Lumbar spinal stenosis (LSS) causes ischemia, inflammation, demyelination and results in cauda equina (CE) syndrome, with pain and locomotor functional deficits. We investigated whether exogenous administration of S-nitrosoglutathione (GSNO), an endogenous redox modulating anti-neuroinflammatory agent, hastens functional recovery in a CE compression (CEC) rat model. CEC was induced in adult female rats by the surgical implantation of two silicone blocks within the epidural spaces of L4-L6 vertebrae. GSNO (50 μg/kg body weight) was administered by gavage 1 h after the injury, and the treatment was continued daily thereafter. GSNO induced change in the pain threshold was evaluated for four days after the compression. Tissue analyses and locomotor function evaluation were carried out at two weeks and four weeks after the CEC respectively. GSNO significantly improved motor function in CEC rats as evidenced by an increased latency on rotarod compared with vehicle-treated CEC rats. CEC induced hyperalgesia was decreased by GSNO. GSNO also increased the expression of VEGF, reduced cellular infiltration (H&E staining) and apoptotic cell death (TUNEL assay), and hampered demyelination (LFB staining and g-ratio). These data demonstrate that administration of GSNO after CEC decreased inflammation, hyperalgesia and cell death leading to improved locomotor function of CEC rats. The therapeutic potential of GSNO observed in the present study with CEC rats suggests that GSNO is a candidate drug to test in LSS patients.
J. Steurer, A. Nydegger, U. Held, F. Brunner, J. Hodler, F. Porchet, K. Min, A. F. Mannion and B. Michel, “Lumb-Sten: The Lumbar Spinal Stenosis Outcome Study,” BMC Musculoskeletal Disorders, Vol. 11, 2010, p. 254. doi:10.1186/1471-2474-11-254
S. Dagenais, J. Caro and S. Haldeman, “A Systematic Review of Low Back Pain Cost of Illness Studies in the United States and Internationally,” The Spine Journal, Vol. 8, No. 1, 2008, pp. 8-20. doi:10.1016/j.spinee.2007.10.005
J. N. Katz, “Lumbar Disc Disorders and Low-Back Pain: Socioeconomic Factors and Consequences,” The Journal of Bone and Joint Surgery of American, Vol. 88, No. 2, 2006, pp. 21-24. doi:10.2106/JBJS.E.01273
E. Siebert, H. Pruss, R. Klingebiel, V. Failli, K. M. Einhaupl and J. M. Schwab, “Lumbar Spinal Stenosis: Syndrome, Diagnostics and Treatment,” Nature Reviews Neurology, Vol. 5, 2009, pp. 392-403. doi:10.1038/nrneurol.2009.90
J. M. Schwab, K. Brechtel, C. A. Mueller, V. Failli, H. P. Kaps, S. K. Tuli and H. J. Schluesener, “Experimental Strategies to Promote Spinal Cord Regeneration: An Integrative Perspective,” Progress in Neurobiology, Vol. 78, No. 3, 2006, pp. 91-116. doi:10.1016/j.pneurobio.2005.12.004
M. E. Schwab and D. Bartholdi, “Degeneration and Regeneration of Axons in the Lesioned Spinal Cord,” Physiological Reviews, Vol. 76, No. 2, 1996, pp. 319-370.
O. A. Bestawros, O. H. Vreeland and M. L. Goldman, “Epidural Venography in the Diagnosis of Lumbar Spinal Stenosis,” Radiology, Vol. 131, No. 2, 1979, pp. 423-426.
H. N. Herkowitz, S. W. Wiesel, R. E. Booth Jr. and R. H. Rothman, “Metrizamide Myelography and Epidural Venography. Their Role in the Diagnosis of Lumbar Disc Herniation and Spinal Stenosis,” Spine, Vol. 7, No. 1, 1982, pp. 55-64.
J. R. Bethea, “Spinal Cord Injury-Induced Inflammation: a Dual-Edged Sword,” Progress in Brain Research, Vol. 128, 2000, pp. 33-42. doi:10.1016/S0079-6123(00)28005-9
O. N. Hausmann, “Post-Traumatic Inflammation Following Spinal Cord Injury,” Spinal Cord, Vol. 41, 2003, pp. 369-378. doi:10.1038/sj.sc.3101483
S. Hall, J. D. Bartleson, B. M. Onofrio, H. L. Baker Jr., H. Okazaki and J. D. O’Duffy, “Lumbar Spinal Stenosis. Clinical Features, Diagnostic Procedures, and Results of Surgical Treatment in 68 Patients,” Annals of Internal Medicine, Vol. 103, No. 2, 1985, pp. 271-275.
O. Niggemeyer, J. M. Strauss and K. P. Schulitz, “Comparison of Surgical Procedures for Degenerative Lumbar Spinal Stenosis: A Meta-Analysis of the Literature from 1975 to 1995,” European Spine Journal, Vol. 6, No. 6, 1997, pp. 423-429. doi:10.1007/BF01834073
H. Iwamoto, H. Kuwahara, H. Matsuda, A. Noriage and Y. Yamano, “Production of Chronic Compression of the Cauda Equina in Rats for Use in Studies of Lumbar Spinal Canal Stenosis,” Spine, Vol. 20, 1995, pp. 2750-2757.
S. Kikuchi, S. Konno, S. Kayama, K. Sato and K. Olmarker, “Increased Resistance to Acute Compression Injury in Chronically Compressed Spinal Nerve Roots. An Experimental Study,” Spine, Vol. 21, 1996, pp. 2544-2550.
Y. Takenobu, N. Katsube, M. Marsala and K. Kondo, “Model of Neuropathic Intermittent Claudication in the Rat: Methodology and Application,” Journal of Neuro-science Methods, Vol. 104, No. 2, 2001, pp. 191-198. doi:10.1016/S0165-0270(00)00342-3
K. Watanabe, S. Konno, M. Sekiguchi and S. Kikuchi, “Spinal Stenosis: Assessment of Motor Function, VEGF Expression and Angiogenesis in an Experimental Model in the Rat,” European Spine Journal, Vol. 16, No. 11, 2007, pp. 1913-1918. doi:10.1007/s00586-007-0394-y
S. P. Singh, J. S. Wishnok, M. Keshive, W. M. Deen and S. R. Tannenbaum, “The Chemistry of the S-Nitrosoglutathione/Glutathione System,” Proceedings of the National Academy of Sciences of USA, Vol. 93, No. 25, 1996, pp. 14428-14433. doi:10.1073/pnas.93.25.14428
M. W. Foster, T. J. McMahon and J. S. Stamler, “S-Nitrosylation in Health and Disease,” Trends in Molecular and Medicine, Vol. 9, No. 4, 2003, pp. 160-168. doi:10.1016/S1471-4914(03)00028-5
M. W. Foster, D. T. Hess and J. S. Stamler, “Protein S-Nitrosylation in Health and Disease: A Current Perspective,” Trends in Molecular and Medicine, Vol. 15, No. 9, 2009, pp. 391-404. doi:10.1016/j.molmed.2009.06.007
C. C. Chiueh, “S-Nitrosoglutathione (GSNO) Mediates Brain Response to Hypoxia,” Pediatric Research, Vol. 51, 2002, p. 414. doi:10.1203/00006450-200204000-00002
M. Khan, Y. B. Im, A. Shunmugavel, A. G. Gilg, R. K. Dhindsa, A. K. Singh and I. Singh, “Administration of S-Nitrosoglutathione after Traumatic Brain Injury Pro- tects the Neurovascular Unit and Reduces Secondary Injury in a Rat Model of Controlled Cortical Impact,” Journal of Neuroinflammation, Vol. 6, 2009, p. 32. doi:10.1186/1742-2094-6-32
M. Khan, B. Sekhon, S. Giri, M. Jatana, A. G. Gilg, K. Ayasolla, C. Elango, A. K. Singh and I. Singh, “S-Ni- trosoglutathione Reduces Inflammation and Protects Brain against Focal Cerebral Ischemia in a Rat Model of Experimental Stroke,” Journal of Cerebral Blood Flow and Metabolism, Vol. 25, 2005, pp. 177-192. doi:10.1038/sj.jcbfm.9600012
A. Shunmugavel, M. Khan, P. C. Chou and I. Singh, “Spinal Cord Injury Induced Arrest in Estrous Cycle of Rats Is Ameliorated by S-Nitrosoglutathione: Novel Therapeutic Agent to Treat Amenorrhea,” Journal of Sexual Medicine, Vol. 9, No. 1, 2012, pp. 148-158. doi:10.1111/j.1743-6109.2011.02526.x
F. D’Acquisto, M. C. Maiuri, F. de Cristofaro and R. Carnuccio, “Nitric Oxide Prevents Inducible Cyclooxy-genase Expression by Inhibiting Nuclear Factor-Kappa B and Nuclear Factor-Interleukin-6 Activation,” Naunyn-Schmiedeberg’s Archives of Pharmacology, Vol. 364, No. 2, 2001, pp. 157-165. doi:10.1007/s002100100435
J. D. Fortenberry, M. L. Owens, N. X. Chen and L. A. Brown, “S-Nitrosoglutathione Inhibits TNF-Alpha-Induced NFkappaB Activation in Neutrophils,” Inflammation Research, Vol. 50, 2001, pp. 89-95.
R. Prasad, S. Giri, N. Nath, I. Singh and A. K. Singh, “GSNO Attenuates EAE Disease by S-Nitrosylation- Mediated Modulation of Endothelial-Monocyte Interactions,” Glia, Vol. 55, No. 1, 2007, pp. 65-77. doi:10.1002/glia.20436
A. S. Aledia, L. M. Tran, B. O. King, D. L. Serna, J. Eng, B. U. Jones, J. C. Chen and J. H. Roum, “S-Nitrosoglutathione Preserves Platelet Function during in Vitro Ventricular Assist Device Circulation,” Asaio Journal, Vol. 48, No. 5, 2002, pp. 526-531. doi:10.1097/00002480-200209000-00015
M. W. Radomski, D. D. Rees, A. Dutra and S. Moncada, “S-Nitroso-Glutathione Inhibits Platelet Activation in Vitro and in Vivo,” British Journal of Pharmacology, Vol. 107, No. 3, 1992, pp. 745-749. doi:10.1111/j.1476-5381.1992.tb14517.x
Z. Kaposzta, A. Clifton, J. Molloy, J. F. Martin and H. S. Markus, “S-Nitrosoglutathione Reduces Asymptomatic Embolization after Carotid Angioplasty,” Circulation, Vol. 106, 2002, pp. 3057-3062. doi:10.1161/01.CIR.0000041251.07332.28
Z. Kaposzta, J. F. Martin and H. S. Markus, “Switching off Embolization from Symptomatic Carotid Plaque Using S-Nitrosoglutathione,” Circulation, Vol. 105, 2002, pp. 1480-1484. doi:10.1161/01.CIR.0000012347.47001.97
J. Molloy, J. F. Martin, P. A. Baskerville, S. C. Fraser and H. S. Markus, “S-Nitrosoglutathione Reduces the Rate of Embolization in Humans,” Circulation, Vol. 98, 1998, pp. 1372-1375. doi:10.1161/01.CIR.98.14.1372
S. Mohr, B. Zech, E. G. Lapetina and B. Brune, “Inhibition of Caspase-3 by S-Nitrosation and Oxidation Caused by Nitric Oxide,” Biochemical Biophysical Research Communications, Vol. 238, No. 2, 1997, pp. 387-391. doi:10.1006/bbrc.1997.7304
C. C. Chiueh and P. Rauhala, “The Redox Pathway of S-Nitrosoglutathione, Glutathione and Nitric Oxide in Cell to Neuron Communications,” Free Radical Research, Vol. 31, 1999, pp. 641-650. doi:10.1080/10715769900301211
M. Khan, M. Jatana, C. Elango, A. S. Paintlia, A. K. Singh and I. Singh, “Cerebrovascular Protection by Various Nitric Oxide Donors in Rats after Experimental Stroke,” Nitric Oxide, Vol. 15, No. 2, 2006, pp. 114-124. doi:10.1016/j.niox.2006.01.008
P. Rauhala, A. M. Lin and C. C. Chiueh, “Neuroprotection by S-Nitrosoglutathione of Brain Dopamine Neurons from Oxidative Stress,” The Faseb Journal, Vol. 12, 1998, pp. 165-173.
A. Schrammel, A. C. Gorren, K. Schmidt, S. Pfeiffer and B. Mayer, “S-Nitrosation of Glutathione by Nitric Oxide, Peroxynitrite, and (*)NO/O(2)(*-),” Free Radical Biology and Medicine, Vol. 34, No. 8, 2003, pp. 1078-1088. doi:10.1016/S0891-5849(03)00038-8
K. Obata, H. Yamanaka, K. Kobayashi, Y. Dai, T. Mizushima, H. Katsura, T. Fukuoka, A. Tokunaga and K. Noguchi, “Role of Mitogen-Activated Protein Kinase Activation in Injured and Intact Primary Afferent Neurons for Mechanical and Heat Hypersensitivity after Spinal Nerve Ligation,” Journal of Neuroscience, Vol. 24, No. 45, 2004, pp. 10211-10222. doi:10.1523/JNEUROSCI.3388-04.2004
L. O. Randall and J. J. Selitto, “A Method for Measurement of Analgesic Activity on Inflamed Tissue,” Arch Int Pharmacodyn Ther, Vol. 111, No. 4, 1957, pp. 409-419.
E. G. Gray, “Electron Microscopy of Presynaptic Organelles of the Spinal Cord,” Journal of Anatomy, Vol. 97, 1963, pp. 101-106.
T. Chomiak and B. Hu, “What Is the Optimal Value of the g-Ratio for Myelinated Fibers in the Rat CNS? A Theoretical Approach,” PLoS One, Vol. 4, No. 11, 2009, Article ID: e7754. doi:10.1371/journal.pone.0007754
T. Yonetake, M. Sekiguchi, S. Konno, S. Kikuchi and F. Kanaya, “Compensatory Neovascularization after Cauda Equina Compression in Rats,” Spine, Vol. 33, 2008, pp. 140-145.
J. Kiernan, “Interactions between Mast Cells and Nerves. Neurogenic Inflammation,” Trends in Pharmacological Science, Vol. 11, No. 8, 1990, p. 316. doi:10.1016/0165-6147(90)90233-X
H. Lassmann and H. M. Wisniewski, “Chronic Relapsing Experimental Allergic Encephalomyelitis: Clinicopa- thological Comparison with Multiple Sclerosis,” Arch Neurology, Vol. 36, No. 8, 1979, pp. 490-497. doi:10.1001/archneur.1979.00500440060011
S. Li, T. Li, Y. Luo, H. Yu, Y. Sun, H. Zhou, X. Liang, J. Huang and S. Tang, “Retro-Orbital Injection of FITC-Dextran Is an Effective and Economical Method for Observing Mouse Retinal Vessels,” Molecular Vision, Vol. 17, 2011, pp. 3566-3573.
F. Matsuda, H. Sakakima and Y. Yoshida, “The Effects of Early Exercise on Brain Damage and Recovery after Focal Cerebral Infarction in Rats,” Acta Physiology (Oxford), Vol. 201, No. 2, 2011, pp. 275-287. doi:10.1111/j.1748-1716.2010.02174.x
T. Watanabe, S. Kato, K. Sato and K. Nagata, “Nitric Oxide Regulation System in Degenerative Lumbar Disease,” The Kurume Medical Journal, Vol. 52, No. 1-2, 2005, pp. 39-47. doi:10.2739/kurumemedj.52.39
M. Brock and J. Ramsbacher, “Lumbar Spinal Stenosis,” Critical Reviews in Neurosurgery, Vol. 8, 1998, pp. 333-337. doi:10.1007/s003290050098
M. Sekiguchi, S. Kikuchi and R. R. Myers, “Experimental Spinal Stenosis: Relationship between Degree of Cauda Equina Compression, Neuropathology, and Pain,” Spine, Vol. 29, 2004, pp. 1105-1111.
J. Orendacova, D. Cizkova, J. Kafka, N. Lukacova, M. Marsala, I. Sulla, J. Marsala and N. Katsube, “Cauda Equina Syndrome,” Progress in Neurobiology, Vol. 64, 2001, pp. 613-637. doi:10.1016/S0301-0082(00)00065-4
P. C. Chou, A. Shunmugavel, H. E. Sayed, M. M. Desouki, S. A. Nguyen, M. Khan, I. Singh and M. Bilgen, “Preclinical Use of Longitudinal MRI for Screening the Efficacy of S-Nitrosoglutathione in Treating Spinal Cord Injury,” Journal of Magnetic Resonance Imaging, Vol. 33, 2011, pp. 1301-1311. doi:10.1002/jmri.22574
M. Khan, H. Sakakima, T. S. Dhammu, A. Shunmugavel, Y. B. Im, A. G. Gilg, A. K. Singh and I. Singh, “S-Nitrosoglutathione Reduces Oxidative Injury and Promotes Mechanisms of Neurorepair Following Traumatic Brain Injury in Rats,” Journal of Neuroinflammation, Vol. 8, 2011, p. 78. doi:10.1186/1742-2094-8-78
W. F. Blakemore, “Remyelination of the Superior Cerebellar Peduncle in the Mouse Following Demyelination Induced by Feeding Cuprizone,” Journal of Neurological Science, Vol. 20, No. 1, 1973, pp. 73-83. doi:10.1016/0022-510X(73)90119-6
J. Lok, P. Gupta, S. Guo, W. J. Kim, M. J. Whalen and K. van Leyen and E. H. Lo, “Cell-Cell Signaling in the Neurovascular Unit,” Neurochemical Research, Vol. 32, No. 12, 2007, pp. 2032-2045. doi:10.1007/s11064-007-9342-9
M. Sekiguchi, Y. Aoki, S. Konno and S. Kikuchi, “The Effects of Cilostazol on Nerve Conduction Velocity and Blood Flow: Acute and Chronic Cauda Equina Compression in a Canine Model,” Spine, Vol. 33, 2008, pp. 2605- 2611.
S. Kobayashi, H. Baba, K. Takeno, S. Shimada, M. Kubota, T. Yayama, T. Miyazaki, K. Uchida and Y. Suzuki, “Blood Flow Analysis of Compressed Nerve Root after Intravenous Injection of Lipo-Prostaglandin E1,” Journal of Orthopaedic Research, Vol. 27, 2009, pp. 1252-1257. doi:10.1002/jor.20881
C. C. Chan, “Inflammation: Beneficial or Detrimental after Spinal Cord Injury?” Recent Patents on CNS Drug Discovery, Vol. 3, 2008, pp. 189-199. doi:10.2174/157488908786242434
E. Holmberg, S. X. Zhang, P. D. Sarmiere, B. R. Kluge, J. T. White and S. Doolen, “Statins Decrease Chondroitin Sulfate Proteoglycan Expression and Acute Astrocyte Activation in Central Nervous System Injury,” Experimental Neurology, Vol. 214, No. 1, 2008, pp. 78-86. doi:10.1016/j.expneurol.2008.07.020
M. Shirasaka, B. Takayama, M. Sekiguchi, S. Konno and S. Kikuchi, “Vasodilative Effects of Prostaglandin E1 Derivate on Arteries of Nerve Roots in a Canine Model of a Chronically Compressed Cauda Equina,” BMC Musculoskeletal Disorders, Vol. 9, 2008, p. 41. doi:10.1186/1471-2474-9-41
A. B. Seabra, E. Pankotai, M. Feher, A. Somlai, L. Kiss, L. Biro, C. Szabo, M. Kollai, M. G. de Oliveira and Z. Lacza, “S-Nitrosoglutathione-Containing Hydrogel Increases Dermal Blood Flow in Streptozotocin-Induced Diabetic Rats,” British Journal Dermatology, Vol. 156, 2007, pp. 814-818. doi:10.1111/j.1365-2133.2006.07718.x
F. T. Nickel, F. Seifert, S. Lanz and C. Maihofner, “Mechanisms of Neuropathic Pain,” European Neuro-psychopharmacology, Vol. 22, 2012, pp. 81-91. doi:10.1016/j.euroneuro.2011.05.005
Z. Khalil, T. Liu and R. D. Helme, “Free Radicals Contribute to the Reduction in Peripheral Vascular Responses and the Maintenance of Thermal Hyperalgesia in Rats with Chronic Constriction Injury,” Pain, Vol. 79, 1999, pp. 31-37. doi:10.1016/S0304-3959(98)00143-2
Z. Khalil and B. Khodr, “A Role for Free Radicals and Nitric Oxide in Delayed Recovery in Aged Rats with Chronic Constriction Nerve Injury,” Free Radical Biology & Medicine, Vol. 31, 2001, pp. 430-439. doi:10.1016/S0891-5849(01)00597-4
Y. B. Choi and S. A. Lipton, “Redox Modulation of the NMDA Receptor,” Cellular and Molecular Life Sciences, Vol. 57, 2000, pp. 1535-1541. doi:10.1007/PL00000638
S. A. Lipton, Y. B. Choi, Z. H. Pan, S. Z. Lei, H. S. Chen, N. J. Sucher, J. Loscalzo, D. J. Singel and J. S. Stamler, “A Redox-Based Mechanism for the Neuroprotective and Neurodestructive Effects of Nitric Oxide and Related Nitroso-Compounds,” Nature, Vol. 364, 1993, pp. 626-632. doi:10.1038/364626a0
C. C. Chiueh, T. Andoh, A. R. Lai, E. Lai and G. Krishna, “Neuroprotective Strategies in Parkinson’s Disease: Protection against Progressive Nigral Damage Induced by Free Radicals,” Neurotoxicity Research, Vol. 2, 2000, pp. 293-310. doi:10.1007/BF03033799
P. Pacher, J. S. Beckman and L. Liaudet, “Nitric Oxide and Peroxynitrite in Health and Disease,” Physiological Reviews, Vol. 87, 2007, pp. 315-424. doi:10.1152/physrev.00029.2006