Role of µ-Calpain I and Lysosomal Cathepsins in Hippocampal Neuronal Necrosis After Transient Global Ischemia in Primates

  • Anton B. Tonchev
  • Tetsumori Yamashima


Transient global cerebral ischemia inflicts damage on selective neuronal populations. The most sensitive of these are pyramidal neurons in the cornu Ammonis (CA) 1 sector of the hippocampus. In contrast to focal ischemic insult, neuronal death after global ischemia is postponed by a few days, then designated delayed neuronal death (DND). This time lag provides scientists with the intriguing opportunity of using this time window to counteract the pro-death mechanisms. The latter have been a subject of intensive investigations for more than two decades, with different types of cell demise put on the scene, including necrosis, apoptosis, and autophagy. Here, we shall review the molecular events known to occur in a primate model of transient global cerebral ischemia,0 focusing on the enzymes µ-calpain and cathepsin(s), and their involvement in neuronal necrosis. A decade after the “calpain–cathepsin hypothesis” of DND had been proposed, a paradigm shift is occurring in our understanding of necrosis. It was classically considered to be an uncontrolled and poorly regulated process, while recent evidence seems to suggest that necrosis is a highly orchestrated and evolutionally conserved program of cell death. Calpain and cathepsins appear to be central molecular players in this program, and thus represent appropriate molecular targets for neuroprotection.


Necrotic Cell Death Autophagosome Formation Calpain Inhibitor Neuronal Necrosis Global Brain Ischemia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Adhami F, Liao G, Morozov YM et al (2006) Cerebral ischemia-hypoxia induces intravascular coagulation and autophagy. Am J Pathol 169:566–583PubMedCrossRefGoogle Scholar
  2. Artal-Sanz M, Samara C, Syntichaki P et al (2006) Lysosomal biogenesis and function is critical for necrotic cell death in Caenorhabditis elegans. J Cell Biol 173:231–239PubMedCrossRefGoogle Scholar
  3. Benetti R, Del Sal G, Monte M et al (2001) The death substrate Gas2 binds m-calpain and increases susceptibility to p53-dependent apoptosis. EMBO J 20:2702–2714PubMedCrossRefGoogle Scholar
  4. Cao G, Xing J, Xiao X et al (2007) Critical role of calpain I in mitochondrial release of apoptosis-inducing factor in ischemic neuronal injury. J Neurosci 29:9278–9293CrossRefGoogle Scholar
  5. Chapman HA, Riese RJ, Shi GP (1997) Emerging roles for cysteine proteases in human biology. Annu Rev Physiol 59:63–88PubMedCrossRefGoogle Scholar
  6. Croall DE, Demartino GN (1991) Calcium-activated neutral protease (calpain) system: structure, function, and regulation. Physiol Rev 81:813–847Google Scholar
  7. Colbourne F, Sutherland GR, Auer RN (1999) Electron microscopic evidence against apoptosis as the mechanism of neuronal death in global ischemia. J Neurosci 19:4200–4210PubMedGoogle Scholar
  8. Debnath J, Baehrecke EH, Kroemer G (2005) Does autophagy contribute to cell death? Autophagy 1:66–74PubMedCrossRefGoogle Scholar
  9. Demarchi F, Bertoli C, Copetti T et al (2006) Calpain is required for macroautophagy in mammalian cells. J Cell Biol 175:595–605PubMedCrossRefGoogle Scholar
  10. Demarchi F, Bertoli C, Copetti T et al (2007) Calpain as a novel regulator of autophagosome formation. Autophagy 3:235–237PubMedGoogle Scholar
  11. Deshpande JK, Siesjö BK, Wieloch T (1987) Calcium accumulation and neuronal damage in the rat hippocampus following cerebral ischemia. J Cereb Blood Flow Metab 7:89–95PubMedCrossRefGoogle Scholar
  12. Edinger AL, Thompson CB (2004) Death by design: apoptosis, necrosis and autophagy. Curr Opin Cell Biol 16:663–669PubMedCrossRefGoogle Scholar
  13. Goll DE, Thompson VF, Li H et al (2003) The calpain system. Physiol Rev 83:731–801PubMedGoogle Scholar
  14. Golstein P, Kroemer G (2007) Cell death by necrosis: towards a molecular definition. Trends Biochem Sci 32:37–43PubMedCrossRefGoogle Scholar
  15. Hara T, Nakamura K, Matsui M et al (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441:885–889PubMedCrossRefGoogle Scholar
  16. Keppler D, Sameni M, Moin K et al (1996) Tumor progression and angiogenesis: cathepsin & Co. Biochem Cell Biol 74:799–810PubMedCrossRefGoogle Scholar
  17. Kirino T (1982) Delayed neuronal death in the gebril hippocampus following ischemia. Brain Res 239:57–69PubMedCrossRefGoogle Scholar
  18. Kohda Y, Yamashima T, Sakuda K et al (1996) Dynamic changes of cathepsin B and L expression in the monkey hippocampus after transient ischemia. Biochem Biophys Res Commun 228:616–622PubMedCrossRefGoogle Scholar
  19. Komatsu M, Waguri S, Chiba T et al (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441:880–884PubMedCrossRefGoogle Scholar
  20. Kundu M, Thompson CB (2008) Autophagy: basic principles and relevance to disease. Annu Rev Pathol 3:427–455. doi:  10.1146/annurev.pathol.2.010506.091842 Google Scholar
  21. 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 150:93–102PubMedCrossRefGoogle Scholar
  22. MacManus JP, Buchan AM, Hill IE et al (1993) Global ischemia can cause DNA fragmentation indicative of apoptosis in rat brain. Neurosci Lett 164:89–92PubMedCrossRefGoogle Scholar
  23. Martins E, Yanase H, Sakai K et al (1988) Accumulation of calcium and loss of potassium in the hippocampus following transient cerebral ischemia: a proton microprobe study. J Cereb Blood Flow Metab 8:531–538PubMedCrossRefGoogle Scholar
  24. Monnerie H, Le Roux PD (2008) Glutamate alteration of glutamic acid decarboxylase (GAD) in GABAergic neurons: the role of cysteine proteases. Exp Neurol 213:145–153PubMedCrossRefGoogle Scholar
  25. Mitani A, Takeyasu S, Yanase H et al (1994) Changes in intracellular Ca2+ and energy levels during in vitro ischemia in the gebril hippocampal slice. J Neurochem 62:626–634PubMedCrossRefGoogle Scholar
  26. Nakamura K, Hatakeyama T, Furuta S et al (1993) The role of early Ca2+ influx in the pathogenesis of delayed neuronal death after brief forebrain ischemia in gerbils. Brain Res 613:181–192PubMedCrossRefGoogle Scholar
  27. Nitatori T, Sato N, Waguri S et al (1995) Delayed neuronal death in the CA1 pyramidal cell layer of the gebril hippocampus following cerebral ischemia is apoptosis. J Neurosci 15:1001–1011PubMedGoogle Scholar
  28. Pope A, Nixon RA (1984) Proteases of human brain. Neurochem Res 9:291–323PubMedCrossRefGoogle Scholar
  29. Porn-Ares MI, Samali A, Orrenius S (1998) Cleavage of the calpain inhibitor, calpastatin, during apoptosis. Cell Death Differ 5:1028–1033PubMedCrossRefGoogle Scholar
  30. Petito CK, Feldmann E, Pulsinelli WA et al (1987) Delayed hippocampal damage in humans following cardiorespiratory arrest. Neurology 37:1281–1286PubMedGoogle Scholar
  31. Pulsinelli WA, Brierly JB, Plum F (1982) Temporal profile of neuronal damage in a model of transient brain ischemia. Ann Neurol 11:491–498PubMedCrossRefGoogle Scholar
  32. Proskuryakov SY, Konoplyannikov AG, Gabai VL (2003) Necrosis: a specific form of programmed cell death? Exp Cell Res 283:1–16PubMedCrossRefGoogle Scholar
  33. Rami A (2003) Ischemic neuronal death in the rat hippocampus: the calpain–calpastatin–caspase hypothesis. Neurobiol Dis 13:75–88PubMedCrossRefGoogle Scholar
  34. Rami A, Langhagen A, Steiger S (2008) Focal cerebral ischemia induces upregulation of Beclin 1 and autophagy-like cell death. Neurobiol Dis 29(1):132–141. doi: 10.1016/j.nbd.2007.08.005 Google Scholar
  35. Rubinsztein DC (2006) The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 443:780–786PubMedCrossRefGoogle Scholar
  36. Samara C, Syntichaki P, Tavernarakis N (2008) Autophagy is required for necrotic cell death in Caenorhabditis elegans. Cell Death Differ 15:105–112PubMedCrossRefGoogle Scholar
  37. Sorimachi H, Ishiura S, Suzuki K (1997) Structure and physiological function of calpains. Biochem J 328:721–732PubMedGoogle Scholar
  38. Stoka V, Turk V, Turk B (2007) Lysosomal cysteine cathepsins: signaling pathways in apoptosis. Biol Chem 388:555–560PubMedCrossRefGoogle Scholar
  39. Syntichaki P, Xu K, Driscoll M et al (2002) Specific aspartyl and calpain proteases are required for neurodegeneration in C. elegans. Nature 419:939–944PubMedCrossRefGoogle Scholar
  40. Tonchev AB, Yamashima T (1999) Ischemic delayed neuronal death: role of the cysteine proteases calpain and cathepsins. Neuropathology 19:356–365CrossRefGoogle Scholar
  41. Tsuchiya K, Kohda Y, Yoshida M et al (1999) Postical blockade of ischemic hippocampal neuronal death in primates using selective cathepsin inhibitors. Exp Neurol 155:187–194PubMedCrossRefGoogle Scholar
  42. Tsukada T, Watanabe M, Yamashima T (2001) Implications of CAD and DNase II in ischemic neuronal necrosis specific for the primate hippocampus. J Neurochem 79:1196–1206PubMedCrossRefGoogle Scholar
  43. Yamashima T, Saido TC, Takita M et al (1996) Transient brain ischemia provokes Ca2+, PIP2 and calpain responses prior to delayed neuronal death in monkeys. Eur J Neurosci 8:1932–1944PubMedCrossRefGoogle Scholar
  44. Yamashima T, Kohda Y, Tsuchiya K et al (1998) Inhibition of ischemic hippocampal neuronal death in primates with cathepsin B inhibitor CA-074: a novel strategy for neuroprotection based on “calpain–cathepsin hypothesis”. Eur J Neurosci 10:1723–1733PubMedCrossRefGoogle Scholar
  45. Yamashima T (2000) Implication of cysteine proteases calpain, cathepsin and caspase in ischemic neuronal death of primates. Prog Neurobiol 62:273–295PubMedCrossRefGoogle Scholar
  46. Yamashima T, Tonchev AB, Tsukada T et al (2003) Sustained calpain activation associated with lysosomal rupture executes necrosis of the postischemic CA1 neurons in primates. Hippocampus 13:791–800PubMedCrossRefGoogle Scholar
  47. Yamashima T (2004) Ca2+-dependent proteases in ischemic neuronal death: a conserved ‘calpain–cathepsin cascade’ from nematodes to primates. Cell Calcium 36:285–293PubMedCrossRefGoogle Scholar
  48. Yamashima T, Tonchev AB, Borlongan CV (2007) Differential response to ischemia in adjacent hippocampal sectors: neuronal death in CA1 versus neurogenesis in dentate gyrus. Biotechnol J 2:596–607PubMedCrossRefGoogle Scholar
  49. Zola-Morgan S, Squire LR, Amaral DG (1986) Human amnesia and the medical temporal region: Enduring memory impairment following a bilateral lesion limited to field CA1 of the hippocampus. J Neurosci 6:2950–2967PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Restorative NeurosurgeryKanazawa University Graduate School of Medical ScienceKanazawaJapan

Personalised recommendations