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Regulation of Adrenocorticotropin and Brain Actions of Corticoids

The Exacerbation of Hippocampal Excitotoxicity by Glucocorticoids Is Not Mediated by Apoptosis

Roy M. · Sapolsky R.M.

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Department of Biological Sciences, Stanford University, Stanford, Calif., USA

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Neuroendocrinology 2003;77:24–31

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Article / Publication Details

First-Page Preview
Abstract of Regulation of Adrenocorticotropin and Brain Actions of Corticoids

Received: June 24, 2002
Accepted: November 19, 2002
Published online: March 10, 2003
Issue release date: January 2003

Number of Print Pages: 8
Number of Figures: 3
Number of Tables: 0

ISSN: 0028-3835 (Print)
eISSN: 1423-0194 (Online)

For additional information: https://www.karger.com/NEN

Abstract

Both endogenous and exogenous glucocorticoids (GCs) are known to cause apoptosis in a number of peripheral tissues and in some cases in the CNS. Additionally, GCs can exacerbate the neuron loss associated with such acute neurological insults as hypoxia-ischemia, excitotoxicity, and metabolic disruption. This exacerbation is accompanied by increased accumulation of glutamate in the synapse, excessive cytosolic calcium, and increased oxygen radical activity, markers usually attributed to pathways of necrotic cell death. It is also known that acute insults can involve apoptotic mediators. In this context, one outstanding question that has received little attention is whether the exacerbation of insult-mediated cell death in neurons is apoptotic in mechanism. In this study we investigate whether the GC-mediated exacerbation of hippocampal excitotoxicity in culture involves apoptosis. Specifically, we show that while the magnitude of hippocampal neuron death caused by the excitotoxin kainic acid is indeed worsened in the presence of GCs, there is no evidence of increased markers of apoptosis. Specifically, we show that neither kainic acid nor GCs alone, or in combination, cause activation of caspase 3, a critical executor of insult-induced apoptosis. Furthermore, while kainic acid causes a significant incidence of apoptotic nuclear condensation, the incidence of this morphological indicator of apoptosis is not worsened by GCs. Thus, GCs appear to augment excitotoxic death in hippocampal neurons without augmenting the occurrence of apoptosis. We suggest that this finding is to be expected, given some energetic features of GC action and the energetic demands of apoptosis.

© 2003 S. Karger AG, Basel


References

  1. Sapolsky RM, Romero LM, Munck AU: How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr Rev 2000;21:55–89.
  2. Joels M, de Kloet ER: Control of neuronal excitability by corticosteroid hormones. Trends Neurosci 1992;15:25–30.
  3. Bodnoff SR, Humphreys AG, Lehman JC, Diamond DM, Rose GM, Meaney MJ: Enduring effects of chronic corticosterone treatment on spatial learning, synaptic plasticity, and hippocampal neuropathology in young and mid-aged rats. J Neurosci 1995;15:61–69.
  4. Gould E, Cameron HA, Daniels DC, Woolley CS, McEwen BS: Adrenal hormones suppress cell division in the adult rat dentate gyrus. J Neurosci 1992;12:3642–3650.
  5. Woolley CS, Gould E, McEwen BS: Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons. Brain Res 1990;531:225–231.
  6. Watanabe Y, Gould E, McEwen BS: Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons. Brain Res 1992;588:341–343.
  7. Sapolsky RM, Krey LC, McEwen BS: Prolonged glucocorticoid exposure reduces hippocampal neuron number: Implications for aging. J Neurosci 1985;5:1222–1227.
  8. Sapolsky RM: Stress, glucocorticoids, and damage to the nervous system: The current state of confusion. Stress 1996;1:1–19.
  9. Chihab R, Oillet J, Bossenmeyer C, Daval JL: Glutamate triggers cell death specifically in mature central neurons through a necrotic process. Mol Genet Metab 1998;63:142–147.
  10. Choi DW: Ischemia-induced neuronal apoptosis. Curr Opin Neurobiol 1996;6:667–672.
  11. Fujikawa DG, Shinmei SS, Cai B: Kainic acid-induced seizures produce necrotic, not apoptotic, neurons with internucleosomal DNA cleavage: Implications for programmed cell death mechanisms. Neuroscience 2000;98:41–53.
  12. Gwag BJ, Koh JY, DeMaro JA, Ying HS, Jacquin M, Choi DW: Slowly triggered excitotoxicity occurs by necrosis in cortical cultures. Neuroscience 1997;77:393–401.
    External Resources
  13. Simonian NA, Getz RL, Leveque JC, Konradi C, Coyle JT: Kainic acid induces apoptosis in neurons. Neuroscience 1996;75:1047–1055.
  14. Wyllie AH, Kerr JF, Currie AA: Cell death: The significance of apoptosis. Int Rev Cytol 1980;68:251–306.
  15. Chan SL, Mattson MP: Caspase and calpain substrates: Roles in synaptic plasticity and cell death. J Neurosci Res 1999;58:167–190.
  16. Ankarcrona M, Dypbukt JM, Bonfoco E, Zhivotovsky B, Orrenius S, Lipton SA, Nicotera P: Glutamate-induced neuronal death: A succession of necrosis or apoptosis depending on mitochondrial function. Neuron 1995;15:961–973.
  17. Bonfoco E, Krainc D, Ankarcrona M, Nicotera P, Lipton SA: Apoptosis and necrosis: Two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures. Proc Natl Acad Sci USA 1995;92:7162–166.
  18. McIntosh LJ, Sapolsky RM: Glucocorticoids increase the accumulation of reactive oxygen species and enhance adriamycin-induced toxicity in neuronal culture. Exp Neurol 1996;141:201–206.
  19. Lowy MT, Wittenberg L, Novotney S: Adrenalectomy attenuates kainic acid-induced spectrin proteolysis and heat shock protein 70 induction in hippocampus and cortex. J Neurochem 1994;63:886–894.
  20. Elliott EM, Sapolsky RM: Corticosterone enhances kainic acid-induced calcium elevation in cultured hippocampal neurons. J Neurochem 1992;59:1033–1040.
  21. Stein-Behrens BA, Elliott EM, Miller CA, Schilling JW, Newcombe R, Sapolsky RM: Glucocorticoids exacerbate kainic acid-induced extracellular accumulation of excitatory amino acids in the rat hippocampus. J Neurochem 1992;58:1730–1735.
  22. Reagan LP, McEwen BS: Controversies surrounding glucocorticoid-mediated cell death in the hippocampus. J Chem Neuroanat 1997;13:149–167.
    External Resources
  23. Masters JN, Finch CE, Sapolsky RM: Glucocorticoid endangerment of hippocampal neurons does not involve deoxyribonucleic acid cleavage. Endocrinology 1989;124:3083–3088.
  24. Meier TJ, Ho DY, Sapolsky RM: Increased expression of calbindin D28k via herpes simplex virus amplicon vector decreases calcium ion mobilization and enhances neuronal survival after hypoglycemic challenge. J Neurochem 1997;69:1039–1047.
  25. Sapolsky RM, Packan DR, Vale WW: Glucocorticoid toxicity in the hippocampus: In vitro demonstration. Brain Res 1988;453:367–371.
  26. Koh JY, Wie MB, Gwag BJ, Sensi SL, Canzoniero LM, Demaro J, Csernansky C, Choi DW: Staurosporine-induced neuronal apoptosis. Exp Neurol 1995;135:153–159.
  27. Bertrand R, Solary E, O’Connor P, Kohn KW, Pommier Y: Induction of a common pathway of apoptosis by staurosporine. Exp Cell Res 1994;211:314–321.
  28. Bredesen DE: Neural apoptosis. Ann Neurol 1995;38:839–851.
  29. Nicotera P, Lipton SA: Excitotoxins in neuronal apoptosis and necrosis. J Cereb Blood Flow Metab 1999;19:583–591.
  30. Tenneti L, Lipton SA: Involvement of activated caspase-3-like proteases in N-methyl-D-aspartate-induced apoptosis in cerebrocortical neurons. J Neurochem 2000;74:134–142.
  31. Singleton JR, Baker BL, Thorburn A: Dexamethasone inhibits insulin-like growth factor signaling and potentiates myoblast apoptosis. Endocrinology 2000;141:2945–2950.
  32. Eberhardt AW, Yeager-Jones A, Blair HC: Regional trabecular bone matrix degeneration and osteocyte death in femora of glucocorticoid-treated rabbits. Endocrinology 2001;142:1333–1340.
  33. Rogatsky I, Hittelman AB, Pearce D, Garabedian MJ: Distinct glucocorticoid receptor transcriptional regulatory surfaces mediate the cytotoxic and cytostatic effects of glucocorticoids. Mol Cell Biol 1999;19:5036–5049.
  34. Gohel A, McCarthy MB, Gronowicz G: Estrogen prevents glucocorticoid-induced apoptosis in osteoblasts in vivo and in vitro. Endocrinology 1999;140:5339–5347.
  35. Yazawa H, Sasagawa I, Nakada T: Apoptosis of testicular germ cells induced by exogenous glucocorticoid in rats. Hum Reprod 2000;15:1917–1920.
  36. Wyllie AH: Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 1980;284:555–556.
  37. Mann CL, Cidlowski JA: Glucocorticoids regulate plasma membrane potential during rat thymocyte apoptosis in vivo and in vitro. Endocrinology 2001;142:421–429.
  38. Gold R, Buttgereit F, Toyka KV: Mechanism of action of glucocorticosteroid hormones: Possible implications for therapy of neuroimmunological disorders. J Neuroimmunol 2001;117:1–8.
  39. Riccardi C, Cifone MG, Migliorati G: Glucocorticoid hormone-induced modulation of gene expression and regulation of T-cell death: Role of GITR and GILZ, two dexamethasone-induced genes. Cell Death Differ 1999;6:1182–1189.
  40. Yang Y, Fang S, Jensen JP, Weissman AM, Ashwell JD: Ubiquitin protein ligase activity of IAPs and their degradation in proteasomes in response to apoptotic stimuli. Science 2000;288:874–877.
  41. Miyashita T, Nagao K, Krajewski S, Salvesen GS, Reed JC, Inoue T, Yamada M: Investigation of glucocorticoid-induced apoptotic pathway: Processing of caspase-6 but not caspase-3. Cell Death Differ 1998;5:1034–1041.
  42. Touchette N: Cell death program may hold new key for cancer therapy. J NIH Res 1992;4:35.
  43. Mann CL, Hughes FM Jr, Cidlowski JA: Delineation of the signaling pathways involved in glucocorticoid-induced and spontaneous apoptosis of rat thymocytes. Endocrinology 2000;141:528–538.
  44. Compton MM, Cidlowski JA: Rapid in vivo effects of glucocorticoids on the integrity of rat lymphocyte genomic deoxyribonucleic acid. Endocrinology 1986;118:38–45.
  45. Evans-Storms RB, Cidlowski JA: Regulation of apoptosis by steroid hormones. J Steroid Biochem Mol Biol 1995;53:1–8.
  46. Khan AA, Soloski MJ, Sharp AH, Schilling G, Sabatini DM, Li SH, Ross CA, Snyder SH: Lymphocyte apoptosis: Mediation by increased type 3 inositol 1,4,5-trisphosphate receptor. Science 1996;273:503–507.
  47. Sousa N, Paula-Barbosa MM, Almeida OF: Ligand and subfield specificity of corticoid-induced neuronal loss in the rat hippocampal formation. Neuroscience 1999;89:1079–1087.
  48. Griffiths MR, Cooper AJ, Barber DJ, Mitchell IJ: Pharmacological mechanisms mediating phencyclidine-induced apoptosis of striatopallidal neurons: The roles of glutamate, dopamine, acetylcholine and corticosteroids. Brain Res 2000;855:1–10.
  49. Mitchell IJ, Cooper AJ, Griffiths MR, Barber DJ: Phencyclidine and corticosteroids induce apoptosis of a subpopulation of striatal neurons: A neural substrate for psychosis? Neuroscience 1998;84:489–501.
  50. Haynes LE, Griffiths MR, Hyde RE, Barber DJ, Mitchell IJ: Dexamethasone induces limited apoptosis and extensive sublethal damage to specific subregions of the striatum and hippocampus: Implications for mood disorders. Neuroscience 2001;104:57–69.
  51. Persengiev SP: The neuroprotective and antiapoptotic effects of melatonin in cerebellar neurons involve glucocorticoid receptor and p130 signal pathways. J Steroid Biochem Mol Biol 2001;77:151–158.
  52. Ahlbom E, Gogvadze V, Chen M, Celsi G, Ceccatelli S: Prenatal exposure to high levels of glucocorticoids increases the susceptibility of cerebellar granule cells to oxidative stress-induced cell death. Proc Natl Acad Sci USA 2000;97:14726–14730.
  53. Hassan AH, von Rosenstiel P, Patchev VK, Holsboer F, Almeida OF: Exacerbation of apoptosis in the dentate gyrus of the aged rat by dexamethasone and the protective role of corticosterone. Exp Neurol 1996;140:43–52.
  54. McCullers DL, Herman JP: Mineralocorticoid receptors regulate bcl-2 and p53 mRNA expression in hippocampus. Neuroreport 1998;9:3085–3089.
  55. DeVries AC, Joh HD, Bernard O, Hattori K, Hurn PD, Traystman RJ, Alkayed NJ: Social stress exacerbates stroke outcome by suppressing Bcl-2 expression. Proc Natl Acad Sci USA 2001;98:11824–11828.
  56. Lucassen PJ, Vollmann-Honsdorf GK, Gleisberg M, Czeh B, De Kloet ER, Fuchs E: Chronic psychosocial stress differentially affects apoptosis in hippocampal subregions and cortex of the adult tree shrew. Eur J Neurosci 2001;14:161–166.
  57. Nakai M, Qin ZH, Chen JF, Wang Y, Chase TN: Kainic acid-induced apoptosis in rat striatum is associated with nuclear factor-kappaB activation. J Neurochem 2000;74:647–658.
  58. Sasson R, K. Tajima K, Amsterdam A: Glucocorticoids protect against apoptosis induced by serum deprivation, cyclic adenosine 3′,5′-monophosphate and p53 activation in immortalized human granulosa cells: Involvement of Bcl-2. Endocrinology 2001;142:802–811.
  59. Sloviter RS, Dean E, Neubort S: Electron microscopic analysis of adrenalectomy-induced hippocampal granule cell degeneration in the rat: Apoptosis in the adult central nervous system. J Comp Neurol 1993;330:337–351.
  60. Sloviter RS, Sollas AL, Dean E, Neubort S: Adrenalectomy-induced granule cell degeneration in the rat hippocampal dentate gyrus: Characterization of an in vivo model of controlled neuronal death. J Comp Neurol 1993;330:324–336.
  61. Woolley CS, Gould E, Sakai RR, Spencer RL, McEwen BS: Effects of aldosterone or RU28362 treatment on adrenalectomy-induced cell death in the dentate gyrus of the adult rat. Brain Res 1991;554:312–315.
  62. Brandoli C, Shi B, Pflug B, Andrews P, Wrathall JR, Mocchetti I: Dexamethasone reduces the expression of p75 neurotrophin receptor and apoptosis in contused spinal cord. Brain Res Mol Brain Res 2001;87:61–70.
  63. Nicotera P: Apoptosis and age-related disorders: Role of caspase-dependent and caspase-independent pathways. Toxicol Lett 2002;127:189–195.
  64. Kadekaro M, Ito M, Gross PM: Local cerebral glucose utilization is increased in acutely adrenalectomized rats. Neuroendocrinology 1988;47:329–334.
  65. Horner HC, Packan DR, Sapolsky RM: Glucocorticoids inhibit glucose transport in cultured hippocampal neurons and glia. Neuroendocrinology 1990;52:57–64.
  66. Sapolsky RM: Glucocorticoid toxicity in the hippocampus: Reversal by supplementation with brain fuels. J Neurosci 1986;6:2240–2244.
  67. Saleh A, Srinivasula SM, Acharya S, Fishel R, Alnemri ES: Cytochrome c and dATP-mediated oligomerization of Apaf-1 is a prerequisite for procaspase-9 activation. J Biol Chem 1999;274:17941–17945.
  68. Hu Y, Benedict MA, Ding L, Nunez G: Role of cytochrome c and dATP/ATP hydrolysis in Apaf-1-mediated caspase-9 activation and apoptosis. EMBO J 1999;18:3586–3595.
  69. Hunot S, Flavell RA: Apoptosis: Death of a monopoly? Science 2001;292:865–866.
  70. Lucassen PJ, Muller MB, Holsboer F, Bauer J, Holtrop A, Wouda J, Hoogendijk WJ, De Kloet ER, Swaab DF: Hippocampal apoptosis in major depression is a minor event and absent from subareas at risk for glucocorticoid overexposure. Am J Pathol 2001;158:453–468.

Article / Publication Details

First-Page Preview
Abstract of Regulation of Adrenocorticotropin and Brain Actions of Corticoids

Received: June 24, 2002
Accepted: November 19, 2002
Published online: March 10, 2003
Issue release date: January 2003

Number of Print Pages: 8
Number of Figures: 3
Number of Tables: 0

ISSN: 0028-3835 (Print)
eISSN: 1423-0194 (Online)

For additional information: https://www.karger.com/NEN


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