Matrix metalloproteinases (MMPs) constitute a family of zinc-dependent endopeptidases that mediate extracellular matrix turnover and associated processes, such as cell survival, growth, and differentiation. This paper discusses important functions of MMP in the normal and injured nervous system, focusing on the role played by these proteases in neurological pain syndromes, most prominently in neuropathic pain and migraine headaches. In the past decade, metalloproteinases emerged as key modulators of neuropathic pain, with MMP-9 acting as an initiator of the neuropathic cascade. Increased MMP activity was detected in migraine patients, independent of aura, in tight association with metabolic derangements. The therapeutic implications of MMP inhibition are considered in the context of neurogenic pain regulation. 1. Background Matrix metalloproteinases (MMPs) are a family of over twenty zinc-dependent endopeptidases that play essential roles in a wide range of proteolytic processes. Their first-recognized and most prominent function is in cleaving components of the extracellular matrix (ECM). Additional substrates identified in recent years include other proteinases, chemotactic factors, growth factors, cell surface receptors, and cell adhesion molecules [1–3]. Acting upon all these substrates allows metalloproteinases to influence a multitude of processes, from cellular differentiation and migration to signaling, survival, and apoptosis (Table 1). Although most MMPs are secreted molecules, several transmembrane and glycosylphosphatidylinositol-anchored membrane proteins are also included in this family. According to their structure and substrate specificity, MMPs are categorized as collagenases (MMP-1, MMP-8, MMP-13, and MMP-18), gelatinases (MMP-2 and MMP-9), stromelysins (MMP-3, MMP-10, and -11), membrane-type MMPs (MMP-14 or MT1-MMP, MMP-15 or MT2-MMP, MMP-16 or MT3-MMP, MMP-17 or MT4-MMP, MMP-24 or MT5-MMP, and MMP-25 or MT6-MMP), and other MMPs [3]. Table 1: Matrix metalloproteinases modulate tissue structure and cellular activities by participating in complex biological processes. In accordance with MMP involvement in tissue turnover, their activity undergoes tight regulation through multiple mechanisms, including transcription and translation of proprotease genes, and proform activation. Although most members of the protease family are not expressed constitutively, they are rapidly upregulated when cytokines, chemokines, growth factors, ECM components, and other transcriptional regulators act upon the cell [3, 4]. Most MMPs are translated as
References
[1]
A. Page-McCaw, A. J. Ewald, and Z. Werb, “Matrix metalloproteinases and the regulation of tissue remodelling,” Nature Reviews Molecular Cell Biology, vol. 8, no. 3, pp. 221–233, 2007.
[2]
V. W. Yong, “Metalloproteinases: mediators of pathology and regeneration in the CNS,” Nature Reviews Neuroscience, vol. 6, no. 12, pp. 931–944, 2005.
[3]
V. W. Yong, S. M. Agrawal, and D. P. Stirling, “Targeting MMPs in acute and chronic neurological conditions,” Neurotherapeutics, vol. 4, no. 4, pp. 580–589, 2007.
[4]
C. Yan and D. D. Boyd, “Regulation of matrix metalloproteinase expression expression,” Journal of Cellular Physiology, vol. 211, no. 1, pp. 19–26, 2007.
[5]
R. R. Ji, Z. Z. Xu, X. Wang, and E. H. Lo, “Matrix metalloprotease regulation of neuropathic pain,” Trends in Pharmacological Sciences, vol. 30, no. 7, pp. 336–340, 2009.
[6]
R. K. Nuttall, C. Silva, W. Hader et al., “Metalloproteinases are enriched in microglia compared with leukocytes and they regulate cytokine levels in activated microglia,” GLIA, vol. 55, no. 5, pp. 516–526, 2007.
[7]
C. Vaillant, C. Meissirel, M. Mutin, M. F. Belin, L. R. Lund, and N. Thomasset, “MMP-9 deficiency affects axonal outgrowth, migration, and apoptosis in the developing cerebellum,” Molecular and Cellular Neuroscience, vol. 24, no. 2, pp. 395–408, 2003.
[8]
J. Luo, “The role of matrix metalloproteinases in the morphogenesis of the cerebellar cortex,” Cerebellum, vol. 4, no. 4, pp. 239–245, 2005.
[9]
C. A. Webber, J. C. Hocking, V. W. Yong, C. L. Stange, and S. McFarlane, “Metalloproteases and guidance of retinal axons in the developing visual system,” Journal of Neuroscience, vol. 22, no. 18, pp. 8091–8100, 2002.
[10]
R. C. Soler, Y. H. Gui, K. K. Linask, and R. J. Muschel, “MMP-9 (gelatinase B) mRNA is expressed during mouse neurogenesis and may be associated with vascularization,” Developmental Brain Research, vol. 88, no. 1, pp. 37–52, 1995.
[11]
H. Hayashita-Kinoh, H. Kinoh, A. Okada et al., “Membrane-type 5 matrix metalloproteinase is expressed in differentiated neurons and regulates axonal growth,” Cell Growth and Differentiation, vol. 12, no. 11, pp. 573–580, 2001.
[12]
D. M. Jaworski and N. Fager, “Regulation of tissue inhibitor of metalloproteinase-3 (Timp-3) mRNA expression during rat CNS development,” Journal of Neuroscience Research, vol. 61, no. 4, pp. 396–408, 2000.
[13]
P. H. Larsen, A. G. DaSilva, K. Conant, and V. W. Yong, “Myelin formation during development of the CNS is delayed in matrix metalloproteinase-9 and -12 null mice,” Journal of Neuroscience, vol. 26, no. 8, pp. 2207–2214, 2006.
[14]
J. Dzwonek, M. Rylski, and L. Kaczmarek, “Matrix metalloproteinases and their endogenous inhibitors in neuronal physiology of the adult brain,” FEBS Letters, vol. 567, no. 1, pp. 129–135, 2004.
[15]
S. E. Meighan, P. C. Meighan, P. Choudhury et al., “Effects of extracellular matrix-degrading proteases matrix metalloproteinases 3 and 9 on spatial learning and synaptic plasticity,” Journal of Neurochemistry, vol. 96, no. 5, pp. 1227–1241, 2006.
[16]
V. Nagy, O. Bozdagi, A. Matynia et al., “Matrix metalloproteinase-9 is required for hippocampal late-phase long-term potentiation and memory,” Journal of Neuroscience, vol. 26, no. 7, pp. 1923–1934, 2006.
[17]
P. H. Larsen, J. E. Wells, W. B. Stallcup, G. Opdenakker, and V. W. Yong, “Matrix Metalloproteinase-9 Facilitates Remyelination in Part by Processing the Inhibitory NG2 Proteoglycan,” Journal of Neuroscience, vol. 23, no. 35, pp. 11127–11135, 2003.
[18]
J. Y. C. Hsu, R. McKeon, S. Goussev et al., “Matrix metalloproteinase-2 facilitates wound healing events that promote functional recovery after spinal cord injury,” Journal of Neuroscience, vol. 26, no. 39, pp. 9841–9850, 2006.
[19]
M. A. Pizzi and M. J. Crowe, “Transplantation of fibroblasts that overexpress matrix metalloproteinase-3 into the site of spinal cord injury in rats,” Journal of Neurotrauma, vol. 23, no. 12, pp. 1750–1765, 2006.
[20]
Y. Zhang, H. J. Klassen, B. A. Tucker, M. T. R. Perez, and M. J. Young, “CNS progenitor cells promote a permissive environment for neurite outgrowth via a matrix metalloproteinase-2-dependent mechanism,” Journal of Neuroscience, vol. 27, no. 17, pp. 4499–4506, 2007.
[21]
B. Q. Zhao, S. Wang, H. Y. Kim et al., “Role of matrix metalloproteinases in delayed cortical responses after stroke,” Nature Medicine, vol. 12, no. 4, pp. 441–445, 2006.
[22]
B. Q. Zhao, E. Tejima, and E. H. Lo, “Neurovascular proteases in brain injury, hemorrhage and remodeling after stroke,” Stroke, vol. 38, no. 2, pp. 748–752, 2007.
[23]
V. W. Yong, R. K. Zabad, S. Agrawal, A. Goncalves DaSilva, and L. M. Metz, “Elevation of matrix metalloproteinases (MMPs) in multiple sclerosis and impact of immunomodulators,” Journal of the Neurological Sciences, vol. 259, no. 1-2, pp. 79–84, 2007.
[24]
A. Weaver, A. Goncalves da Silva, R. K. Nuttall et al., “An elevated matrix metalloproteinase (MMP) in an animal model of multiple sclerosis is protective by affecting Th1/Th2 polarization,” FASEB Journal, vol. 19, no. 12, pp. 1668–1670, 2005.
[25]
L. J. Noble, F. Donovan, T. Igarashi, S. Goussev, and Z. Werb, “Matrix metalloproteinases limit functional recovery after spinal cord injury by modulation of early vascular events,” Journal of Neuroscience, vol. 22, no. 17, pp. 7526–7535, 2002.
[26]
J. E. A. Wells, T. K. Rice, R. K. Nuttall et al., “An adverse role for matrix metalloproteinase 12 after spinal cord injury in mice,” Journal of Neuroscience, vol. 23, no. 31, pp. 10107–10115, 2003.
[27]
S. R. Lee, K. Tsuji, S. R. Lee, and E. H. Lo, “Role of matrix metalloproteinases in delayed neuronal damage after transient global cerebral ischemia,” Journal of Neuroscience, vol. 24, no. 3, pp. 671–678, 2004.
[28]
D. Leppert, S. L. Leib, C. Grygar, K. M. Miller, U. B. Schaad, and G. A. Holl？nder, “Matrix metalloproteinase (MMP)-8 and MMP-9 in cerebrospinal fluid during bacterial meningitis: association with blood-brain barrier damage and neurological sequelae,” Clinical Infectious Diseases, vol. 31, no. 1, pp. 80–84, 2000.
[29]
G. A. Rosenberg, M. Kornfeld, E. Estrada, R. O. Kelley, L. A. Liotta, and W. G. Stetler-Stevenson, “TIMP-2 reduces proteolytic opening of blood-brain barrier by type IV collagenase,” Brain Research, vol. 576, no. 2, pp. 203–207, 1992.
[30]
A. M. Manicone and J. K. McGuire, “Matrix metalloproteinases as modulators of inflammation,” Seminars in Cell and Developmental Biology, vol. 19, no. 1, pp. 34–41, 2008.
[31]
D. Leppert, E. Waubant, R. Galardy, N. W. Bunnett, and S. L. Hauser, “T cell gelatinases madiate basement membrane transmigration in vitro,” Journal of Immunology, vol. 154, no. 9, pp. 4379–4389, 1995.
[32]
S. Chandler, K. M. Miller, J. M. Clements et al., “Matrix metalloproteinases, tumor necrosis factor and multiple sclerosis: an overview,” Journal of Neuroimmunology, vol. 72, no. 2, pp. 155–161, 1997.
[33]
L. A. Cunningham, M. Wetzel, and G. A. Rosenberg, “Multiple roles for MMPs and TIMPs in cerebral ischemia,” GLIA, vol. 50, no. 4, pp. 329–339, 2005.
[34]
G. Opdenakker, I. Nelissen, and J. Van Damme, “Functional roles and therapeutic targeting of gelatinase B and chemokines in multiple sclerosis,” The Lancet Neurology, vol. 2, no. 12, pp. 747–756, 2003.
[35]
J. Scholz and C. J. Woolf, “The neuropathic pain triad: neurons, immune cells and glia,” Nature Neuroscience, vol. 10, no. 11, pp. 1361–1368, 2007.
[36]
A. R. Folgueras, T. Valdés-Sánchez, E. Llano et al., “Metalloproteinase MT5-MMP is an essential modulator of neuro-immune interactions in thermal pain stimulation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 38, pp. 16451–16456, 2009.
[37]
C. A. Christianson, B. L. Fitzsimmons, J. H. Shim et al., “Spinal matrix metalloproteinase 3 mediates inflammatory hyperalgesia via a tumor necrosis factor-dependent mechanism,” Neuroscience, vol. 200, pp. 199–210, 2012.
[38]
H. Kobayashi, S. Chattopadhyay, K. Kato et al., “MMPs initiate Schwann cell-mediated MBP degradation and mechanical nociception after nerve damage,” Molecular and Cellular Neuroscience, vol. 39, no. 4, pp. 619–627, 2008.
[39]
Y. Kawasaki, L. Zhang, J. K. Cheng, and R. R. Ji, “Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1β, interleukin-6, and tumor necrosis factor-α in regulating synaptic and neuronal activity in the superficial spinal cord,” Journal of Neuroscience, vol. 28, no. 20, pp. 5189–5194, 2008.
[40]
Y. Kim, A. G. Remacle, A. V. Chernov et al., et al., “The MMP-9/TIMP-1 axis controls the status of differentiation and function of myelin-forming Schwann cells in nerve regeneration,” PLoS ONE, vol. 7, no. 3, Article ID e33664, 2012.
[41]
Y. Kawasaki, Z. Z. Xu, X. Wang et al., “Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain,” Nature Medicine, vol. 14, no. 3, pp. 331–336, 2008.
[42]
C. Sommer and M. Kress, “Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia,” Neuroscience Letters, vol. 361, no. 1–3, pp. 184–187, 2004.
[43]
C. J. Woolf and R. J. Mannion, “Neuropathic pain: aetiology, symptoms, mechanisms, and management,” The Lancet, vol. 353, no. 9168, pp. 1959–1964, 1999.
[44]
Z. Y. Zhuang, P. Gerner, C. J. Woolf, and R. R. Ji, “ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model,” Pain, vol. 114, no. 1-2, pp. 149–159, 2005.
[45]
H. Zhang, M. Chang, C. N. Hansen, D. M. Basso, and L. J. Noble-Haeusslein, “Role of matrix metalloproteinases and therapeutic benefits of their inhibition in spinal cord injury,” Neurotherapeutics, vol. 8, no. 2, pp. 206–220, 2011.
[46]
K. S. Fernandes, D. G. Brum, A. C. Palei et al., “Functional MMP-9 polymorphisms modulate plasma MMP-9 levels in multiple sclerosis patients,” Journal of Neuroimmunology, vol. 249, no. 1-2, pp. 56–59, 2012.
[47]
H. Zahednasab, M. Saadatnia, M. R. Jabalameli, H. Zarkesh-Esfahani, A. Esmaeili, and S. A. Bahreini, “Controversial role of MMP-9 gene in MS disease,” Journal of Neuroimmunology, vol. 230, no. 1-2, p. 191, 2011.
[48]
A. Créange, T. Sharshar, J. C. Rapha？l, and R. Gherardi, “Cellular aspect of neuroinflammation in Guillain-Barré syndrome: a key to a new therapeutic option?” Revue Neurologique, vol. 158, no. 1, pp. 15–27, 2002.
[49]
D. Leppert, P. Hughes, S. Huber et al., “Matrix metalloproteinase upregulation in chronic inflammatory demyelinating polyneuropathy and nonsystemic vasculitic neuropathy,” Neurology, vol. 53, no. 1, pp. 62–70, 1999.
[50]
G. Gurer, S. Erdem, C. Kocaefe, M. ？zgü？, and E. Tan, “Expression of matrix metalloproteinases in vasculitic neuropathy,” Rheumatology International, vol. 24, no. 5, pp. 255–259, 2004.
[51]
E. Robak, A. Wierzbowska, M. Chmiela, L. Kulczycka, A. Sysa-J？drejowska, and T. Robak, “Circulating total and active metalloproteinase-9 and tissue inhibitor of metalloproteinases-1 in patients with systemic lupus erythomatosus,” Mediators of Inflammation, vol. 2006, Article ID 17898, 7 pages, 2006.
[52]
C. Mawrin, A. Brunn, C. R？cken, and J. M. Schr？der, “Peripheral neuropathy in systemic lupus erythematosus: pathomorphological features and distribution pattern of matrix metalloproteinases,” Acta Neuropathologica, vol. 105, no. 4, pp. 365–372, 2003.
[53]
S. Renaud, B. Erne, P. Fuhr et al., “Matrix metalloproteinases-9 and -2 in secondary vasculitic neuropathies,” Acta Neuropathologica, vol. 105, no. 1, pp. 37–42, 2003.
[54]
S. Chandler, R. Coates, A. Gearing, J. Lury, G. Wells, and E. Bone, “Matrix metalloproteinases degrade myelin basic protein,” Neuroscience Letters, vol. 201, no. 3, pp. 223–226, 1995.
[55]
M. Devor, “Sodium channels and mechanisms of neuropathic pain,” Journal of Pain, vol. 7, no. 1, supplement, pp. S3–S12, 2006.
[56]
R. R. Ji and G. Strichartz, “Cell signaling and the genesis of neuropathic pain,” Science's STKE, vol. 2004, no. 252, Article ID reE14, 2004.
[57]
M. Calvo and D. L. Bennett, “The mechanisms of microgliosis and pain following peripheral nerve injury,” Experimental Neurology, vol. 234, no. 2, pp. 271–282, 2012.
[58]
V. I. Shubayev and R. R. Myers, “Matrix metalloproteinase-9 promotes nerve growth factor-induced neurite elongation but not new sprout formation in vitro,” Journal of Neuroscience Research, vol. 77, no. 2, pp. 229–239, 2004.
[59]
J. Zuo, T. A. Ferguson, Y. J. Hernandez, W. G. Stetler-Stevenson, and D. Muir, “Neuronal matrix metalloproteinase-2 degrades and inactivates a neurite- inhibiting chondroitin sulfate proteoglycan,” Journal of Neuroscience, vol. 18, no. 14, pp. 5203–5211, 1998.
[60]
F. Khojasteh, M. Hasanpour-Ezati, J. Mirnajafi-Zadeh, and S. Semnanian, “Role of matrix metalloproteinase II in the analgesia induced by neuronal nitric oxide inhibition in rat,” Physiology and Pharmacology, vol. 13, no. 1, pp. 10–17, 2009.
[61]
T. Yamamoto, O. Saito, K. Shono, S. Ohtori, and H. Ino, “Analgesic effect of intrathecally administered matrix metalloproteinase 2 (MMP-2) in the rat formalin test,” Neuroscience Letters, vol. 347, no. 2, pp. 77–80, 2003.
[62]
K. Nishida, S. Kuchiiwa, S. Oiso et al., “Up-regulation of matrix metalloproteinase-3 in the dorsal root ganglion of rats with paclitaxel-induced neuropathy,” Cancer Science, vol. 99, no. 8, pp. 1618–1625, 2008.
[63]
K. Komori, T. Nonaka, A. Okada et al., “Absence of mechanical allodynia and Aβ-fiber sprouting after sciatic nerve injury in mice lacking membrane-type 5 matrix metalloproteinase,” FEBS Letters, vol. 557, no. 1–3, pp. 125–128, 2004.
[64]
J. Rodriguez Parkitna, M. Korostynski, D. Kaminska-Chowaniec et al., “Comparison of gene expression profiles in neuropathic and inflammatory pain,” Journal of Physiology and Pharmacology, vol. 57, no. 3, pp. 401–414, 2006.
[65]
P. J. Siddall, J. M. McClelland, S. B. Rutkowski, and M. J. Cousins, “A longitudinal study of the prevalence and characteristics of pain in the first 5 years following spinal cord injury,” Pain, vol. 103, no. 3, pp. 249–257, 2003.
[66]
M. R. Detloff, L. C. Fisher, V. McGaughy, E. E. Longbrake, P. G. Popovich, and D. M. Basso, “Remote activation of microglia and pro-inflammatory cytokines predict the onset and severity of below-level neuropathic pain after spinal cord injury in rats,” Experimental Neurology, vol. 212, no. 2, pp. 337–347, 2008.
[67]
A. S. C. Rice, W. P. Farquhar-Smith, and I. Nagy, “Endocannabinoids and pain: spinal and peripheral analgesia in inflammation and neuropathy,” Prostaglandins Leukotrienes and Essential Fatty Acids, vol. 66, no. 2-3, pp. 243–256, 2002.
[68]
R. Ramer and B. Hinz, “Cyclooxygenase-2 and tissue inhibitor of matrix metalloproteinases-1 confer the antimigratory effect of cannabinoids on human trabecular meshwork cells,” Biochemical Pharmacology, vol. 80, no. 6, pp. 846–857, 2010.
[69]
W. H. Li, Y. M. Lee, J. Y. Kim et al., “Transient receptor potential vanilloid-1 mediates heat-shock-induced matrix metalloproteinase-1 expression in human epidermal keratinocytes,” Journal of Investigative Dermatology, vol. 127, no. 10, pp. 2328–2335, 2007.
[70]
M. G. Dombourian, N. A. Turner, T. A. Gerovac et al., “B1 and TRPV-1 receptor genes and their relationship to hyperalgesia following spinal cord injury,” Spine, vol. 31, no. 24, pp. 2778–2782, 2006.
[71]
F. M. Cutrer and A. Charles, “The neurogenic basis of migraine,” Headache, vol. 48, no. 9, pp. 1411–1414, 2008.
[72]
T. Dalkara, A. Nozari, and M. A. Moskowitz, “Migraine aura pathophysiology: the role of blood vessels and microembolisation,” The Lancet Neurology, vol. 9, no. 3, pp. 309–317, 2010.
[73]
Y. Gursoy-Ozdemir, J. Qiu, N. Matsuoka et al., “Cortical spreading depression activates and upregulates MMP-9,” Journal of Clinical Investigation, vol. 113, no. 10, pp. 1447–1455, 2004.
[74]
F. Richter and A. Lehmenkühler, “Cortical spreading depression (CSD): a neurophysiological correlate of migraine aura,” Schmerz, vol. 22, no. 5, pp. 544–550, 2008.
[75]
V. K. Gupta, “CSD, BBB and MMP-9 elevations: animal experiments versus clinical phenomena in migraine,” Expert Review of Neurotherapeutics, vol. 9, no. 11, pp. 1595–1614, 2009.
[76]
K. Imamura, T. Takeshima, E. Fusayasu, and K. Nakashima, “Increased plasma matrix metalloproteinase-9 levels in migraineurs,” Headache, vol. 48, no. 1, pp. 135–139, 2008.
[77]
A. Martins-Oliveira, J. G. Speciali, F. Dach et al., “Different circulating metalloproteinases profiles in women with migraine with and without aura,” Clinica Chimica Acta, vol. 408, no. 1-2, pp. 60–64, 2009.
[78]
R. Leira, T. Sobrino, M. Rodríguez-Yá？ez, M. Blanco, S. Arias, and J. Castillo, “MMP-9 immunoreactivity in acute migraine,” Headache, vol. 47, no. 5, pp. 698–702, 2007.
[79]
M. Ashina, J. F. Tvedskov, K. Lipka, J. Bilello, M. Penkowa, and J. Olesen, “Matrix metalloproteinases during and outside of migraine attacks without aura,” Cephalalgia, vol. 30, no. 3, pp. 303–310, 2010.
[80]
C. Bernecker, S. Pailer, P. Kieslinger et al., “Increased matrix metalloproteinase activity is associated with migraine and migraine-related metabolic dysfunctions,” European Journal of Neurology, vol. 18, no. 4, pp. 571–576, 2011.
[81]
V. W. Yong, J. Wells, F. Giuliani, S. Casha, C. Power, and L. M. Metz, “The promise of minocycline in neurology,” The Lancet Neurology, vol. 3, no. 12, pp. 744–751, 2004.
[82]
J. Hu, P. E. Van den Steen, Q. X. A. Sang, and G. Opdenakker, “Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases,” Nature Reviews Drug Discovery, vol. 6, no. 6, pp. 480–498, 2007.
[83]
J. A. Jacobsen, J. L. Major Jourden, M. T. Miller, and S. M. Cohen, “To bind zinc or not to bind zinc: an examination of innovative approaches to improved metalloproteinase inhibition,” Biochimica et Biophysica Acta, vol. 1803, no. 1, pp. 72–94, 2010.
[84]
J. T. Peterson, “Matrix metalloproteinase inhibitor development and the remodeling of drug discovery,” Heart Failure Reviews, vol. 9, no. 1, pp. 63–79, 2004.
[85]
A. W. Griffioen, “AG-3340 agouron pharmaceuticals inc,” IDrugs, vol. 3, no. 3, pp. 336–345, 2000.
[86]
F. Yu, H. Kamada, K. Niizuma, H. Endo, and P. H. Chan, “Induction of MMP-9 expression and endothelial injury by oxidative stress after spinal cord injury,” Journal of Neurotrauma, vol. 25, no. 3, pp. 184–195, 2008.
[87]
Z. Gu, J. Cui, S. Brown et al., “A highly specific inhibitor of matrix metalloproteinase-9 rescues laminin from proteolysis and neurons from apoptosis in transient focal cerebral ischemia,” Journal of Neuroscience, vol. 25, no. 27, pp. 6401–6408, 2005.
[88]
M. Gooyit, M. Lee, V. A. Schroeder et al., “Selective water-soluble gelatinase inhibitor prodrugs,” Journal of Medicinal Chemistry, vol. 54, no. 19, pp. 6676–6690, 2011.
[89]
S. Wojtowicz-Praga, “Clinical potential of matrix metalloprotease inhibitors,” Drugs in R D, vol. 1, no. 2, pp. 117–129, 1999.
[90]
C. C. Solorzano, R. Ksontini, J. H. Pruitt et al., “Involvement of 26-kDa cell-associated TNF-α in experimental hepatitis and exacerbation of liver injury with a matrix metalloproteinase inhibitor,” Journal of Immunology, vol. 158, no. 1, pp. 414–419, 1997.
[91]
P. H. Gordon, D. H. Moore, R. G. Miller et al., “Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial,” The Lancet Neurology, vol. 6, no. 12, pp. 1045–1053, 2007.
[92]
A. Khiat, M. D'Amour, F. Souchon, and Y. Boulanger, “MRS study of the effects of minocycline on markers of neuronal and microglial integrity in ALS,” Magnetic Resonance Imaging, vol. 28, no. 10, pp. 1456–1460, 2010.
[93]
G. T. Gim, J. H. Lee, E. Park et al., “Electroacupuncture attenuates mechanical and warm allodynia through suppression of spinal glial activation in a rat model of neuropathic pain,” Brain Research Bulletin, vol. 86, no. 5-6, pp. 403–411, 2011.
