The Korean Journal of Pain

The Korean Pain Society (대한통증학회)
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Effect of epidural polydeoxyribonucleotide in a rat model of lumbar foraminal stenosis

  • Lee, Ho-Jin (Department of Anesthesiology and Pain Medicine, Seoul National University Hospital) ;
  • Ju, Jiyoun (Department of Anesthesiology and Pain Medicine, Seoul National University Bundang Hospital) ;
  • Choi, Eunjoo (Department of Anesthesiology and Pain Medicine, Seoul National University College of Medicine) ;
  • Nahm, Francis Sahngun (Department of Anesthesiology and Pain Medicine, Seoul National University College of Medicine) ;
  • Choe, Ghee Young (Department of Pathology, Seoul National University Bundang Hospital) ;
  • Lee, Pyung Bok (Department of Anesthesiology and Pain Medicine, Seoul National University College of Medicine)
  • Received : 2021.04.11
  • Accepted : 2021.06.17
  • Published : 2021.10.01
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Abstract

Background: We aimed to investigate the effect of epidural polydeoxyribonucleotide (PDRN) on mechanical allodynia and motor dysfunction in a rat model of lumbar foraminal stenosis (LFS). Methods: This study was conducted in two stages, using male Sprague-Dawley rats. The rats were randomly divided into eight groups. In the first stage, the groups were as follows: vehicle (V), sham (S), and epidural PDRN at 5 (P5), 8 (P8), and 10 (P10) mg/kg; and in the second stage, they were as follows: intraperitoneal PDRN 8 mg/kg, epidural 3,7-dimethyl-1-propargilxanthine (DMPX) (0.1 mg/kg), and DMPX (0.1 mg/kg). The LFS model was established, except for the S group. After an epidural injection of the test solutions, von Frey and treadmill tests were conducted for 3 weeks. Subsequently, histopathologic examinations were conducted in the V, S, P5, and P10 groups. Results: A total of 65 rats were included. The P8 and P10 groups showed significant recovery from mechanical allodynia and motor dysfunction at all time points after drug administration compared to the V group. These effects were abolished by concomitant administration of DMPX. On histopathological examination, no epineurial inflammation or fibrosis was observed in the epidural PDRN groups. Conclusions: Epidural injection of PDRN significantly improves mechanical allodynia and motor dysfunction in a rat model of LFS, which is mediated by the spinal adenosine A2A receptor. The present data support the need for further research to determine the role of epidural PDRN in spinal stenosis treatment.

Keywords

Acknowledgement

The authors appreciate the Division of Statistics in the Medical Research Collaborating Center at Seoul National University Bundang Hospital, Korea, for the assistance with the statistical analyses. The authors thank Mr. Myung Hun Park for his assistance with animal care and establishing an experimental model.

References

  1. Lurie J, Tomkins-Lane C. Management of lumbar spinal stenosis. BMJ 2016; 352: h6234. https://doi.org/10.1136/bmj.h6234
  2. Costandi S, Chopko B, Mekhail M, Dews T, Mekhail N. Lumbar spinal stenosis: therapeutic options review. Pain Pract 2015; 15: 68-81. https://doi.org/10.1111/papr.12188
  3. Deyo RA. Treatment of lumbar spinal stenosis: a balancing act. Spine J 2010; 10: 625-7. https://doi.org/10.1016/j.spinee.2010.05.006
  4. Chad DA. Lumbar spinal stenosis. Neurol Clin 2007; 25: 407-18. https://doi.org/10.1016/j.ncl.2007.01.003
  5. Watanabe R, Parke WW. Vascular and neural pathology of lumbosacral spinal stenosis. J Neurosurg 1986; 64: 64-70. https://doi.org/10.3171/jns.1986.64.1.0064
  6. Binder DK, Schmidt MH, Weinstein PR. Lumbar spinal stenosis. Semin Neurol 2002; 22: 157-66. https://doi.org/10.1055/s-2002-36539
  7. Albrecht DS, Ahmed SU, Kettner NW, Borra RJH, CohenAdad J, Deng H, et al. Neuroinflammation of the spinal cord and nerve roots in chronic radicular pain patients. Pain 2018; 159: 968-77. https://doi.org/10.1097/j.pain.0000000000001171
  8. Cipriano PW, Yoon D, Gandhi H, Holley D, Thakur D, Hargreaves BA, et al. 18F-FDG PET/MRI in chronic sciatica: early results revealing spinal and nonspinal abnormalities. J Nucl Med 2018; 59: 967-72. https://doi.org/10.2967/jnumed.117.198259
  9. Squadrito F, Bitto A, Irrera N, Pizzino G, Pallio G, Minutoli L, et al. Pharmacological activity and clinical use of PDRN. Front Pharmacol 2017; 8: 224. https://doi.org/10.3389/fphar.2017.00224
  10. Kang KN, Kim TW, Koh JW, Oh HB, Mun JU, Seo MS, et al. Effect of transforaminal epidural polydeoxyribonucleotide injections on lumbosacral radiculopathy: a case report. Medicine (Baltimore) 2017; 96: e7174. https://doi.org/10.1097/MD.0000000000007174
  11. Park D. Application of ultrasound-guided C5 nerve root block using polydeoxyribonucleotide in traumatic C5 nerve root injury caused by fracture of the articular process of the cervical spine: a case report. Medicine (Baltimore) 2017; 96: e8728. https://doi.org/10.1097/MD.0000000000008728
  12. Kilkenny C, Browne W, Cuthill IC, Emerson M, Altman DG; NC3Rs Reporting Guidelines Working Group. Animal research: reporting in vivo experiments: the ARRIVE guidelines. Br J Pharmacol 2010; 160: 1577-9. https://doi.org/10.1111/j.1476-5381.2010.00872.x
  13. Park SH, Lee PB, Choe GY, Moon JY, Nahm FS, Kim YC. Therapeutic effect of epidurally administered lipo-prostaglandin e1 agonist in a rat spinal stenosis model. Korean J Pain 2014; 27: 219-28. https://doi.org/10.3344/kjp.2014.27.3.219
  14. Nahm FS, Lee PB, Choe GY, Lim YJ, Kim YC. Therapeutic effect of epidural hyaluronic acid in a rat model of foraminal stenosis. J Pain Res 2017; 10: 241-8. https://doi.org/10.2147/JPR.S122861
  15. Ikawa M, Atsuta Y, Tsunekawa H. Ectopic firing due to artificial venous stasis in rat lumbar spinal canal stenosis model: a possible pathogenesis of neurogenic intermittent claudication. Spine (Phila Pa 1976) 2005; 30: 2393-7. https://doi.org/10.1097/01.brs.0000184718.56122.90
  16. Charan J, Kantharia ND. How to calculate sample size in animal studies? J Pharmacol Pharmacother 2013; 4: 303-6. https://doi.org/10.4103/0976-500X.119726
  17. Hu SJ, Xing JL. An experimental model for chronic compression of dorsal root ganglion produced by intervertebral foramen stenosis in the rat. Pain 1998; 77: 15-23. https://doi.org/10.1016/S0304-3959(98)00067-0
  18. Choi SS, Kim YC, Lim YJ, Lee CJ, Lee PB, Lee SC, et al. The neurological safety of epidural gabapentin in rats: a light microscopic examination. Anesth Analg 2005; 101: 1422-6. https://doi.org/10.1213/01.ANE.0000180197.32577.9B
  19. Bitto A, Polito F, Altavilla D, Minutoli L, Migliorato A, Squadrito F. Polydeoxyribonucleotide (PDRN) restores blood flow in an experimental model of peripheral artery occlusive disease. J Vasc Surg 2008; 48: 1292-300. https://doi.org/10.1016/j.jvs.2008.06.041
  20. Dixon WJ. Efficient analysis of experimental observations. Annu Rev Pharmacol Toxicol 1980; 20: 441-62. https://doi.org/10.1146/annurev.pa.20.040180.002301
  21. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 1994; 53: 55-63. https://doi.org/10.1016/0165-0270(94)90144-9
  22. Kawakami M, Matsumoto T, Hashizume H, Kuribayashi K, Tamaki T. Epidural injection of cyclooxygenase-2 inhibitor attenuates pain-related behavior following application of nucleus pulposus to the nerve root in the rat. J Orthop Res 2002; 20: 376-81. https://doi.org/10.1016/S0736-0266(01)00114-0
  23. Nakai K, Takenobu Y, Eguchi K, Takimizu H, Honjo K, Akimaru S, et al. The effects of OP-1206 alpha-CD on walking dysfunction in the rat neuropathic intermittent claudication model. Anesth Analg 2002; 94: 1537-41. https://doi.org/10.1097/00000539-200206000-00030
  24. Dunn OJ. Multiple comparisons among means. J Am Stat Assoc 1961; 56: 52-64. https://doi.org/10.1080/01621459.1961.10482090
  25. Kaelin-Lang A, Lauterburg T, Burgunder JM. Expression of adenosine A2a receptor gene in rat dorsal root and autonomic ganglia. Neurosci Lett 1998; 246: 21-4. https://doi.org/10.1016/S0304-3940(98)00216-X
  26. Sawynok J. Adenosine receptor targets for pain. Neuroscience 2016; 338: 1-18. https://doi.org/10.1016/j.neuroscience.2015.10.031
  27. Dare E, Schulte G, Karovic O, Hammarberg C, Fredholm BB. Modulation of glial cell functions by adenosine receptors. Physiol Behav 2007; 92: 15-20. https://doi.org/10.1016/j.physbeh.2007.05.031
  28. Lee SH, Yoo SH, Lee HJ, Han D, Lee J, Jeon SH, et al. Antiallodynic effects of polydeoxyribonucleotide in an animal model of neuropathic pain and complex regional pain syndrome. J Korean Med Sci 2020; 35: e225. https://doi.org/10.3346/jkms.2020.35.e225
  29. Jirathanathornnukul N, Limthongkul W, Yingsakmongkol W, Singhatanadgige W, Parkpian V, Honsawek S. Increased expression of vascular endothelial growth factor is associated with hypertrophic ligamentum flavum in lumbar spinal canal stenosis. J Investig Med 2016; 64: 882-7. https://doi.org/10.1136/jim-2015-000024
  30. Kim SE, Ko IG, Jin JJ, Hwang L, Kim CJ, Kim SH, et al. Polydeoxyribonucleotide exerts therapeutic effect by increasing VEGF and inhibiting inflammatory cytokines in ischemic colitis rats. Biomed Res Int 2020; 2020: 2169083.
  31. Friedly JL, Comstock BA, Turner JA, Heagerty PJ, Deyo RA, Sullivan SD, et al. A randomized trial of epidural glucocorticoid injections for spinal stenosis. N Engl J Med 2014; 371: 11-21. https://doi.org/10.1056/NEJMoa1313265
  32. Carreon LY, Bratcher KR, Ammous F, Glassman SD. Costeffectiveness of lumbar epidural steroid injections. Spine (Phila Pa 1976) 2018; 43: 35-40. https://doi.org/10.1097/BRS.0000000000000989
  33. Even JL, Crosby CG, Song Y, McGirt MJ, Devin CJ. Effects of epidural steroid injections on blood glucose levels in patients with diabetes mellitus. Spine (Phila Pa 1976) 2012; 37: E46-50. https://doi.org/10.1097/BRS.0b013e31821fd21f
  34. Mandel S, Schilling J, Peterson E, Rao DS, Sanders W. A retrospective analysis of vertebral body fractures following epidural steroid injections. J Bone Joint Surg Am 2013; 95: 961-4. https://doi.org/10.2106/JBJS.L.00844
  35. Friedly JL, Comstock BA, Heagerty PJ, Bauer Z, Rothman MS, Suri P, et al. Systemic effects of epidural steroid injections for spinal stenosis. Pain 2018; 159: 876-83. https://doi.org/10.1097/j.pain.0000000000001158
  36. Tuel SM, Meythaler JM, Cross LL. Cushing's syndrome from epidural methylprednisolone. Pain 1990; 40: 81-4. https://doi.org/10.1016/0304-3959(90)91054-M
  37. Aldrete JA. Epidural injections of indomethacin for postlaminectomy syndrome: a preliminary report. Anesth Analg 2003; 96: 463-8. https://doi.org/10.1213/00000539-200302000-00031
  38. Freeman BJ, Ludbrook GL, Hall S, Cousins M, Mitchell B, Jaros M, et al. Randomized, double-blind, placebo-controlled, trial of transforaminal epidural etanercept for the treatment of symptomatic lumbar disc herniation. Spine (Phila Pa 1976) 2013; 38: 1986-94. https://doi.org/10.1097/01.brs.0000435140.61593.4c
  39. Senocak O, Hurel DM, Sener U, Ugurel B, Oztura I, Ertekin C. Motor conduction time along the cauda equina in patients with lumbar spinal stenosis. Spine (Phila Pa 1976) 2009; 34: 1410-4. https://doi.org/10.1097/BRS.0b013e3181a19082
  40. Park JW, Kim MS, Kim SK, Lee KC, Lee JW. Regenerative effect of the polydeoxyribonucleotide after sciatic nerve transection in mouse. Tissue Eng Regen Med 2015; 12: 457-63. https://doi.org/10.1007/s13770-015-0023-5
  41. Galeano M, Bitto A, Altavilla D, Minutoli L, Polito F, Calo M, et al. Polydeoxyribonucleotide stimulates angiogenesis and wound healing in the genetically diabetic mouse. Wound Repair Regen 2008; 16: 208-17. https://doi.org/10.1111/j.1524-475X.2008.00361.x
  42. Andreollo NA, Santos EF, Araujo MR, Lopes LR. Rat's age versus human's age: what is the relationship? Arq Bras Cir Dig 2012; 25: 49-51. https://doi.org/10.1590/S0102-67202012000100011
  43. Turner PV, Brabb T, Pekow C, Vasbinder MA. Administration of substances to laboratory animals: routes of administration and factors to consider. J Am Assoc Lab Anim Sci 2011; 50: 600-13.