Journal of Korean Neurosurgical Society

  • 제49권2호
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  • Pages.83-91
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  • 2011
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  • 2005-3711(pISSN)
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  • 1598-7876(eISSN)
대한신경외과학회 (The Korean Neurosurgical Society)
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The Effect of Minocycline on Motor Neuron Recovery and Neuropathic Pain in a Rat Model of Spinal Cord Injury

  • Cho, Dong-Charn (Department of Neurosurgery, Hanyang University College of Medicine) ;
  • Cheong, Jin-Hwan (Department of Neurosurgery, Hanyang University College of Medicine) ;
  • Yang, Moon-Sul (Department of Neurosurgery, Hanyang University College of Medicine) ;
  • Hwang, Se-Jin (Department of Anatomy, Hanyang University College of Medicine) ;
  • Kim, Jae-Min (Department of Neurosurgery, Hanyang University College of Medicine) ;
  • Kim, Choong-Hyun (Department of Neurosurgery, Hanyang University College of Medicine)
  • 투고 : 2010.09.15
  • 심사 : 2011.02.27
  • 발행 : 2011.02.28
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초록

Objective : Minocycline, a second-generation tetracycline-class antibiotic, has been well established to exert a neuroprotective effect in animal models and neurodegenerative disease through the inhibition of microglia. Here, we investigated the effects of minocycline on motor recovery and neuropathic pain in a rat model of spinal cord injury. Methods : To simulate spinal cord injury, the rats' spinal cords were hemisected at the 10th thoracic level (T10). Minocycline was injected intraperitoneally, and was administered 30 minutes prior surgery and every second postoperative day until sacrifice 28 days after surgery. Motor recovery was assessed via the Basso-Beattie-Bresnahan test Mechanical hyperalgesia was measured throughout the 28-day post -operative course via the von Frey test Microglial and astrocyte activation was assessed by immunohistochemical staining for ionized calcium binding adaptor molecule 1 (lba1) and glial fibrillary acidic protein (GFAP) at two sites: at the level of hemisection and at the 5th lumbar level (L5). Results : In rats, spinal cord hemisection reduced locomotor function and induced a mechanical hyperalgesia of the ipsilateral hind limb. The expression of lba1 and GFAP was also increased in the dorsal and ventral horns of the spinal cord at the site of hemisection and at the L5 level. Intraperitoneal injection of minocycline facilitated overall motor recovery and attenuated mechanical hyperalgesia. The expression of lba1 and GFAP in the spinal cord was also reduced in rats treated with minocycline. Conclusion : By inhibiting microglia and astrocyte activation, minocycline may facilitate motor recovery and attenuate mechanical hyperalgesia in individuals with spinal cord injuries.

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참고문헌

  1. Amin AR, Attur MG, Thakker GD, Patel PD, Vyas PR, Patel RN, et al. : A novel mechanism of action of tetracyclines : effects on nitric oxide synthases. Proc Natl Acad Sci U S A 93 : 14014-14019, 1996 https://doi.org/10.1073/pnas.93.24.14014
  2. Anthes DL, Theriault E, Tator CH : Ultrastructural evidence for arteriolar vasospasm after spinal cord trauma. Neurosurgery 39 : 804-814, 1996 https://doi.org/10.1097/00006123-199610000-00032
  3. Baptiste DC, Fehlings MG : Pharmacological approaches to repair the injured spinal cord. J Neurotrauma 23 : 318-334, 2006 https://doi.org/10.1089/neu.2006.23.318
  4. Basso DC, Beattie MG, Bresnahan JC : Graded histological and locomotor outcomes after spinal cord contusion using the NYU weight-drop device versus transection. Exp Neurol 139 : 244-256, 1996 https://doi.org/10.1006/exnr.1996.0098
  5. Bracken MB : Treatment of acute spinal cord injury with methylprednisolone : results of a multicenter, randomized clinical trial. J Neurotrauma 8 Suppl 1: S47-S50; discussion S51-S52, 1991
  6. Bracken MB, Shepard MJ, Holford TR, Leo-Summers L, Aldrich EF, Fazl M, et al. : Methylprednisolone or tirilazad mesylate administration after acute spinal cord injury : 1-year follow up. Results of the third National Acute Spinal Cord Injury randomized controlled trial. J Neurosurg 89 : 699-706, 1998 https://doi.org/10.3171/jns.1998.89.5.0699
  7. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL : Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53 : 55-63, 1994 https://doi.org/10.1016/0165-0270(94)90144-9
  8. Colburn RW, Rickman AJ, DeLeo JA : The effect of site and type of nerve injury on spinal glial activation and neuropathic pain behavior. Exp Neurol 157 : 289-304, 1999 https://doi.org/10.1006/exnr.1999.7065
  9. DeVivo MJ : Causes and costs of spinal cord injury in the United States. Spinal Cord 35 : 809-13, 1997 https://doi.org/10.1038/sj.sc.3100501
  10. Festoff BW, Ameenuddin S, Arnold PM, Wong A, Santacruz KS, Citron BA : Minocycline neuroprotects, reduces microgliosis, and inhibits caspase protease expression early after spinal cord injury. J Neurochem 97 : 1314-1326, 2006 https://doi.org/10.1111/j.1471-4159.2006.03799.x
  11. Golub LM, Ramamurthy NS, McNamara TF, Greenwald RA, Rifkin BR : Tetracyclines inhibit connective tissue breakdown : new therapeutic implications for an old family of drugs. Crit Rev Oral Biol Med 2 : 297-321, 1991 https://doi.org/10.1177/10454411910020030201
  12. Hall ED : The neuroprotective pharmacology of methylprednisolone. J Neurosurg 76 : 13-22, 1992 https://doi.org/10.3171/jns.1992.76.1.0013
  13. Hauben E, Gothilf A, Cohen A, Butovsky O, Nevo U, Smirnov I, et al. : Vaccination with dendritic cells pulsed with peptides of myelin basic protein promotes functional recovery from spinal cord injury. J Neurosci 23 : 8808-8819, 2003
  14. Hurlbert RJ : Methylprednisolone for acute spinal cord injury : an inappropriate standard of care. J Neurosurg 93 : 1-7, 2000 https://doi.org/10.3171/jns.2000.93.1.0001
  15. Jiang F, Liu T, Cheng M, Pang XY, Bai ZT, Zhou JJ, et al. : Spinal astrocyte and microglial activation contributes to rat pain-related behaviors induced by the venom of scorpion buthus martensi karch. Eur J Pharmacol 623 : 52-64, 2009 https://doi.org/10.1016/j.ejphar.2009.09.028
  16. Jones TB, Basso DM, Sodhi A, Pan JZ, Hart RP, MacCallum RC, et al. : Pathological cns autoimmune disease triggered by traumatic spinal cord injury : implications for autoimmune vaccine therapy. J Neurosci 22 : 2690-2700, 2002
  17. Kwon BK, Tetzlaff W, Grauer JN, Beiner J, Vaccaro AR : Pathophysiology and pharmacologic treatment of acute spinal cord injury. Spine J 4 : 451-464, 2004 https://doi.org/10.1016/j.spinee.2003.07.007
  18. Lammertse DP : Update on pharmaceutical trials in acute spinal cord injury. J Spinal Cord Med 27 : 319-325, 2004 https://doi.org/10.1080/10790268.2004.11753769
  19. Lee YL, Shih K, Bao P, Ghirnikar RS, Eng LF : Cytokine chemokine expression in contused rat spinal cord. Neurochem Int 36 : 417-425, 2000 https://doi.org/10.1016/S0197-0186(99)00133-3
  20. Popovich PG : Immunological regulation of neuronal degeneration and regeneration in the injured spinal cord. Prog Brain Res 128 : 43-58, 2000
  21. Qiu J : China spinal cord injury network: Changes from within. Lancet Neurol 8 : 606-607, 2009 https://doi.org/10.1016/S1474-4422(09)70162-0
  22. Rabchevsky AG, Fugaccia I, Sullivan PG, Blades DA, Scheff SW : Efficacy of methylprednisolone therapy for the injured rat spinal cord. J Neurosci Res 68 : 7-18, 2002 https://doi.org/10.1002/jnr.10187
  23. Rideout HJ, Stefanis L : Caspase inhibition : a potential therapeutic strategy in neurological diseases. Histol Histopathol 16 : 895-908, 2001
  24. Romero-Sandoval A, Chai N, Nutile-McMenemy N, DeLeo JA : A comparison of spinal iba1 and gfap expression in rodent models of acute and chronic pain. Brain Res 1219 : 116-126, 2008 https://doi.org/10.1016/j.brainres.2008.05.004
  25. Rothman SM, Winkelstein BA : Chemical and mechanical nerve root insults induce differential behavioral sensitivity and glial activation that are enhanced in combination. Brain Res 1181 : 30-43, 2007 https://doi.org/10.1016/j.brainres.2007.08.064
  26. Saganová K, Orendácova J, Cízková D, Vanický I : Limited minocycline neuroprotection after balloon-compression spinal cord injury in the rat. Neurosci Lett 433 : 246-249, 2008 https://doi.org/10.1016/j.neulet.2008.01.041
  27. Schwab JM, Brechtel K, Mueller CA, Failli V, Kaps HP, Tuli SK, et al. : Experimental strategies to promote spinal cord regeneration--an integrative perspective. Prog Neurobiol 78 : 91-116, 2006 https://doi.org/10.1016/j.pneurobio.2005.12.004
  28. Schwab JM, Seid K, Schluesener HJ : Traumatic brain injury induces prolonged accumulation of cyclooxygenase-1 expressing microglia/brain macrophages in rats. J Neurotrauma 18 : 881-890, 2001 https://doi.org/10.1089/089771501750451802
  29. Shin MS, Chung BS, Kim YS : Effect of cyclosporin a in a rat spinal cord injury model. J Korean Neurosurg Soc 27 : 1361-1369, 1998
  30. Short DT, El Masry WS, Jones PW : High dose methylprednisolone in the management of acute spinal cord injury-a systematic review from a clinical perspective. Spinal Cord 38 : 273-286, 2000 https://doi.org/10.1038/sj.sc.3100986
  31. Smirnova IV, Citron BA, Arnold PM, Festoff BW : Neuroprotective signal transduction in model motor neurons exposed to thrombin : G-protein modulation effects on neurite outgrowth, Ca(2+) mobilization, and apoptosis. J Neurobiol 48 : 87-100, 2001 https://doi.org/10.1002/neu.1044
  32. Springer JE, Azbill RD, Knapp PE : Activation of the caspase-3 apoptotic cascade in traumatic spinal cord injury. Nat Med 5 : 943-946, 1999 https://doi.org/10.1038/11387
  33. Teng YD, Choi H, Onario RC, Zhu S, Desilets FC, Lan S, et al. : Minocycline inhibits contusion-triggered mitochondrial cytochrome c release and mitigates functional deficits after spinal cord injury. Proc Natl Acad Sci U S A 101 : 3071-3076, 2004 https://doi.org/10.1073/pnas.0306239101
  34. Tikka T, Fiebich BL, Goldsteins G, Keinanen R, Koistinaho J : Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. J Neurosci 21 : 2580-2588, 2001
  35. Tozaki-Saitoh H, Tsuda M, Miyata H, Ueda K, Kohsaka S, Inoue K : P2y12 receptors in spinal microglia are required for neuropathic pain after peripheral nerve injury. J Neurosci 28 : 4949-4956, 2008 https://doi.org/10.1523/JNEUROSCI.0323-08.2008
  36. von Bernhardi R, Ramirez G : Microglia astrocyte interaction in alzheimer's disease : friends or foes for the nervous system? Biol Res 34 : 123-128, 2001
  37. Wasserman JK, Schlichter LC : Neuron death and inflammation in a rat model of intracerebral hemorrhage : effects of delayed minocycline treatment. Brain Res 1136 : 208-218, 2007 https://doi.org/10.1016/j.brainres.2006.12.035
  38. Yune TY, Lee JY, Jung GY, Kim SJ, Jiang MH, Kim YC, et al. : Minocycline alleviates death of oligodendrocytes by inhibiting pro-nerve growth factor production in microglia after spinal cord injury. J Neurosci 27 : 7751-7761, 2007 https://doi.org/10.1523/JNEUROSCI.1661-07.2007

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  5. Neuropathic pain: An evolutionary hypothesis vol.78, pp.5, 2012, https://doi.org/10.1016/j.mehy.2012.01.044
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  11. Toll-Like Receptor 4–Dependent Microglial Activation Mediates Spinal Cord Ischemia–Reperfusion Injury vol.128, pp.11, 2011, https://doi.org/10.1161/circulationaha.112.000024
  12. Persistent At-Level Thermal Hyperalgesia and Tactile Allodynia Accompany Chronic Neuronal and Astrocyte Activation in Superficial Dorsal Horn following Mouse Cervical Contusion Spinal Cord Injury vol.9, pp.9, 2014, https://doi.org/10.1371/journal.pone.0109099
  13. Investigational drugs for the treatment of spinal cord injury: review of preclinical studies and evaluation of clinical trials from Phase I to II vol.24, pp.5, 2015, https://doi.org/10.1517/13543784.2015.1009629
  14. Minocycline Reduces the Severity of Autonomic Dysreflexia after Experimental Spinal Cord Injury vol.35, pp.24, 2011, https://doi.org/10.1089/neu.2018.5703
  15. Postirradiation Necrosis after Slow Microvascular Breakdown in the Adult Rat Spinal Cord is Delayed by Minocycline Treatment vol.190, pp.2, 2018, https://doi.org/10.1667/rr15039.1
  16. Spontaneous and Stimulus-Evoked Respiratory Rate Elevation Corresponds to Development of Allodynia in Spinal Cord-Injured Rats vol.36, pp.12, 2011, https://doi.org/10.1089/neu.2018.5936
  17. The gut-brain axis and beyond: Microbiome control of spinal cord injury pain in humans and rodents vol.9, pp.None, 2011, https://doi.org/10.1016/j.ynpai.2020.100059
  18. Sumatriptan improves the locomotor activity and neuropathic pain by modulating neuroinflammation in rat model of spinal cord injury vol.43, pp.1, 2011, https://doi.org/10.1080/01616412.2020.1819090
  19. Antibiotics with therapeutic effects on spinal cord injury: a review vol.35, pp.2, 2011, https://doi.org/10.1111/fcp.12605
  20. Antibiotics with therapeutic effects on spinal cord injury: a review vol.35, pp.2, 2011, https://doi.org/10.1111/fcp.12605