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. 2006 Apr 5;12(3):329–336. doi: 10.1111/j.1750-3639.2002.tb00447.x

Neuronal Apoptosis in the Dentate Gyrus in Humans with Subarachnoid Hemorrhage and Cerebral Hypoxia

Roland Nau MD 1,, Sabine Haase 1, Stephanie Bunkowski 1, Wolfgang Brück MD 2
PMCID: PMC8095980  PMID: 12146801

Abstract

Apoptosis of dentate granule cells is a typical feature of several animal models of disease. In 20 autopsy cases of subarachnoid hemorrhage (SAH) and global cerebral hypoxia caused by protracted shock or respiratory failure, we evaluated by light microscopy and in situ tailing whether this pattern of neuronal damage also occurs in humans. In subarachnoid hemorrhage, 4.0/mm2 (0–13.0/mm2) a poptotic neurons were observed in the dentate gyrus, in cerebral hypoxia 3.6/mm2 (0–19.9/mm2) (p>0.05), and in 10 aged‐matched control cases dying rapidly from non‐neurological diseases 0/mm2 (0–0/mm2) (median [range]) (p<0.001 versus SAH and hypoxia). Neuronal apoptosis in the dentate gyrus was most frequent, when death occurred later than 24 hours and less than 11 days after disease onset. Neuronal damage in the hippocampus was always necrotic. It was more severe in hypoxia than in SAH (median neuronal damage score 3 [range: 0–3] versus 0 [0–3], p<0.001).

Apoptosis appears to be the predominant mechanism of death in dentate granule cells irrespective of the underlying disease, whereas neuronal death in the hippocampus generally is of necrotic morphology.

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(For a perspective on cell death mechanisms, see article by Graeber & Moran, p. 385)

References

  • 1. Bengzon J, Kokaia Z, Elmer E, Nanobashvili, Kokaia M, Lindvall O (1997) Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures. Proc Natl Acad Sci USA 94:10432–10437. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. Blankenberg FG, Strauss HW (2001) Will imaging of apoptosis play a role in clinical care? A tale of mice and man. Apoptosis 6:117–123. [DOI] [PubMed] [Google Scholar]
  • 3. Blomgren K, Zhu C, Wang X, Karlsson JO, Leverin AL, Bahr BA, Mallard C, Hagberg H (2001) Synergistic activation of caspase‐3 by m‐calpain after neonatal hypoxia‐ischemia: a mechanism of “pathological apoptosis.” J Biol Chem 276:10191–10198. [DOI] [PubMed] [Google Scholar]
  • 4. Bonfoco E, Krainc D, Ankarcrona M, Nicotera P, Lipton SA (1995) 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 92:7162–7166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. Böttiger BW, Schmitz B, Wiessner C, Vogel P, Hossmann KA (1998) Neuronal stress response and neuronal cell damage after cardiocirculatory arrest in rats. J Cereb Blood Flow Metab 18:1077–1087. [DOI] [PubMed] [Google Scholar]
  • 6. Braun JS, Sublett JE, Freyer D, Mitchell TJ, Cleveland JL, Tuomanen EI, Weber JR (2002) Pneumococcal pneumolysin and H2O2 mediate brain cell apoptosis during meningitis. J Clin Invest 109:19–27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. Brück Y, Brück W, Kretzschmar HA, Lassmann H (1996) Evidence for neuronal apoptosis in pontosubicular neuron necrosis. Neuropath Appl Neurobiol 22:23–29. [PubMed] [Google Scholar]
  • 8. Cohen JJ (1993) Apoptosis. Immunol Today 14:126–130. [DOI] [PubMed] [Google Scholar]
  • 9. Colicos MA, Dash PK (1996) Apoptotic morphology of dentate gyrus granule cells following experimental cortical impact injury in rats: possibile role in spatial memory deficits. Brain Res 739:120–131. [DOI] [PubMed] [Google Scholar]
  • 10. Conrad CD, Roy EJ (1995) Dentate gyrus destruction and spatial learning impairment after corticosteroid removal in young and middle‐aged rats. Hippocampus 5:1–15. [DOI] [PubMed] [Google Scholar]
  • 11. Covolan L, Smith RL, Mello LE (2000) Ultrastructural identification of dentate granule cell death from pilocarpine‐induced seizures. Epilepsy Res 41:9–21. [DOI] [PubMed] [Google Scholar]
  • 12. Ekdahl CT, Mohapel P, Elmer E, Lindvall O (2001) Caspase inhibitors increase short‐term survival of progenitor cell progeny in the adult rat dentate gyrus following status epilepticus. Eur J Neurosci 14:937–945. [DOI] [PubMed] [Google Scholar]
  • 13. Gerber J, Brück W, Stadelmann C, Bunkowski S, Lassmann H, Nau R (2001) Expression of death‐related proteins in dentate granule cells in human bacterial meningitis. Brain Pathol 11:422–431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. Gerber J, Raivich G, Wellmer A, Noeske C, Kunst T, Werner A, Brück W, Nau R (2001) A mouse model of Streptococcus pneumoniae meningitis mimicking several features of human disease. Acta Neuropathol 101:499–508. [DOI] [PubMed] [Google Scholar]
  • 15. Gold R, Schmied M, Rothe G, Zischler H, Breitschopf H, Wekerle H, Lassmann H (1993) Detection of DNA fragmentation in apoptosis: application of in situ nick translation to cell culture systems and tissue sections. J Histochem Cytochem 41:1023–1030. [DOI] [PubMed] [Google Scholar]
  • 16. Grasl‐Kraupp B, Ruttkay‐Nedecky B, Koudelka H, Bukowska K, Bursch W, Schulte‐Hermann R (1995) In situ detection of fragmented DNA (TUNEL assay) fails to discriminate among apoptosis, necrosis, and autolytic cell death: a cautionary note. Hepatology 21:1465–1468. [DOI] [PubMed] [Google Scholar]
  • 17. Hampton MB, Orrenius S (1997) Dual regulation of caspase activity by hydrogen peroxide: implications for apoptosis. FEBS Lett 414:552–556. [DOI] [PubMed] [Google Scholar]
  • 18. Hassan AHS, von Rosenstiel P, Patchev VK, Holsboer F, Almeida OFX (1996) Exacerbation of apoptosis in the dentate gyrus of the aged rat by dexamethasone and the protective role of corticosterone. Exp Neurol 140:43–52. [DOI] [PubMed] [Google Scholar]
  • 19. Hicks RR, Smith DH, Lowenstein DH, Saint Marie R, McIntosh TK (1993) Mild experimental brain injury in the rat induces cognitive deficits associated with regional neuronal loss in the hippocampus. J Neurotrauma 10:405–414. [DOI] [PubMed] [Google Scholar]
  • 20. Honig LS, Rosenberg RN (2000) Apoptosis and neurologic disease. Am J Med 108:317–330. [DOI] [PubMed] [Google Scholar]
  • 21. Hopkins RO, Kesner RP, Goldstein M (1995) Memory for novel and familiar spatial and linguistic temporal distance information in hypoxic subjects. J Int Neuropsychol Soc 1:454–468. [DOI] [PubMed] [Google Scholar]
  • 22. Hu BR, Liu CL, Ouyang Y, Blomgren K, Siesjö BK (2000) Involvement of caspase‐3 in cell death after hypoxiaischemia declines during brain maturation. J Cerebr Blood Flow Metab 20:1294–1300. [DOI] [PubMed] [Google Scholar]
  • 23. Hu Z, Yuri K, Ozawa H, Lu H, Kawata M (1997) The in vivo time course for elimination of adrenalectomy‐induced apoptotic profiles from the granule cell layer of the rat hippocampus. J Neurosci 17:3981–3989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. Iwai T, Hara A, Niwa M, Notaki M, Uematsu T, Sakai N, Yamada H (1995) Temporal profile of nuclear DNA fragmentation in situ in gerbil hippocampus following transient forebrain ischemia. Brain Res 671:305–308. [DOI] [PubMed] [Google Scholar]
  • 25. Kaya SS, Mahmood A, Li Y, Yavuz E, Goksel M, Chopp M (1999) Apoptosis and expression of p53 response proteins and cyclin D1 after cortical impact in rat brain. Brain Res 818:23–33. [DOI] [PubMed] [Google Scholar]
  • 26. Koedel U, Pfister H‐W (1999) Oxidative stress in bacterial meningitis. Brain Pathol 9:57–67. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27. Lafon‐Cazal M, Pietri S, Culcasi M, Bockaert J (1993) NMDA‐dependent superoxide production and neurotoxicity. Nature 364:535–537. [DOI] [PubMed] [Google Scholar]
  • 28. Leib SL, Kim YS, Chow LL, Sheldon RA, Täuber MG (1996) Reactive oxygen intermediates contribute to necrotic and apoptotic neuronal injury in an infant rat model of bacterial meningitis due to group B streptococci. J Clin Invest 98:2632–2639. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. Li Y, Chopp M, Powers C (1997) Granule cell apoptosis and protein expression in hippocampal dentate gyrus after forebrain ischemia in the rat. J Neurol Sci 150:93–102. [DOI] [PubMed] [Google Scholar]
  • 30. Linnik MD, Miller JA, Sprinkle‐Cavallo J, Mason PJ, Thompson FY, Montgomery LR, Schroeder KK (1995) Apoptotic DNA fragmentation in the rat cerebral cortex induced by permanent middle cerebral artery occlusion. Brain Res Mol Brain Res 32:116–124. [DOI] [PubMed] [Google Scholar]
  • 31. Marks N, Berg MJ (1999) Recent advances on neuronal caspase in development and neurodegeneration. Neurochem Int 35:195–220. [DOI] [PubMed] [Google Scholar]
  • 32. Martin LJ, Al‐Abdulla NA, Brambrink AM, Kirsch JR, Sieber FE, Portera‐Cailliau C (1998) Neurodegeneration in excitotoxicity, global cerebral ischemia, and target deprivation: a perspective on the contributions of apoptosis and necrosis. Brain Res Bull 46:281–309. [DOI] [PubMed] [Google Scholar]
  • 33. Martin LJ, Sieber FE, Traystman RJ (2000) Apoptosis and necrosis occur in separate neuronal populations in hippocampus and cerebellum after ischemia and are associated with differential alterations in metabotropic glutamate receptor signaling pathways. J Cerebr Blood Flow Metab 20:153–167. [DOI] [PubMed] [Google Scholar]
  • 34. Matz PG, Copin JC, Chan PH (2000) Cell death after exposure to subarachnoid hemolysate correlates inversely with expression of CuZn‐superoxide dismutase. Stroke 31:2450–2459. [DOI] [PubMed] [Google Scholar]
  • 35. Matz PG, Fujimura M, Chan PH (2000) Subarachnoid hemolysate produces DNA fragmentation in a pattern similar to apoptosis in mouse brain. Brain Res 858:312–319. [DOI] [PubMed] [Google Scholar]
  • 36. von Mering, M , Wellmer A, Michel U, Bunkowski S, Tlustochowska A, Brück W, Kuhnt U, Nau R (2001) Transcriptional regulation of caspases in experimental pneumococcal meningitis. Brain Pathol 11:282–295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37. Migheli A, Cavalla P, Marino S, Schiffer D (1994) A study of apoptosis in normal and pathological nervous tissue after in situ end‐labeling of DNA strand breaks. J Neuropathol Exp Neurol 53:606–616. [DOI] [PubMed] [Google Scholar]
  • 38. Nagai R, Tsunoda S, Hori Y, Asada H (2000) Selective vulnerability to radiation in the hippocampal dentate granule cells. Surg Neurol 53:503–506. [DOI] [PubMed] [Google Scholar]
  • 39. Nakajima W, Ishida A, Lange MS, Gabrielson KL, Wilson MA, Martin LJ, Blue ME, Johnston MV (2000) Apoptosis has a prolonged role in the neurodegeneration after hypoxic ischemia in the newborn rat. J Neurosci 20:7994–8004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. Nau R, Soto A, Brück W (1999) Apoptosis of neurons in the dentate gyrus in humans dying from bacterial meningitis. J Neuropathol Exp Neurol 58:265–274. [DOI] [PubMed] [Google Scholar]
  • 41. Northington FJ, Ferriero DM, Graham EM, Traystman RJ, Martin LJ (2001) Early neurodegeneration after hypoxia‐ischemia in neonatal rat is necrosis while delayed neuronal death is apoptosis. Neurobiol Dis 8:207–219. [DOI] [PubMed] [Google Scholar]
  • 42. Peissner W, Kocher M, Treuer H, Gillardon F (1999) Ionizing radiation‐induced apoptosis of proliferating stem cells in the dentate gyrus of the adult rat hippocampus. Brain Res Mol Brain Res 71:61–68. [DOI] [PubMed] [Google Scholar]
  • 43. Pellegrini‐Giampietro D, Cherici G, Alesiani M, Carla V, Moroni F (1990) Excitatory amino acid release and free radical formation may cooperate in the genesis of ischemia‐induced neuronal damage. J Neurosci 10:1035–1041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44. Pulera MR, Adams LM, Liu H, Santos DG, Nishimura RN, Yang F, Cole GM, Wasterlain CG (1998) Apoptosis in a neonatal rat model of cerebral hypoxia‐ischemia. Stroke 29:2622–2630. [DOI] [PubMed] [Google Scholar]
  • 45. Reynolds IJ, Hastings TG (1995) Glutamate induces the production of reactive oxygen species in cultured forebrain neurons following NMDA receptor activation. J Neurosci 15:3318–3327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46. Richardson JT (1991). Cognitive performance following rupture and repair of intracranial aneurysm. Acta Neurol Scand 83:110–122. [DOI] [PubMed] [Google Scholar]
  • 47. Sastry PS, Rao KS (2000) Apoptosis and the nervous system. J Neurochem 74:1–20. [DOI] [PubMed] [Google Scholar]
  • 48. Saukkonen K, Sande S, Cioffe C, Wolpe S, Sherry B, Cerami A, Tuomanen E (1990) The role of cytokines in the generation of inflammation and tissue damage in experimental gram‐positive meningitis. J Exp Med 171:439–448. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49. Schmidt H, Tlustochowska A, Stuertz K, Djukic M, Gerber J, Schütz E, Kuhnt U, Nau R (2001) Organotypic hippocampal cultures ‐ a model of brain tissue damage in Streptococcus pneumoniae meningitis. J Neuroimmunol 113:30–39. [DOI] [PubMed] [Google Scholar]
  • 50. Scoville WB, Milner B (1957) Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiat 20:11–21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51. Sloviter RS (2002) Apoptosis: a guide for the perplexed. Trends Pharmacol Sci 23:19–24. [DOI] [PubMed] [Google Scholar]
  • 52. Sloviter RS, Dean E, Neubort S (1993) Electron microscopic analysis of adrenalectomy‐induced hippocampal granule cell degeneration in the rat: apoptosis in the adult central nervous system. J Comp Neurol 330:337–351. [DOI] [PubMed] [Google Scholar]
  • 53. Sloviter RS, Valiquette G, Abrams GM, Ronk EC, Sollas AL, Paul LA, Neubort S (1989) Selective loss of hippocampal granule cells in the mature rat brain after adrenalectomy. Science 243:535–538. [DOI] [PubMed] [Google Scholar]
  • 54. Tumani H, Smirnov A, Barchfeld S, Olgemöller U, Maier K, Lange P, Brück W, Nau R (2000) Inhibition of glutamine synthetase in rabbit pneumococcal meningitis is associated with neuronal apoptosis in the dentate gyrus. Glia 30:11–18. [DOI] [PubMed] [Google Scholar]
  • 55. Vaher PR, Luine VN, Gould E, McEwen BS (1994) Effects of adrenalectomy on spatial memory performance and dentate gyrus morphology. Brain Res 656:71–78. [DOI] [PubMed] [Google Scholar]
  • 56. Volterra A, Trotti D, Tromba C, Floridi S, Racagni G (1994) Glutamate uptake inhibition by oxygen free radicals in rat cortical astrocytes. J Neurosci 14:2924–2932. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57. Wang HD, Fukuda T, Suzuki T, Hashimoto K, Liou SY, Momoi T, Kosaka T, Yamamoto K, Nakanishi H (1999) Differential effects of Bcl‐2 overexpression on hippocampal CA1 neurons and dentate granule cells following hypoxic ischemia in adult mice. J Neurosci Res 57:1–12. [DOI] [PubMed] [Google Scholar]
  • 58. Yakovlev AG, Knoblach SM, Fan L, Fox GB, Goodnight R, Faden AI (1997) Activation of CPP32‐like caspases contributes to neuronal apoptosis and neurological dysfunction after traumatic brain injury. J Neurosci 17:7415–7424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59. Zola‐Morgan SM, Squire LR (1990) The primate hippocampal formation: evidence for a time‐limited role in memory storage. Science 250:288–290. [DOI] [PubMed] [Google Scholar]
  • 60. Zysk G, Brück W, Gerber J, Brück Y, Prange HW, Nau R (1996) Anti‐inflammatory treatment influences neuronal apoptotic cell death in the dentate gyrus in experimental pneumococcal meningitis. J Neuropathol Exp Neurol 55:722–728. [DOI] [PubMed] [Google Scholar]

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