Activation of caspase-12 by endoplasmic reticulum stress induced by transient middle cerebral artery occlusion in mice

M. Shibata, H. Hattori, T. Sasaki, J. Gotoh, J. Hamada, Y. Fukuuchi

Research output: Contribution to journalArticlepeer-review

122 Citations (Scopus)


We sought to clarify the involvement of caspase-12, a representative molecule related to endoplasmic reticulum (ER) stress-induced cell-death signaling pathways, in neuronal death resulting from ischemia/reperfusion in mice. Transient focal cerebral ischemia (1 h) was produced by intraluminal occlusion of the middle cerebral artery (MCA). We assessed the expression patterns of caspase-12, Bip/GRP78, an ER-resident molecular chaperone whose expression serves as a good marker of ER stress, and caspase-7 by Western blotting and/or immunohistochemistry. Double-fluorescent staining of caspase-12 immunohistochemistry and the terminal deoxynucleotidyl transferase-mediated DNA nick-end labeling (TUNEL) method was performed to clarify the involvement of caspase-12 in cell death. We confirmed that ER stress was induced during reperfusion in our model, as witnessed by up-regulated Bip/GRP78 expression in the MCA territory. Western blot analysis revealed that caspase-12 activation occurred at 5-23 h of reperfusion, and immunoreactivity for caspase-12 was enhanced mainly in striatal neurons on the ischemic side at the same time points. We found the co-localization of caspase-12 immunoreactivity and DNA fragmentation detectable by the TUNEL method. We did not detect the presence of caspase-7 in the ER fraction at the period of caspase-12 cleavage. Our results imply that cerebral ischemia/reperfusion induces ER stress and that caspase-12 activation concurred with ER stress. Caspase-12 seems to be involved in neuronal death induced by ischemia/reperfusion. Caspase-7 is not likely to contribute to the cleavage of caspase-12 in our experimental model.

Original languageEnglish
Pages (from-to)491-499
Number of pages9
Issue number2
Publication statusPublished - 2003 May 8
Externally publishedYes


  • Bip/GRP78
  • Caspase-12
  • Caspase-7
  • Cerebral ischemia
  • ER stress
  • Reperfusion injury

ASJC Scopus subject areas

  • General Neuroscience


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