuhan, 430077, China

    Na Qu, Xiang-Yu Zhou, Li Han, Lei Wang, Jia-Xin Xu, Teng Zhang, Qiao Chen & Qi Zhang

  3. Affiliated Mental Health Centre, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Na Qu

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  1. Na Qu
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Correspondence to Qi Zhang or Qing Tian.

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Na Qu and Xiang-Yu Zhou contributed equally to the paper.

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Qu, N., Zhou, XY., Han, L. et al. Combination of PPT with LiCl Treatment Prevented Bilateral Ovariectomy-Induced Hippocampal-Dependent Cognition Deficit in Rats. Mol Neurobiol 53, 894–904 (2016). https://doi.org/10.1007/s12035-014-9050-9

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