Blocking the P2X7 receptor improves outcomes after axonal fusion

Rodriguez-Feo, Charles; Sexton, Kevin W.; Boyer, Richard B.; Pollins, Alonda C.; Cardwell, Nancy L.; Nanney, Lillian B.; Shack, R. Bruce; Mikesh, Michelle; McGill, Christopher H.; Driscoll, Christopher W.; Bittner, George D.; Thayer, Wesley P.

doi:10.1016/j.jss.2013.04.082

Cited by 18 publications

(29 citation statements)

References 26 publications

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“…The data from PEG-fused allografts are in agreement with previously published data on PEG fusion of sciatic nerves after a 1-mm-long crush severance (Britt et al, 2010) or cut severance Rodriguez-Feo et al, 2013) producing 1-mm separation of the cut ends that were then reapposed by microsutures, after which moderate (15-30 SFI units) but significant SFI-assessed behavioral recovery was noted at 3 days to 1 week. Behavioral recovery greatly increases starting at 2-3 weeks postoperatively, plateaus at 4-6 weeks postoperatively (Britt et al, 2010;Bittner et al, 2012), and is maintained for at least 12 postoperative weeks.…”

Section: Results Of Peg-fused Sciatic Allograftssupporting

confidence: 90%

“…By using microsutures to closely appose cut axonal ends separated by several millimeters, lost behavioral function could be similarly restored when all procedures were again performed in calcium‐free saline (Bittner et al, ). Sciatic nerves cut in calcium‐containing solutions or extracellular fluids could also be repaired, although the animals were only tested for action potential through‐conduction immediately postoperatively (Bittner et al, ) or followed for 1 week behaviorally (Rodriguez‐Feo et al, ). In the course of these procedures, we noted that careful trimming of cut axonal ends in Ca‐free hypotonic saline enhanced their close apposition and the PEG fusion of cut ends.…”

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confidence: 99%

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Polyethylene glycol-fused allografts produce rapid behavioral recovery after ablation of sciatic nerve segments

Riley

Bittner

Mikesh

et al. 2014

Journal of Neuroscience Research

141

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Restoration of neuronal functions by outgrowths regenerating at ~1mm/d from the proximal stumps of severed peripheral nerves takes many weeks or months, if it occurs at all, especially after ablation of nerve segments. Distal segments of severed axons typically degenerate in 1–3 days. The purpose of this study was to show that Wallerian degeneration could be prevented or retarded and lost behavioral function restored following ablation of 0.5 – 1 cm segments of rat sciatic nerves in host animals. This is achieved using 0.8 – 1.1cm microsutured donor allografts treated with bioengineered solutions varying in ionic and polyethylene glycol (PEG) concentrations (modified PEG-fusion procedure), being careful not to stretch any portion of donor or host sciatic nerves. Our data show that PEG-fusion permanently restores axonal continuity within minutes as initially assessed by action potential conduction and intracellular diffusion of dye. Behavioral functions mediated by the sciatic nerve are largely restored within 2 – 4 wk as measured by the Sciatic Functional Index (SFI). Increased restoration of sciatic behavioral functions after ablating 0.5 – 1 cm segments is associated with greater numbers of viable myelinated axons within, and distal to, PEG-fused allografts. Many such viable myelinated axons are almost-certainly spared from Wallerian degeneration by PEG-fusion. PEG-fusion of donor allografts may produce a paradigm-shift in the treatment of peripheral nerve injuries.

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Section: Results Of Peg-fused Sciatic Allograftssupporting

confidence: 90%

mentioning

confidence: 99%

Polyethylene glycol-fused allografts produce rapid behavioral recovery after ablation of sciatic nerve segments

Riley

Bittner

Mikesh

et al. 2014

Journal of Neuroscience Research

141

View full text Add to dashboard Cite

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“…PEG-fusion results for both sexes were very similar for measures such as CAP restoration, dye diffusion, muscle fiber morphology, and SFI recovery (Britt et al,2010; Bittner et al, 2012, 2016. Riley et al, 2015; Sexton et al, 2012; Rodriguez-Feo et al, 2013; Ghergherehchi et al, 2016). Hence, only females were used in this study to examine effects of PEG-fusion on the same structures because use of both sexes would double animal use.…”

Section: Methodsmentioning

confidence: 99%

Polyethylene glycol treated allografts not tissue matched nor immunosuppressed rapidly repair sciatic nerve gaps, maintain neuromuscular functions, and restore voluntary behaviors in female rats

Mikesh

Ghergherehchi

Rahesh

et al. 2018

J of Neuroscience Research

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Many publications report that ablations of segments of peripheral nerves produce the following unfortunate results: (1) Immediate loss of sensory signaling and motor control; (2) rapid Wallerian degeneration of severed distal axons within days; (3) muscle atrophy within weeks; (4) poor behavioral (functional) recovery after many months, if ever, by slowly-regenerating (∼1mm/d) axon outgrowths from surviving proximal nerve stumps; and (5) Nerve allografts to repair gap injuries are rejected, often even if tissue matched and immunosuppressed. In contrast, using a female rat sciatic nerve model system, we report that neurorrhaphy of allografts plus a well-specified-sequence of solutions (one containing polyethylene glycol: PEG) successfully addresses each of these problems by: (a) Reestablishing axonal continuity/signaling within minutes by nonspecific ally PEG-fusing (connecting) severed motor and sensory axons across each anastomosis; (b) preventing Wallerian degeneration by maintaining many distal segments of inappropriately-reconnected, PEG-fused axons that continuously activate nerve-muscle junctions; (c) maintaining innervation of muscle fibers that undergo much less atrophy than otherwise-denervated muscle fibers; (d) inducing remarkable behavioral recovery to near-unoperated levels within days to weeks, almost certainly by CNS and PNS plasticities well-beyond what most neuroscientists currently imagine; and (e) preventing rejection of PEG-fused donor nerve allografts with no tissue matching or immunosuppression. Similar behavioral results are produced by PEG-fused autografts. All results for Negative Control allografts agree with current neuroscience data 1-5 given above. Hence, PEG-fusion of allografts for repair of ablated peripheral nerve segments expand on previous observations in single-cut injuries, provoke reconsideration of some current neuroscience dogma, and further extend the potential of PEG-fusion in clinical practice.

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“…Current strategies for peripheral nerve repair rely on regeneration or proximal outgrowth aided by microsutures, nerve grafts, or manufactured conduits [2,3]. However, even after repair, it can take months for regenerating axons to reach denervated target tissues when injuries are proximally located [1,4].…”

Section: Introductionmentioning

confidence: 99%

Development of a Novel Suture-less Nerve Coaptation Device

Farinas¹

2018

BJSTR

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Blocking the P2X7 receptor improves outcomes after axonal fusion

Cited by 18 publications

References 26 publications

Polyethylene glycol-fused allografts produce rapid behavioral recovery after ablation of sciatic nerve segments

Polyethylene glycol-fused allografts produce rapid behavioral recovery after ablation of sciatic nerve segments

Polyethylene glycol treated allografts not tissue matched nor immunosuppressed rapidly repair sciatic nerve gaps, maintain neuromuscular functions, and restore voluntary behaviors in female rats

Development of a Novel Suture-less Nerve Coaptation Device

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