P2X7 receptor inhibition improves recovery after spinal cord injury.
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.
Wang
Xiaohai
X
Department of Neurosurgery, Center for Aging and Developmental Biology, University of Rochester Medical Center, Rochester, New York 14642, USA.
Arcuino
Gregory
G
Takano
Takahiro
T
Lin
Jane
J
Peng
Wei Guo
WG
Wan
Pinglan
P
Li
Pingjia
P
Xu
Qiwu
Q
Liu
Qing Song
QS
Goldman
Steven A
SA
Nedergaard
Maiken
M
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D048588:Benzoxazines; D004195:Disease Models, Animal; D004594:Electrophysiology; D005260:Female; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008163:Luminescent Measurements; D018613:Microscopy, Confocal; D009474:Neurons / Q000378:metabolism; D010078:Oxazines; D058919:Purinergic P2 Receptor Antagonists; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058486:Receptors, Purinergic P2X7; D013119:Spinal Cord Injuries / Q000503:physiopathology / Q000628:therapy*
D048588:Benzoxazines; D010078:Oxazines; D058919:Purinergic P2 Receptor Antagonists; D058486:Receptors, Purinergic P2X7; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; C028911:cresyl violet; C017199:2',3'-dialdehyde ATP; D011732:Pyridoxal Phosphate; D000255:Adenosine Triphosphate