Calpain as a Therapeutic Target in Traumatic Brain Injury

Kathryn E. Saatman, Jennifer Creed, Ramesh Raghupathi

Research output: Contribution to journalArticlepeer-review

165 Scopus citations

Abstract

The family of calcium-activated neutral proteases, calpains, appears to play a key role in neuropathologic events following traumatic brain injury (TBI). Neuronal calpain activation has been observed within minutes to hours after either contusive or diffuse brain trauma in animals, suggesting that calpains are an early mediator of neuronal damage. Whereas transient calpain activation triggers numerous cell signaling and remodeling events involved in normal physiological processes, the sustained calpain activation produced by trauma is associated with neuron death and axonal degeneration in multiple models of TBI. Nonetheless, the causal relationship between calpain activation and neuronal death is not fully understood. Much remains to be learned regarding the endogenous regulatory mechanisms for controlling calpain activity, the roles of different calpain isoforms, and the in vivo substrates affected by calpain. Detection of stable proteolytic fragments of the submembrane cytoskeletal protein αII-spectrin specific for cleavage by calpains has been the most widely used marker of calpain activation in models of TBI. More recently, these protein fragments have been detected in the cerebrospinal fluid after TBI, driving interest in their potential utility as TBI-associated biomarkers. Post-traumatic inhibition of calpains, either direct or indirect through targets related to intracellular calcium regulation, is associated with attenuation of functional and behavioral deficits, axonal pathology, and cell death in animal models of TBI. This review focuses on the current state of knowledge of the role of calpains in TBI-induced neuropathology and effectiveness of calpain as a therapeutic target in the acute post-traumatic period.

Original languageEnglish
Pages (from-to)31-42
Number of pages12
JournalNeurotherapeutics
Volume7
Issue number1
DOIs
StatePublished - Jan 2010

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health grants NS058484 (K.E.S.) and HD41699 (R.R.), Kentucky Spinal Cord and Head Injury Research grants 6-12 and 7-10 (K.E.S.), and a Veterans Administration Merit Review grant (R.R.). We thank Dr. Edward D. Hall for preparation of Figure 4 , and Carey Shaner for assistance in manuscript preparation.

Keywords

  • Biomarker
  • calcium
  • neuroprotection
  • protease
  • proteolysis
  • spectrin

ASJC Scopus subject areas

  • Pharmacology
  • Clinical Neurology
  • Pharmacology (medical)

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