Calcium-activated proteolysis in rat neocortex induced by transient focal ischemia

Seung Chyul Hong, Giuseppe Lanzino, Yasunobu Goto, Song K. Kang, Frank Schottler, Neal F. Kassell, Kevin S. Lee

Research output: Contribution to journalArticle

71 Scopus citations

Abstract

Ischemia-induced elevation of intracellular calcium triggers a cascade of events which is considered to play a major role in neuronal death. One candidate to participate in this process is the calcium-sensitive protease, calpain. This protease is activated by calcium, and is capable of degrading critical cytoskeletal and regulatory proteins. In order to further elucidate the role of calpain in focal ischemic damage, the present study investigated the proteolysis of spectrin, a preferred substrate for calpain, in response to transient focal ischemia. Ischemia was induced by occluding reversibly both carotid arteries and the left middle cerebral artery for three hours in Sprague-Dawley rats. Western blotting techniques were used to identify and quantify the amounts of spectrin breakdown products (BDPs) in neocortical samples from the area destined for infarction, the peri-infarct area, and the contralateral hemisphere. Substantial increases in spectrin proteolysis were observed within the first few hours of ischemia in the areas that will undergo infarction. The increase in spectrin BDPs in these areas reached a plateau around the end of the 3 h ischemic period. In the peri-infarct zone, the levels of spectrin BDPs increased in a biphasic manner. A small to moderate increase was observed by the second hour of ischemia, followed by a larger increase between the 6th and 24th hours post-ischemia. The contralateral neocortex showed a significant increase in BDPs at 2 h after the initiation of ischemia. A smaller increase in BDPs was observed thereafter. Substantial calpain-mediated proteolysis thus occurs within 1 h of focal cerebral ischemia in areas destined for infarction, while the responses in the peri-infarct area and contralateral cortex are weaker and delayed. The rapid and sustained proteolytic responses in vulnerable areas suggest that calcium-activated proteolysis is an early indicator of cell damage in focal ischemia. In addition, the findings suggest that therapeutic interventions targeting this mechanism should be initiated within a few hours after ischemia and maintained for at least 24 h.

Original languageEnglish (US)
Pages (from-to)43-50
Number of pages8
JournalBrain Research
Volume661
Issue number1-2
DOIs
StatePublished - Oct 24 1994

Keywords

  • Calpain
  • Focal cerebral ischemia
  • Proteolysis
  • Rat
  • Spectrin

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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    Hong, S. C., Lanzino, G., Goto, Y., Kang, S. K., Schottler, F., Kassell, N. F., & Lee, K. S. (1994). Calcium-activated proteolysis in rat neocortex induced by transient focal ischemia. Brain Research, 661(1-2), 43-50. https://doi.org/10.1016/0006-8993(94)91178-9