Editors' ChoiceSpinal Cord Injury

Hit me with your best shot… to regenerate

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Science Translational Medicine  17 Jan 2018:
Vol. 10, Issue 424, eaar7517
DOI: 10.1126/scitranslmed.aar7517

Abstract

Intraneural ATP injection improves axonal recovery following spinal cord injury.

Neurons in the central nervous system have a limited ability to regenerate upon injury, and a better understanding of mechanisms involved in regeneration processes is critical to the development of clinical interventions to mitigate permanent nerve damage following trauma. The concept of a conditioning lesion, whereby a neuron increases axonal growth following an injury, may provide insight into such regenerative processes. Injured neurons release adenosine triphosphate (ATP), and although ATP is best known for its role in cellular energy status, it also activates signaling pathways when present outside the cell. The role of extracellular ATP as a signaling molecule that modulates the up-regulation of cellular repair pathways is the subject of ongoing research.

Wu et al. leveraged both cellular and animal models to characterize the effect of exogenous ATP injection on the regenerative capacity of peripheral neurons. ATP injection into the sciatic nerve simultaneous with spinal cord injury increased the length of neurites across the lesion. A single injection of ATP also increased the concentration of the growth factor intraleukin-6 in both dorsal root ganglion and sciatic nerve acutely (three days) after treatment. The expression of the signal transducer and activator of transcription 3 (STAT3) was also increased by ATP injection, suggesting a mechanism for increased transcription of growth related molecules. The effect of a single ATP injection was slightly less than that of a conditioning lesion, but a second ATP injection one week following the primary injection elicited a marked improvement in neurite outgrowth compared with the single injection. This double ATP treatment also sustained the activation of STAT3, which remained evident at 20 days post-treatment. The authors further showed that the effect on STAT3 is likely mediated through the P2Y purinergic receptor 2 (P2Y2), as P2Y2 knockout mice lacked the effects on transcription factors shown in wild-type animals.

Although this study provides novel mechanistic insight into nerve regenerative processes, additional work needs to be performed to investigate the translational utility of this approach. Treatment simultaneous with the injury is not clinically feasible, thus the timing between injury and treatment warrants further study. Furthermore, the clinical effects of multiple injections are unknown. Nonetheless, the improved regenerative capacity with minimal axonal damage and no functional abnormalities showed here suggest that modulation of extracellular ATP could eventually be a viable treatment strategy for spinal cord injury.

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