P2X7 Receptor Inhibition Improves Recovery After Spinal Cord Injury

Nat Med. 2004 Aug;10(8):821-7. doi: 10.1038/nm1082. Epub 2004 Jul 18.

Abstract

Secondary injury exacerbates the extent of spinal cord insults, yet the mechanistic basis of this phenomenon has largely been unexplored. Here we report that broad regions of the peritraumatic zone are characterized by a sustained process of pathologic, high ATP release. Spinal cord neurons expressed P2X7 purine receptors (P2X7R), and exposure to ATP led to high-frequency spiking, irreversible increases in cytosolic calcium and cell death. To assess the potential effect of P2X7R blockade in ameliorating acute spinal cord injury (SCI), we delivered P2X7R antagonists OxATP or PPADS to rats after acute impact injury. We found that both OxATP and PPADS significantly improved functional recovery and diminished cell death in the peritraumatic zone. These observations demonstrate that SCI is associated with prolonged purinergic receptor activation, which results in excitotoxicity-based neuronal degeneration. P2X7R antagonists inhibit this process, reducing both the histological extent and functional sequelae of acute SCI.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / analogs & derivatives*
  • Adenosine Triphosphate / metabolism
  • Adenosine Triphosphate / pharmacology*
  • Animals
  • Apoptosis / drug effects
  • Benzoxazines
  • Disease Models, Animal
  • Electrophysiology
  • Female
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Luminescent Measurements
  • Microscopy, Confocal
  • Neurons / metabolism
  • Oxazines
  • Purinergic P2 Receptor Antagonists*
  • Pyridoxal Phosphate / analogs & derivatives*
  • Pyridoxal Phosphate / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Purinergic P2X7
  • Spinal Cord Injuries / physiopathology
  • Spinal Cord Injuries / therapy*

Substances

  • Benzoxazines
  • Oxazines
  • Purinergic P2 Receptor Antagonists
  • Receptors, Purinergic P2X7
  • pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid
  • cresyl violet
  • 2',3'-dialdehyde ATP
  • Pyridoxal Phosphate
  • Adenosine Triphosphate