Nature Medicine
10, 821 - 827 (2004)
Published online: 18 July 2004; | doi:10.1038/nm1082
P2X7 receptor inhibition improves recovery after spinal cord injuryXiaohai Wang1, Gregory Arcuino2, Takahiro Takano1, Jane Lin3, Wei Guo Peng1, 2, Pinglan Wan2, Pingjia Li1, Qiwu Xu2, Qing Song Liu2, Steven A Goldman4, 5
& Maiken Nedergaard1, 21
Department of Neurosurgery, Center for Aging and Developmental Biology, University of Rochester Medical Center, Rochester, New York 14642, USA. 2
Department of Cell Biology, New York Medical College, Valhalla, New York 10595, USA. 3
Department of Pathology, New York Medical College, Valhalla, New York 10595, USA. 4
Department of Neurology, University of Rochester Medical Center, Rochester, New York 14642, USA. 5
Department of Neurology and Neuroscience, Cornell University Medical College, New York, New York 10021, USA.
Correspondence should be addressed to Maiken Nedergaard Nedergaard@urmc.rochester.eduSecondary 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.
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