PXL01 alters macrophage response with no effect on axonal outgrowth or Schwann cell response after nerve repair in rats

Abstract

Background: Adjunctive pharmacological treatment may improve nerve regeneration. We investigated nerve regeneration processes of PXL01 – a lactoferrin-derived peptide – after repair of the sciatic nerve in healthy Wistar rats. Materials & methods: PXL01, sodium hyaluronate (carrier) or sodium chloride was administered around the repair. After 6 days axonal outgrowth, Schwann cell response, pan- (CD68) and pro-healing (CD206) macrophages in sciatic nerve, sensory neuronal response in dorsal root ganglia (DRG) and expression of heat shock protein 27 (HSP27) in sciatic nerves and DRGs were analyzed. Results: Despite a lower number of pan-macrophages, other investigated variables in sciatic nerves or DRGs did not differ between the treatment groups. Conclusion: PLX01 applied locally inhibits inflammation through pan-macrophages in repaired sciatic nerves without any impact on nerve regeneration or pro-healing macrophages.

GRAPHICAL ABSTRACT

Author highlights

• Local application of PXL01 decreases inflammation in the injured and immediate repaired nerve without changing the polarization of the macrophages.

• Local application of PXL01 does not improve or have any negative effect on nerve regeneration.

• Local application of PXL01 does not alter Schwann cell activity or neuroprotective effect of HSP27 in the injured and repaired nerve or in the sensory neurons.

• Hyaluronate, the PXL01 vehicle, does not alter nerve regeneration and has no effect on inflammation.

• CD206, known as antimannose receptor antibody, also stains the paranodal region in the contralateral-uninjured nerve.

• Results imply that PXL01 treatment can be used to treat scarred and tethered nerves, one of the defined neuromas after surgery, without a negative effect on the regeneration processes.

Keywords: :

• apoptosis
• HSP27
• sodium hyaluronate
• inflammation
• macrophages
• nerve injury
• nerve repair
• PXL01
• Schwann cells
• sensory neuron

Supplemental material

Supplemental data for this article can be accessed at https://doi.org/10.1080/17460751.2024.2361515

Acknowledgments

We thank the company Promore Pharma (Fogdevreten 2, SE-171 65 Solna, Sweden) for supplying the pharmaceutical production and delivery. We thank Tina Folker for expert administrative support.

Author contributions

HRDB contributed to the conception or design of the work; the acquisition, analysis and interpretation of data for the work and drafting the work and revising it critically for important intellectual content, and final approval of the version to be published; AND agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

SL contributed to the conception or design of the work AND revising it critically for important intellectual content AND final approval of the version to be published; AND agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

MM contributed to the conception or design of the work AND revising it critically for important intellectual content AND final approval of the version to be published; AND agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

DLB contributed to the conception or design of the work; the acquisition, analysis and interpretation of data for the work and drafting the work and revising it critically for important intellectual content; and final approval of the version to be published; AND agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Financial disclosure

The project was supported by grants from the Swedish Research Council (2021-01942), Lund University, Skåne University Hospital, Elly Olsson's Foundation, Region Skåne, Sydvästra Skånes Diabetesförening and the Swedish Diabetes Foundation (DIA2020-492). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no conflicts of interest, except that MM at the time of the investigation, was employee at the Promore Pharma AB. The authors have no other competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The study was approved by the Animal Ethics Committee of Lund University, Lund, Sweden (protocol code 5.8.18-06842/2019; date of approval 5 June 2019). The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations.

Additional information

Funding

The project was supported by grants from the Swedish Research Council (2021-01942), Lund University, Skåne University Hospital, Elly Olsson's Foundation, Region Skåne, Sydvästra Skånes Diabetesförening and the Swedish Diabetes Foundation (DIA2020-492).