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Basic science
Spinal cord stimulation attenuates paclitaxel-induced gait impairment and mechanical hypersensitivity via peripheral neuroprotective mechanisms in tumor-bearing rats
  1. Ahmed Olalekan Bakare1,
  2. Kimberly Stephens2,3,
  3. Karla R Sanchez1,
  4. Vivian Liu4,
  5. Lei Zheng5,
  6. Vasudha Goel6,
  7. Yun Guan1,7 and
  8. Eellan Sivanesan1
  1. 1Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  2. 2Arkansas Children's Research Institute, Little Rock, Arkansas, USA
  3. 3Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
  4. 4Department of Computer Science, Johns Hopkins Whiting School of Engineering, Baltimore, Maryland, USA
  5. 5Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  6. 6Department of Anesthesiology, University of Minnesota, Minneapolis, Minnesota, USA
  7. 7Department of Neurological Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  1. Correspondence to Dr Eellan Sivanesan, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; esivane1{at}jhmi.edu

Abstract

Background Taxanes such as paclitaxel (PTX) induce dose-dependent chemotherapy-induced peripheral neuropathy (CIPN), which is associated with debilitating chronic pain and gait impairment. Increased macrophage-related proinflammatory activities have been reported to mediate the development and maintenance of neuropathic pain. While spinal cord stimulation (SCS) has been used for a number of pain conditions, the mechanisms supporting its use for CIPN remain to be elucidated. Thus, we aimed to examine whether SCS can attenuate Schwann cell-mediated and macrophage-mediated neuroinflammation in the sciatic nerve of Rowlette Nude (RNU) rats with PTX-induced gait impairment and mechanical hypersensitivity.

Methods Adult male tumor-bearing RNU rats were used for this study examining PTX treatment and SCS. Gait and mechanical hypersensitivity were assessed weekly. Cytokines, gene expression, macrophage infiltration and polarisation, nerve morphology and Schwann cells were examined in sciatic nerves using multiplex immunoassay, bulk RNA sequencing, histochemistry and immunohistochemistry techniques.

Results SCS (50 Hz, 0.2 milliseconds, 80% motor threshold) attenuated the development of mechanical hypersensitivity (20.93±0.80 vs 12.23±2.71 grams, p<0.0096) and temporal gait impairment [swing (90.41±7.03 vs 117.27±9.71%, p<0.0076), and single stance times (94.92±3.62 vs 112.75±7.27%, p<0.0245)] induced by PTX (SCS+PTX+Tumor vs Sham SCS+PTX+Tumor). SCS also attenuated the reduction in Schwann cells, myelin thickness and increased the concentration of anti-inflammatory cytokine interleukin (IL)−10. Bulk RNA sequencing revealed differential gene expression after SCS, with 607 (59.2%) genes upregulated while 418 (40.8%) genes were downregulated. Notably, genes related to anti-inflammatory cytokines and neuronal growth were upregulated, while genes related to proinflammatory-promoting genes, increased M2γ polarisation and decreased macrophage infiltration and Schwann cell loss were downregulated.

Conclusion SCS may attenuate PTX-induced pain and temporal gait impairment, which may be partly attributed to decreases in Schwann cell loss and macrophage-mediated neuroinflammation in sciatic nerves.

  • spinal cord stimulation
  • neurotoxicity syndromes
  • pain management
  • peripheral nerve injuries
  • cancer pain

Data availability statement

Data are available upon reasonable request.

https://doi.org/10.1136/rapm-2024-105433

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    Data availability statement

    Data are available upon reasonable request.

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    Footnotes

    • X @DoctorSivaMD

    • Contributors Conceptualised and designed the study: ES. Conducted or assisted with experiments: AOB, KES, KRS, VL and ES. Analysed and visualised the results: AOB, KES and ES. Project administration and supervision: ES. Wrote the original draft: AOB and ES. Critical intellectual revision of the manuscript: AOB, KES, LZ, VG, YG and ES. Guarantor to accept full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish: ES. All authors read and approved the final manuscript.

    • Funding This study was conducted at the Johns Hopkins University and supported by grants from The American Society of Regional Anesthesia and Pain Medicine (ASRA) (ES); The National Cancer Institute–National Institutes of Health (Bethesda, Maryland, USA) CA255428 (ES), NS110598 (YG), NS117761 (YG); The Foundation of Anesthesia Education and Research (FAER) (ES); and The Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University - School of Medicine, Stimulating and Advancing ACCM Research (StAAR) Award (ES). Funders had no role in study design, data collection, or data interpretation, or in the decision to submit the work for publication.

    • Competing interests AOB, KES, KRS, VL, VG and ES have no conflicts of interest to declare. LZ receives grant support from Bristol-Meyer Squibb, Merck, Astrazeneca, iTeos, Amgen, NovaRock, Inxmed, and Halozyme. LZ is a paid consultant/Advisory Board Member at Biosion, Alphamab, NovaRock, Ambrx, Akrevia/Xilio, QED, Natera, Novagenesis, Snow Lake Capitals, BioArdis, Amberstone Biosciences, Tempus, Pfizer, Tavotek Lab, ClinicalTrial Options, LLC, and Mingruizhiyao. LZ holds shares at Alphamab, Amberstone, and Mingruizhiyao. YG receives research funding from Medtronic, Inc and TissueTech, Inc.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.