Calpastatin overexpression limits calpain-mediated proteolysis and behavioral deficits following traumatic brain injury

Kathleen M. Schoch, Heather N. Evans, Jennifer M. Brelsfoard, Sindhu K. Madathil, Jiro Takano, Takaomi C. Saido, Kathryn E. Saatman

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


Traumatic brain injury (TBI) results in abrupt, initial cell damage leading to delayed neuronal death. The calcium-activated proteases, calpains, are known to contribute to this secondary neurodegenerative cascade. Although the specific inhibitor of calpains, calpastatin, is present within neurons, normal levels of calpastatin are unable to fully prevent the damaging proteolytic activity of calpains after injury. In this study, increased calpastatin expression was achieved using transgenic mice that overexpress the human calpastatin (hCAST) construct under control of a calcium-calmodulin-dependent kinase II α promoter. Naïve hCAST transgenic mice exhibited enhanced neuronal calpastatin expression and significantly reduced protease activity. Acute calpain-mediated spectrin proteolysis in the cortex and hippocampus induced by controlled cortical impact brain injury was significantly attenuated in calpastatin overexpressing mice. Aspects of posttraumatic motor and cognitive behavioral deficits were also lessened in hCAST transgenic mice compared to their wildtype littermates. However, volumetric analyses of neocortical contusion revealed no histological neuroprotection at either acute or long-term time points. Partial hippocampal neuroprotection observed at a moderate injury severity was lost after severe TBI. This study underscores the effectiveness of calpastatin overexpression in reducing calpain-mediated proteolysis and behavioral impairment after TBI, supporting the therapeutic potential for calpain inhibition. In addition, the reduction in spectrin proteolysis without accompanied neocortical neuroprotection suggests the involvement of other factors that are critical for neuronal survival after contusion brain injury.

Original languageEnglish
Pages (from-to)371-382
Number of pages12
JournalExperimental Neurology
Issue number2
StatePublished - Aug 2012

Bibliographical note

Funding Information:
This work was funded by NIH F31 NS071804 (KMS), NIH P01 NS058484 , P30 NS051220 and KSCHIRT 6–12 (KES).


  • Cognition
  • Controlled cortical impact
  • Neuroprotection
  • Spectrin
  • Transgenic

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience


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