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P2X7 receptor inhibition improves recovery after spinal cord injury

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.

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Figure 1: Bioluminescence detection of ATP release after acute SCI.
Figure 2: Areas of high ATP release are associated with increased apoptosis.
Figure 3: Motor neurons express functional P2X7Rs.
Figure 4: P2X7R activation induces high-frequency firing in spinal cord neurons.
Figure 5: P2X7R antagonists reduce apoptosis and improve functional recovery after SCI.

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Acknowledgements

This study was supported by the National Institute of Neurological Disorders and Stroke and the New York State Spinal Cord Injury Research Program.

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Correspondence to Maiken Nedergaard.

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Wang, X., Arcuino, G., Takano, T. et al. P2X7 receptor inhibition improves recovery after spinal cord injury. Nat Med 10, 821–827 (2004). https://doi.org/10.1038/nm1082

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