DOI QR코드

DOI QR Code

Effects of Ethyl Pyruvate on Allodynia, TNF-${\alpha}$ Expression, and Apoptosis in the Dorsal Root Ganglion after Spinal Nerve Ligation Injury

  • Choi, Dae-Kee (Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Leem, Jeong-Gill (Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Shin, Jin-Woo (Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Suh, Jeong-Hun (Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine)
  • Received : 2012.07.10
  • Accepted : 2012.08.23
  • Published : 2012.10.01

Abstract

Background: It has been demonstrated that the expression of tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) and apoptotic cell death in the dorsal root ganglion (DRG) following spinal nerve constriction injury play a role in the initiation and continuation of hyperalgesia and allodynia. The present study was designed to investigate the effects of ethyl pyruvate (EP) on mechanical and cold allodynia, TNF-${\alpha}$ expression, and apoptosis in DRG after spinal nerve ligation injury. Methods: Rats were divided into 3 groups: control, pre-EP, and post-EP. EP (50 mg/kg) was intraperitoneally injected 30 minutes before (pre-EP) or after (post-EP) surgery. Behavioral tests to determine mechanical and cold allodynia were conducted before surgery and 4 and 7 days after surgery. Seven days after surgery, TNF-${\alpha}$ protein levels in DRG were evaluated by enzyme-linked immunosorbent assay, and DRG apoptosis was determined by immunohistochemical detection of activated caspase-3. Results: Treatment with EP significantly reduced mechanical and cold allodynia following spinal nerve ligation injury. TNF-${\alpha}$ protein levels in the pre-EP ($4.7{\pm}1.2$ pg/200 ${\mu}g$; P < 0.001) and post-EP ($6.4{\pm}1.8$ pg/200 ${\mu}g$; P < 0.001) groups were 2-3 times lower than the control group ($14.4{\pm}1.2$ pg/200 ${\mu}g$). The percentages of neurons and satellite cells that co-localized with caspase-3 were also significantly lower in the pre-EP and post-EP groups than the control group. Conclusions: These results demonstrate that EP has a strong anti-allodynic effect that acts through the inhibition of TNF-${\alpha}$ expression and apoptosis in DRG after spinal nerve ligation injury.

Keywords

References

  1. Kim SH, Chung JM. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 1992; 50: 355-363. https://doi.org/10.1016/0304-3959(92)90041-9
  2. Schäfers M, Geis C, Brors D, Yaksh TL, Sommer C. Anterograde transport of tumor necrosis factor-alpha in the intact and injured rat sciatic nerve. J Neurosci 2002; 22: 536-545.
  3. Kim SH, Nam JS, Choi DK, Koh WW, Suh JH, Song JG, et al. Tumor necrosis factor-alpha and apoptosis following spinal nerve ligation injury in rats. Korean J Pain 2011; 24: 185-190. https://doi.org/10.3344/kjp.2011.24.4.185
  4. Ohtori S, Takahashi K, Moriya H, Myers RR. TNF-alpha and TNF-alpha receptor type 1 upregulation in glia and neurons after peripheral nerve injury: studies in murine DRG and spinal cord. Spine (Phila Pa 1976) 2004; 29: 1082-1088. https://doi.org/10.1097/00007632-200405150-00006
  5. Dubovy P, Jancalek R, Klusakova I, Svizenska I, Pejchalova K. Intra-and extraneuronal changes of immunofluorescence staining for TNF-alpha and TNFR1 in the dorsal root ganglia of rat peripheral neuropathic pain models. Cell Mol Neurobiol 2006; 26: 1205-1217.
  6. Miao P, Madec K, Gong Y, Shen H, Eisenstat D, Melanson M, et al. Axotomy-induced up-regulation of tumor necrosis factor-alpha in the dorsal root ganglia. Neurol Res 2008; 30: 623-631. https://doi.org/10.1179/174313208X289606
  7. Homma Y, Brull SJ, Zhang JM. A comparison of chronic pain behavior following local application of tumor necrosis factor alpha to the normal and mechanically compressed lumbar ganglia in the rat. Pain 2002; 95: 239-246. https://doi.org/10.1016/S0304-3959(01)00404-3
  8. Wagner R, Myers RR. Endoneurial injection of TNF-alpha produces neuropathic pain behaviors. Neuroreport 1996; 7: 2897-2901. https://doi.org/10.1097/00001756-199611250-00018
  9. Wei XH, Zang Y, Wu CY, Xu JT, Xin WJ, Liu XG. Peri-sciatic administration of recombinant rat TNF-alpha induces mechanical allodynia via upregulation of TNF-alpha in dorsal root ganglia and in spinal dorsal horn: the role of NF-kappa B pathway. Exp Neurol 2007; 205: 471-484. https://doi.org/10.1016/j.expneurol.2007.03.012
  10. Sweitzer S, Martin D, DeLeo JA. Intrathecal interleukin-1 receptor antagonist in combination with soluble tumor necrosis factor receptor exhibits an anti-allodynic action in a rat model of neuropathic pain. Neuroscience 2001; 103: 529-539. https://doi.org/10.1016/S0306-4522(00)00574-1
  11. Schäfers M, Lee DH, Brors D, Yaksh TL, Sorkin LS. Increased sensitivity of injured and adjacent uninjured rat primary sensory neurons to exogenous tumor necrosis factor-alpha after spinal nerve ligation. J Neurosci 2003; 23: 3028-3038.
  12. Shubayev VI, Myers RR. Axonal transport of TNF-alpha in painful neuropathy: distribution of ligand tracer and TNF receptors. J Neuroimmunol 2001; 114: 48-56. https://doi.org/10.1016/S0165-5728(00)00453-7
  13. Chen M, Wang J. Initiator caspases in apoptosis signaling pathways. Apoptosis 2002; 7: 313-319. https://doi.org/10.1023/A:1016167228059
  14. Joseph EK, Levine JD. Caspase signalling in neuropathic and inflammatory pain in the rat. Eur J Neurosci 2004; 20: 2896-2902. https://doi.org/10.1111/j.1460-9568.2004.03750.x
  15. Scholz J, Broom DC, Youn DH, Mills CD, Kohno T, Suter MR, et al. Blocking caspase activity prevents transsynaptic neuronal apoptosis and the loss of inhibition in lamina II of the dorsal horn after peripheral nerve injury. J Neurosci 2005; 25: 7317-7323. https://doi.org/10.1523/JNEUROSCI.1526-05.2005
  16. Yu YM, Kim JB, Lee KW, Kim SY, Han PL, Lee JK. Inhibition of the cerebral ischemic injury by ethyl pyruvate with a wide therapeutic window. Stroke 2005; 36: 2238-2243. https://doi.org/10.1161/01.STR.0000181779.83472.35
  17. Wang Q, Ding Q, Zhou Y, Gou X, Hou L, Chen S, et al. Ethyl pyruvate attenuates spinal cord ischemic injury with a wide therapeutic window through inhibiting high-mobility group box 1 release in rabbits. Anesthesiology 2009; 110: 1279-1286 https://doi.org/10.1097/ALN.0b013e3181a160d6
  18. Genovese T, Esposito E, Mazzon E, Di Paola R, Meli R, Caminiti R, et al. Beneficial effects of ethyl pyruvate in a mouse model of spinal cord injury. Shock 2009; 32: 217-227. https://doi.org/10.1097/SHK.0b013e31818d4073
  19. Cho IH, Kim SW, Kim JB, Kim TK, Lee KW, Han PL, et al. Ethyl pyruvate attenuates kainic acid-induced neuronal cell death in the mouse hippocampus. J Neurosci Res 2006; 84: 1505-1511. https://doi.org/10.1002/jnr.21052
  20. Shang GH, Lin DJ, Xiao W, Jia CQ, Li Y, Wang AH, et al. Ethyl pyruvate reduces mortality in an endotoxin-induced severe acute lung injury mouse model. Respir Res 2009; 10: 91. https://doi.org/10.1186/1465-9921-10-91
  21. Guo J, Zhang K, Ji Y, Jiang X, Zuo S. Effects of ethyl pyruvate on myocardial apoptosis and expression of Bcl-2 and Bax proteins after ischemia-reperfusion in rats. J Huazhong Univ Sci Technolog Med Sci 2008; 28: 281-283. https://doi.org/10.1007/s11596-008-0311-6
  22. Tsung A, Kaizu T, Nakao A, Shao L, Bucher B, Fink MP, et al. Ethyl pyruvate ameliorates liver ischemia-reperfusion injury by decreasing hepatic necrosis and apoptosis. Transplantation 2005; 79: 196-204. https://doi.org/10.1097/01.TP.0000151681.07474.2E
  23. Li Y, Dorsi MJ, Meyer RA, Belzberg AJ. Mechanical hyperalgesia after an L5 spinal nerve lesion in the rat is not dependent on input from injured nerve fibers. Pain 2000; 85: 493-502. https://doi.org/10.1016/S0304-3959(00)00250-5
  24. Suzuki R, Dickenson AH. Neuropathic pain: nerves bursting with excitement. Neuroreport 2000; 11: R17-R21. https://doi.org/10.1097/00001756-200008210-00001
  25. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000; 288: 1765-1769. https://doi.org/10.1126/science.288.5472.1765
  26. Sekiguchi M, Sekiguchi Y, Konno S, Kobayashi H, Homma Y, Kikuchi S. Comparison of neuropathic pain and neuronal apoptosis following nerve root or spinal nerve compression. Eur Spine J 2009; 18: 1978-1985. https://doi.org/10.1007/s00586-009-1064-z
  27. Schaeffer V, Meyer L, Patte-Mensah C, Eckert A, Mensah- Nyagan AG. Sciatic nerve injury induces apoptosis of dorsal root ganglion satellite glial cells and selectively modifies neurosteroidogenesis in sensory neurons. Glia 2010; 58: 169-180. https://doi.org/10.1002/glia.20910
  28. Empl M, Renaud S, Erne B, Fuhr P, Straube A, Schaeren-Wiemers N, et al. TNF-alpha expression in painful and nonpainful neuropathies. Neurology 2001; 56: 1371-1377. https://doi.org/10.1212/WNL.56.10.1371
  29. Kao KK, Fink MP. The biochemical basis for the antiinflammatory and cytoprotective actions of ethyl pyruvate and related compounds. Biochem Pharmacol 2010; 80: 151-159. https://doi.org/10.1016/j.bcp.2010.03.007
  30. Ulloa L, Ochani M, Yang H, Tanovic M, Halperin D, Yang R, et al. Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation. Proc Natl Acad Sci U S A 2002; 99: 12351-12356. https://doi.org/10.1073/pnas.192222999
  31. Campana WM, Myers RR. Exogenous erythropoietin protects against dorsal root ganglion apoptosis and pain following peripheral nerve injury. Eur J Neurosci 2003; 18: 1497-1506 https://doi.org/10.1046/j.1460-9568.2003.02875.x
  32. Sekiguchi M, Kobayashi H, Sekiguchi Y, Konno S, Kikuchi S. Sympathectomy reduces mechanical allodynia, tumor necrosis factor-alpha expression, and dorsal root ganglion apoptosis following nerve root crush injury. Spine (Phila Pa 1976) 2008; 33: 1163-1169. https://doi.org/10.1097/BRS.0b013e31817144fc
  33. Jancalek R, Dubovy P, Svizenska I, Klusakova I. Bilateral changes of TNF-alpha and IL-10 protein in the lumbar and cervical dorsal root ganglia following a unilateral chronic constriction injury of the sciatic nerve. J Neuroinflammation 2010; 7: 11. https://doi.org/10.1186/1742-2094-7-11

Cited by

  1. Effect of Ethyl Pyruvate on Paclitaxel-Induced Neuropathic Pain in Rats vol.26, pp.2, 2013, https://doi.org/10.3344/kjp.2013.26.2.135
  2. Ethyl pyruvate alleviates early brain injury following subarachnoid hemorrhage in rats vol.158, pp.6, 2016, https://doi.org/10.1007/s00701-016-2795-3
  3. Effects of Ethyl Pyruvate in Preventing the Development of Diet-induced Atherosclerosis by Blocking the HMGB1 Expression in ApoE-Deficient Mice vol.67, pp.4, 2016, https://doi.org/10.1097/FJC.0000000000000353