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Protective Effect Against 17β-Estradiol on Neuronal Apoptosis in Hippocampus Tissue Following Transient Ischemia/Recirculation in Mongolian Gerbils via Down-Regulation of Tissue Transglutaminase Activity

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Abstract

We analyzed the protective effect of 17β-estradiol (17β-ED) injection against delayed neuronal death in the hippocampus tissue of the brain in Mongolian gerbils after transient ischemia/recirculation treatment, especially in relation with bcl-2 gene expression and enzymatic activity changes of caspase-3 and tissue transglutaminase (tTGase). Daily intraperitoneal injection of 17β-ED to the animal after the ischemia stimulated the expression of an apoptosis suppressor gene, bcl-2, in the hippocampal tissue for a week. The gradually increasing apoptotic enzyme activity of caspase-3 and increased number of TUNEL positive fragmented neuronal nuclei caused by ischemic attack in the gerbil brain were clearly suppressed by 17β-ED administration. The reduced activity and enzyme protein of tTGase, a neurodegenerative marker of apoptosis in the hippocampus after ischemia, were also restored to nearly normal levels by 17β-ED injection. These results suggest that daily 17β-ED administration to the gerbil after transient ischemic insult with progressing neuronal deteriorative changes in hippocampus tissue can effectively prevent apoptotic changes through a molecular cascade involving gene expression regulation.

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References

  1. Kirino T (1982) Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res 239:57–69

    Article  PubMed  CAS  Google Scholar 

  2. Pulsinelli WC, Brierly JB, Plum F (1982) Temporal profile of neuronal damage in a model of transient forebrain ischemia. Ann Neurol 11:491–498

    Article  PubMed  CAS  Google Scholar 

  3. Nitatori T, Sato N, Waguri S, Kurasawa Y, Arai M, Shibatani K, Kominami E, Uchimura Y (1995) Delayed neuronal death in the CA1 pyramidal cell layer in the gerbil hippocampus following transient ischemia is apoptosis. J Neurosci 15:1001–1011

    PubMed  CAS  Google Scholar 

  4. Chen J, Graham SH, Nakajima M, Zhu RL, Jin KL, Stetler RA, Simon RP (1997) Apoptosis receptor genes bcl-2 and bcl-x-long are expressed in the rat brain following global ischemia. J Cereb Blood Flow Metab 17:1–10

    Google Scholar 

  5. Namura S, Zhu J, Fink K, Enders M, Srinivasan A, Tomaselli KJ, Yuan J, Moskovitz MA (1998) Activation and cleavage of caspase-3 in apoptosis induced by experimental cerebral ischemia. J Neurosci 18:3659–3668

    PubMed  CAS  Google Scholar 

  6. Emerson CS,Headrick JP, Vink R (1993) Estrogen improves biochemical and neurologic outcome following traumatic brain injury in male rats, but not in females. Brain Res 608:95–100

    Article  PubMed  CAS  Google Scholar 

  7. Goodman Y, Gruce AJ, Cheng B, Mattson MP (1996) Estrogen attenuate and corticosterone exacerbates excitotoxicity, oxidative injury, and amyloid β-peptide toxicity in hippocampal neurons. J Neurocjem 66:1836–1844

    Article  CAS  Google Scholar 

  8. Sudo S, Wen T-C, Desaki J, Matsuda S, Tanaka J, Arai T, Maeda N, Sakanaka M (1997) βEstradiol protects hippocampal CA1 neurons against transient forebrain ischemia in gerbil. Neurosci Res 29:345–354

    Article  PubMed  CAS  Google Scholar 

  9. Dubal DB, Shughrue PJ, Wilson ME, Merchenthaler I, Wise PM (1999) Estradiol modulates bcl-2 in cerebral ischemia: a potential role for estrogen receptors. J Neurosci 19:6385–6393

    PubMed  CAS  Google Scholar 

  10. Harukuni I, Hurn PD, Crain BJ (2001) Deleterious effect of β-estradiol in a rat model of transient forebrain ischemia. Brain Res 900:137–142

    Article  PubMed  CAS  Google Scholar 

  11. Chan PH (1994) Oxygen radicals in focal cerebral ischemia. Brain Pathol 4:59–65

    Article  PubMed  CAS  Google Scholar 

  12. Culmsee C, Vedder H, Ravati A, Otto D, Ahlemeyer B, Krieg JC, Krieglstein J (1999) 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 19:1263–1269

    Article  PubMed  CAS  Google Scholar 

  13. Chen J, Xu W, Jiang H (2001) 17β-estradiol protects neurons from ischemic damage and attenuates accumulation of extracellular excitatory amino acids. Anesth Analg 92:1520–1523

    Article  PubMed  CAS  Google Scholar 

  14. Dubal DB, Zhu H, Yu J, Rau SW, Shughrue PJ, Merchenthaler I, Kindy MS, Wise PM (2001) Estradiol receptor alpha, not beta, is a critical link in estradiol-mediated protection against brain. Proc Natl Acad Sci USA 98:1952–1957

    Article  PubMed  CAS  Google Scholar 

  15. Oliverio S, Amendola A, Sano FD, Farrace MG, Fesus L, Nemes Z, Piredda L, Spinedi A, Piacentini M (1997) Tissue transglutaminase-dependent posttranslational modification of the retinoblastoma gene product in promonocytic cells undergoing apoptosis. Mol Cell Biol 17:6040–6048

    PubMed  CAS  Google Scholar 

  16. Melino G, Piacentini M (1998) ‘ Tissue’ transglutaminase in cell death: a downstream or a multifunctional upstream effector? FEBS Lett 430:59–63

    Article  PubMed  CAS  Google Scholar 

  17. Thomazy VA, Davies PJ (1999) Expression of tissue transglutaminase in the developing chicken limb is associated both with apoptosis and endochondral ossification. Cell Death Differ 6:146–154

    Article  PubMed  CAS  Google Scholar 

  18. Stone GC, Hammerschlag R (1981) Differential effects of cobalt on the initiation of fast axonal transport. Cell Mol Neurobiol 1:3–17

    Article  PubMed  CAS  Google Scholar 

  19. Matsudaira P (1987) Sequence from picomole quantities of proteins electroblotted onto polyvinyl difluoride membranes. J Biol Chem 262:10035–10038

    PubMed  CAS  Google Scholar 

  20. Matsui T, Fujimura S, Nishida S, Titani K (1993) Human plasma α2-macroglobulin and von Wilbrand factor posses covalently linked ABO Rh blood group antigens in subjects with corresponding ABO phenotype. Blood 82:663–668

    PubMed  CAS  Google Scholar 

  21. Lorand L, Campbell-Wilkes LK, Cooperstein L (1972) A filter paper assay for transamidating enzymes using radioactive amine substrates. Anal Biochem 72:17–23

    Google Scholar 

  22. Ando M, Kunii S, Tatematsu T, Nagata Y (1993) Rapid and transient alterations in transglutaminase activity in rat superior ganglion following denervation or axotomy. Neurosci Res 17:47–52

    Article  PubMed  CAS  Google Scholar 

  23. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein dye binding. Anal Biochem 72:248–252

    Article  PubMed  CAS  Google Scholar 

  24. Pattmann B, Henderson CE (1998) Neuronal cell death. Neuron 20:633–647

    Article  Google Scholar 

  25. Chan HP (2004) Mitochondria and neuronal death/survival signaling pathways in cerebral ischemia. Neurochem Res 29:1943–1949

    Article  PubMed  CAS  Google Scholar 

  26. Kitagawa K, Matsumoto M, Tsujimoto Y, Ohtsuki T, Kuwabata K, Matsushita K, Yang G, Tanabe H, Martinou J-C, Hori M, Yanagihara T (1998) Amelioration of hippocampal neuronal damage after global ischemia by neuronal overexpression of bcl-2 in transgenic mice. Stroke 29:2616–2621

    PubMed  CAS  Google Scholar 

  27. Garcia I, Martinou I, Tsujimoto Y, Martinou JC (1992) Prevention of programmed cell death of sympathetic neurons by bcl-2 proto-oncogene. Science 258:302–304

    Article  PubMed  CAS  Google Scholar 

  28. Allsopp TE, Wyatt S, Paterson HF, Davies AM (1993) The proto-oncogene bcl-2 can selectively rescue neurotrophic factor-dependent neurons from apoptosis. Cell 73:295–307

    Article  PubMed  CAS  Google Scholar 

  29. Farlie PG, Dringen R, Rees SM, Kannourakis G, Bernard O (1995) Bcl-2 transgene expression can protect neurons against developmental and induced cell death. Proc Natl Acad Sci USA 92:4397–4401

    Article  PubMed  CAS  Google Scholar 

  30. Krajewski S, Mai JK, Krajewska M, Sikorska M, Mossakowski MJ, Reed JC (1995) Upregulation of Bax protein levels in neurons following cerebral ischemia. J Neurosci 15:6364–6376

    PubMed  CAS  Google Scholar 

  31. Pike CJ (1999) Estrogen modulates neuronal Bcl-xL expression and β-amyloid induced apoptosis: relevance to Alzheimer’s disease. J Neurochem 72:1552–1563

    Article  PubMed  CAS  Google Scholar 

  32. Jover T, Tanaka H, Calderone A, Oguro K, Bennett MVL, Etgen AM, Zukin RS (2002) estrogen protects agonist global ischemia-induced neuronal death and prevents activation of apoptotic signaling cascades in the hippocampal CA1. J Neurosci 22:2115–2124

    PubMed  CAS  Google Scholar 

  33. Wise MP (2000) Estradiol: A protective factor in the adult brain. J Pediatr Endocr Met 13:1425–1429

    Google Scholar 

  34. Zhao H, Yenaei AM, Cheng D, Sapolsky MR, Steinberg KG (2003) Bcl-2 over-expression protects against neuron loss within the ischemic margin following experimental stroke and inhibits cytochrome C translocation and caspase-3 activity. J Neurochem 85:1026–1036

    Article  PubMed  CAS  Google Scholar 

  35. Greenberg CS, Birckbichler PJ, Rice RH (1992) Transglutaminase: multifunctional cross-linking enzymes that stabilize tissues. FASEB J 3071–3077

  36. Fujita K, Ando M, Yamauchi M, Nagata Y, Honda M (1995) Alteration of transglutaminase activity in rat and human spinal cord after neuronal degeneration. Neurochem Res 20:1195–2001

    Article  PubMed  CAS  Google Scholar 

  37. Folk JE (1980) Transglutaminase. Ann Rev Biochem 49:517–531

    Article  PubMed  CAS  Google Scholar 

  38. Fesus L, Thomazy V, Falus A (1988) Reaching for function of tissue transglutaminase; its possible involvement in biochemical pathway of programmed cell death. Adv Exp Biol 231:119–139

    CAS  Google Scholar 

  39. Johnson VWG, Cox MT, Lockhart PJ, Zinnerman DM, Miller LM, Powers ER (1997) Transglutaminase activity is increased in Alzheimer’s disease brain. Brain Res 751:323–(329)

    Article  PubMed  CAS  Google Scholar 

  40. Fujita K, Shibayama K, Yamauchi M, Kato T, Takahashi H, Iritani K, Yoshimoto N, Nagata Y (1998) Alteration of enzymic activities implicating in neuronal degeneration in the spinal cord of motor neuron degeneration mouse during postnatal development. Neurochem Res 23:561–566

    Google Scholar 

  41. Fesus L (1998) Transglutaminase-catalyzed protein cross-linking in the molecular program of apoptosis and its relationship to neuronal process. Cell Mol Neurobiol 18:683–694

    Article  PubMed  CAS  Google Scholar 

  42. Melino G, Annicchiarico-Petruzzelli M, Piredda L, Candi E, Gentile V, Davies PJ, Piacentini M (1994) Tissue transglutaminase and apoptosis: sense and antisense transfection studies with human neuroblastoma cells. Mol Cell Biol 14:6584–6596

    PubMed  CAS  Google Scholar 

  43. Green DR (1999) Harm’s way: Polyglutamine repeats and the activation of an apoptotic pathway. Neuron 22:416–417

    Article  PubMed  CAS  Google Scholar 

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Fujita, K., Kato, T., Shibayama, K. et al. Protective Effect Against 17β-Estradiol on Neuronal Apoptosis in Hippocampus Tissue Following Transient Ischemia/Recirculation in Mongolian Gerbils via Down-Regulation of Tissue Transglutaminase Activity. Neurochem Res 31, 1059–1068 (2006). https://doi.org/10.1007/s11064-006-9114-y

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