Activation of the caspase-3 apoptotic cascade in traumatic spinal cord injury

Nat Med. 1999 Aug;5(8):943-6. doi: 10.1038/11387.

Abstract

Traumatic spinal cord injury often results in complete loss of voluntary motor and sensory function below the site of injury. The long-term neurological deficits after spinal cord trauma may be due in part to widespread apoptosis of neurons and oligodendroglia in regions distant from and relatively unaffected by the initial injury. The caspase family of cysteine proteases regulates the execution of the mammalian apoptotic cell death program. Caspase-3 cleaves several essential downstream substrates involved in the expression of the apoptotic phenotype in vitro, including gelsolin, PAK2, fodrin, nuclear lamins and the inhibitory subunit of DNA fragmentation factor. Caspase-3 activation in vitro can be triggered by upstream events, leading to the release of cytochrome c from the mitochondria and the subsequent transactivation of procaspase-9 by Apaf-1. We report here that these upstream and downstream components of the caspase-3 apoptotic pathway are activated after traumatic spinal cord injury in rats, and occur early in neurons in the injury site and hours to days later in oligodendroglia adjacent to and distant from the injury site. Given these findings, targeting the upstream events of the caspase-3 cascade has therapeutic potential in the treatment of acute traumatic injury to the spinal cord.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis*
  • Caspase 3
  • Caspase Inhibitors
  • Caspases / metabolism*
  • Cysteine Proteinase Inhibitors / pharmacology
  • Cytochrome c Group / metabolism
  • Cytosol / metabolism
  • DNA Fragmentation
  • Deoxyribonucleases / metabolism
  • Immunoblotting
  • Immunohistochemistry
  • Mitochondria / metabolism
  • Neurons / cytology
  • Neurons / metabolism
  • Oligopeptides / pharmacology
  • Poly-ADP-Ribose Binding Proteins
  • Proteins / immunology
  • Proteins / metabolism
  • Rats
  • Signal Transduction
  • Spinal Cord / cytology
  • Spinal Cord / metabolism
  • Spinal Cord Injuries / enzymology*
  • Spinal Cord Injuries / metabolism
  • Spinal Cord Injuries / pathology
  • Time Factors

Substances

  • Caspase Inhibitors
  • Cysteine Proteinase Inhibitors
  • Cytochrome c Group
  • DNA fragmentation factor, human
  • Oligopeptides
  • Poly-ADP-Ribose Binding Proteins
  • Proteins
  • benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone
  • Deoxyribonucleases
  • Dffb protein, rat
  • CASP3 protein, human
  • Casp3 protein, rat
  • Caspase 3
  • Caspases