Effects of Ethyl Pyruvate on Allodynia, TNF-α Expression, and Apoptosis in the Dorsal Root Ganglion after Spinal Nerve Ligation Injury
2
조회
0
다운로드
1
인용
0
참고문헌
키워드
초록
Background:It has been demonstrated that the expression of tumor necrosis factor-a (TNF-a) 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-a 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-a 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-a protein levels in the pre-EP (4.7 ± 1.2 pg/200 mg; P < 0.001) and post-EP (6.4 ± 1.8 pg/200 mg; P < 0.001) groups were 2−3 times lower than the control group (14.4 ± 1.2 pg/200 mg). 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-a expression and apoptosis in DRG after spinal nerve ligation injury.
Abstract
Background:It has been demonstrated that the expression of tumor necrosis factor-a (TNF-a) 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-a 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-a 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-a protein levels in the pre-EP (4.7 ± 1.2 pg/200 mg; P < 0.001) and post-EP (6.4 ± 1.8 pg/200 mg; P < 0.001) groups were 2−3 times lower than the control group (14.4 ± 1.2 pg/200 mg). 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-a expression and apoptosis in DRG after spinal nerve ligation injury.
참고문헌 (33)
- Kim SH, "An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat", Pain, 50, pp.355~363 (1992)
- Schäfers M, "Anterograde transport of tumor necrosis factor-alpha in the intact and injured rat sciatic nerve", J Neurosci, 22, pp.536~545 (2002)
- Sung Hoon Kim, "Tumor Necrosis Factor-alpha and Apoptosis Following Spinal Nerve Ligation Injury in Rats", The Korean Journal of Pain, 24(4), pp.185~190 (2011), 대한통증학회
- Ohtori S, "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, 29, pp.1082~1088 (2004)
- Dubový P, "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, 26, pp.1205~1217 (2006)
- Miao P, "Axotomy-induced up-regulation of tumor necrosis factor-alpha in the dorsal root ganglia", Neurol Res, 30, pp.623~631 (2008)
- Homma Y, "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, 95, pp.239~246 (2002)
- Wagner R, "Endoneurial injection of TNF-alpha produces neuropathic pain behaviors", Neuroreport, 7, pp.2897~2901 (1996)
- Wei XH, "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, 205, pp.471~484 (2007)
- Sweitzer S, "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, 103, pp.529~539 (2001)
- Schäfers M, "Increased sensitivity of injured and adjacent uninjured rat primary sensory neurons to exogenous tumor necrosis factor-alpha after spinal nerve ligation", J Neurosci, 23, pp.3028~3038 (2003)
- Shubayev VI, "Axonal transport of TNF-alpha in painful neuropathy: distribution of ligand tracer and TNF receptors", J Neuroimmunol, 114, pp.48~56 (2001)
- Chen M, "Initiator caspases in apoptosis signaling pathways", Apoptosis, 7, pp.313~319 (2002)
- Joseph EK, "Caspase signalling in neuropathic and inflammatory pain in the rat", Eur J Neurosci, 20, pp.2896~2902 (2004)
- Scholz J, "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, 25, pp.7317~7323 (2005)
- 한평림, "Inhibition of the cerebral ischemic injury by ethyl pyruvate with a wide therapeutic window", STROKE, 36, pp.2238~2243, LIPPINCOTT WILLIAMS & WILKINS
- Wang Q, "Ethyl pyruvate attenuates spinal cord ischemic injury with a wide therapeutic window through inhibiting high-mobility group box 1 release in rabbits", Anesthesiology, 110, pp.1279~1286 (2009)
- Genovese T, "Beneficial effects of ethyl pyruvate in a mouse model of spinal cord injury", Shock, 32, pp.217~227 (2009)
- Cho IH, "Ethyl pyruvate attenuates kainic acid-induced neuronal cell death in the mouse hippocampus", J Neurosci Res, 84, pp.1505~1511 (2006)
- Shang GH, "Ethyl pyruvate reduces mortality in an endotoxin-induced severe acute lung injury mouse model", Respir Res, 10, pp.91~ (2009)
- Guo J, "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, 28, pp.281~283 (2008)
- Tsung A, "Ethyl pyruvate ameliorates liver ischemia-reperfusion injury by decreasing hepatic necrosis and apoptosis", Transplantation, 79, pp.196~204 (2005)
- Li Y, "Mechanical hyperalgesia after an L5 spinal nerve lesion in the rat is not dependent on input from injured nerve fibers", Pain, 85, pp.493~502 (2000)
- Suzuki R, "Neuropathic pain: nerves bursting with excitement", Neuroreport, 11, pp.17~21 (2000)
- Woolf CJ, "Neuronal plasticity: increasing the gain in pain", Science, 288, pp.1765~1769 (2000)
- Sekiguchi M, "Comparison of neuropathic pain and neuronal apoptosis following nerve root or spinal nerve compression", Eur Spine J, 18, pp.1978~1985 (2009)
- Schaeffer V, "Sciatic nerve injury induces apoptosis of dorsal root ganglion satellite glial cells and selectively modifies neurosteroidogenesis in sensory neurons", Glia, 58, pp.169~180 (2010)
- Empl M, "TNF-alpha expression in painful and nonpainful neuropathies", Neurology, 56, pp.1371~1377 (2001)
- Kao KK, "The biochemical basis for the anti- inflammatory and cytoprotective actions of ethyl pyruvate and related compounds", Biochem Pharmacol, 80, pp.151~159 (2010)
- Ulloa L, "Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation", Proc Natl Acad Sci U S A, 99, pp.12351~12356 (2002)
- Campana WM, "Exogenous erythropoietin protects against dorsal root ganglion apoptosis and pain following peripheral nerve injury", Eur J Neurosci, 18, pp.1497~1506 (2003)
- Sekiguchi M, "Sympathectomy reduces mechanical allodynia, tumor necrosis factor-alpha expression, and dorsal root ganglion apoptosis following nerve root crush injury", Spine, 33, pp.1163~1169 (2008)
- Jancálek R, "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, 7, pp.11~ (2010)
