The influence of neurotransplantation with different allogenic tissues on the course of the spasticity and chronic pain syndrome after experimental spinal cord injury
Objective. To examine the effect of neurotransplantation with different allogenic tissue types on the course of the spasticity and chronic pain syndrome after experimental spinal cord injury.
Materials and methods. Animals: inbred albino male rats (5.5 months old,300 g); experimental groups: 1 — spinal cord injury + immediate homotopical transplantation of olfactory bulb tissue (TOBT, n = 34); 2 — spinal cord injury + analogous transplantation of fetal (E18) cerebellum tissue (TFСT, n = 15); 3 — spinal cord injury + analogous transplantation of fetal (E18) kidney tissue (TFKT, n = 8); 4 — spinal cord injury only (control group, n = 16). The model of injury was left-side spinal cord hemisection at Т11; spasticity in the ipsilateral hind limb was verified by Ashworth scale.
Results. The increase (p < 0.05) of spasticity index was recorded in the control group during the period of 1st — 2nd and 5th month, in TOBT group during the period of 1st — 2nd and 6th month, in TFCT group — during the 3rd week, in TFKT group — during the 2nd week. On the 7th day the spasticity severity in TFCT and TFKT groups was evaluated as 1 point by Ashworth scale, in TOBT and control group it was 0 point. During the 2nd — 4th weeks a high (TFСT, TFKT), intermediate (control group) and low (TOBT) level of spasticity was noticed. The spasticity level in TFСT and TFKT groups exceeded (p < 0.05) the indicator of control group during the 1st — 3rd and 1st — 2nd weeks, respectively. The spasticity level in TOBT group conceded (p < 0.05) to values of the control group (2nd week), TFСT (1st — 6th week) and TFKT (1st — 3rd week). The difference in spasticity values in TFСT and TFKT groups during the experiment was not significant (p > 0.05). On the 24th week of observation the spasticity level in experimental groups was 2.6 ± 0.4 (control group), 2.2 ± 0.2 (TOBT), 2.1 ± 0.3 (TFСT) and 1.9 ± 0.3 (TFKT). Fifty-nine percent of the animals in TOBT group had early spasticity debut with flexion-adduction localization in hip and knee and peripheral paresis (hypotonia/atony) at the ankle joint and high prevalence of severe neurogenic pain manifestation (45 %). Similar spastic localization was noted in 40 % of the animals in TFСT group (for 2nd month) and 25 % of the animals in TFKT group (during 1st — 2nd week). In the control group signs of long-term severe neurogenic pain was found in 19 % animals, in TOBT group — in 27 %, in TFСT group — in 6 % (1 animal), in TFKT group no pain signs observed; the incidence difference was not significant.
Conclusion. Approved types of neurotransplantation exert significant influence on the course of spasticity syndrome; the mechanisms of influence related to the cellular structure, angiogenic and immunogenic properties of the grafts.
Full Text:PDF (Українська)
1. Rizzo MA, Hadjimichael OC, Preiningerova J, Vollmer TL. Prevalence and treatment of spasticity reported by multiple sclerosis patients. Mult Scler. 2004;10(5):589-95. [PubMed]
2. Sommerfeld DK, Eek EU, Svensson AK, Holmqvist LW, von Arbin MH. Spasticity after stroke : its occurrence and association with motor impairments and activity limitations. Stroke. 2004;35(1):134-9, [PubMed]
4. Maynard FM, Karunas RS, Waring WP. Epidemiology of spasticity following traumatic spinal cord injury. Arch Phys Med Rehabil. 1990;71(8):566-9. [PubMed]
5. Skold C, Levi R, Seiger A. Spasticity after traumatic spinal cord injury: nature, severity, and location. Phys Med Rehabil. 1999;80(12):1548-57. [PubMed]
6. Walters JS, Sacks J, Othman R, Rakin AZ, Nemchausky B, Chintam R, Wheeler JS. A database of self-reported secondary medical problems among VA spinal cord injury patients: its role in clinical care and management. J Rehabil Res Dev. 2002;39(1):53-61. [PubMed]
9. Diong J, Harvey LA, Kwah LK, Eyles J, Ling MJ, Ben M, Herbert RD. Incidence and predictors of contracture after spinal cord injury — a prospective cohort study. Spinal Cord. 2012;50(8):579-84. [CrossRef] [PubMed]
11. Christensen MD, Hulsebosch C. Сhronic central pain after spinal cord injury. J Neurotrauma. 1997;14(8):517-37. [PubMed]
12. Finnerup NB, Norrbrink C, Trok K, Piehl F, Johannesen IL, Sшrensen JC, Jensen TS, Werhagen L. Phenotypes and predictors of pain following traumatic spinal cord injury: a prospective study. J Pain. 2014;15(1):40-8. [CrossRef] [PubMed]
14. D’Amico JM, Condliffe EG, Martins KJB, Bennett DJ, Gorassini MA. Recovery of neuronal and network excitability after spinal cord injury and implications for spasticity. Front Int Neurosci. 2014;8(Art.36):1-24. [CrossRef] [PubMed]
15. Murray KC, Nakae A, Stephens MJ, Rank M, D’Amico J, Harvey PJ, Li X, Harris RL, Ballou EW, Anelli R, Heckman CJ, Mashimo T, Vavrek R, Sanelli L, Gorassini MA, Bennett DJ, Fouad K. Recovery of motoneuron and locomotor function after spinal cord injury depends on constitutive activity in 5-HT2C receptors. Nature Med. 2010;16(6):694-701. [CrossRef] [PubMed]
16. Nardone R, Holler Y, Thomschewski A, Holler P, Lochner P, Golaszewski S, Brigo F, Trinka E. Serotonergic transmission after spinal cord injury. J Neural Transm (Vienna). 2015;122(2):279-95. [CrossRef] [PubMed]
17. Di Narzo AF, Kozlenkov A, Ge Y, Zhang B, Sanelli L, May Z, Li Y, Fouad K, Cardozo C, Koonin EV, Bennett DJ, Dracheva S. Decrease of mRNA editing after spinal cord injury is caused by down-regulation of ADAR2 that is triggered by inflammatory response. Sci Rep. 2015;5(Art.12615):1-15. [CrossRef] [PubMed]
18. Ren L-Q, Wienecke J, Chen M, Mшller M, Hultborn H, Zhang M. The time course of serotonin 2C receptor expression after spinal transection of rats: an immunohistochemical study. Neuroscience. 2013;236:31-46. [CrossRef] [PubMed]
19. Burns CM, Chu H, Rueter SM, Hutchinson LK, Canton H, Sanders-Bush E, Emeson RB. Regulation of serotonin-2C receptor G-protein coupling by RNA editing. Nature. 1997;387(6630):303-8. [PubMed]
20. Niswender CM, Copeland SC, Herrick-Davis K, Emeson RB, Sanders-Bush E. RNA editing of the human serotonin 5-hydroxytryptamine 2C receptor silences constitutive activity. J Biol Chem. 1999;274(14):9472-8. [PubMed]
21. Wienecke J, Westerdahl A-C, Hultborn H, Kiehn O, Ryge J. Global gene expression analysis of rodent motor neurons following spinal cord injury associate molecular mechanisms with development of postinjury spasticity. J Neurophysiol. 2010;103(2):761-78. [CrossRef] [PubMed]
23. Nakae A, Nakai K, Tanaka T, Takashina M, Hagihira S, Shibata M, Ueda K, Mashimo T. Serotonin2C receptor mRNA editing in neuropathic pain model. Neurosci Res. 2008;60(2):228-31. [PubMed]
25. Tsymbaliuk VI, Medvediev VV. Spinnoj mozg. Elegia nadezhdy [Spinal cord. Elegy of hope]. Vinnitsa: Nova Knyga; 2010. Russian.
26. Praet J, Santermans E, Daans J, Le Blon D, Hoornaert C, Goossens H, Hens N, Van der Linden A, Berneman Z, Ponsaerts P. Early inflammatory responses following cell grafting in the CNS trigger activation of the subventricular zone: a proposed model of sequential cellular events. Cell Transplant. 2015;24(8):1481-92. [CrossRef] [PubMed]
27. Le Blon D, Hoornaert C, Detrez JR, Bevers S, Daans J, Goossens H, De Vos WH, Berneman Z, Ponsaerts P. Immune remodelling of stromal cell grafts in the central nervous system: therapeutic inflammation or (harmless) side-effect? J Tissue Eng Regen Med. 2016 [Epub ahead of print], [CrossRef] [PubMed]
28. Wu J, Sun T, Ye C, Yao J, Zhu B, He H. Clinical observation of fetal olfactory ensheathing glia transplantation (OEGT) in patients with complete chronic spinal cord injury. Cell Transplant. 2012;21(Suppl.1):33-7. [CrossRef] [PubMed]
29. van Gorp S, Leerink M, Kakinohana O, Platoshyn O, Santucci C, Galik J, Joosten EA, Hruska-Plochan M, Goldberg D, Marsala S, Johe K, Ciacci JD, Marsala M. Amelioration of motor/sensory dysfunction and spasticity in a rat model of acute lumbar spinal cord injury by human neural stem cell transplantation. Stem Cell Res Ther. 2013;4(Art.57):1-22. [CrossRef] [PubMed]
30. Hofstetter CP, Holmstrцm NAV, Lilja JA, Schweinhardt P, Hao J, Spenger C, Wiesenfeld-Hallin Z, Kurpad SN, Frisйn J, Olson L. Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome. Nature Neurosci. 2005;8(3):346-53. [CrossRef] [PubMed]
31. Hendricks WA, Pak ES, Owensby JP, Menta KJ, Glazova M, Moretto J, Hollis S, Brewer KL, Murashov AK. Predifferentiated embryonic stem cells prevent chronic pain behaviors and restore sensory function following spinal cord injury in mice. Mol Med. 2006;12(1-3):34-46. [CrossRef] [PubMed]
32. Macias MY, Syring MB, Pizzi MA, Crowe MJ, Alexanian AR, Kurpad SN. Pain with no gain: Allodynia following neural stem cell transplantation in spinal cord injury. Exp Neurol. 2006;201(2):335-48. [CrossRef] [PubMed]
33. Lee JW, Jergova S, Furmanski O, Gajavelli S, Sagen J. Predifferentiated GABAergic neural precursor transplants for alleviation of dysesthetic central pain following excitotoxic spinal cord injury. Front Physiol. 2012;3(Art.167):1-12. [CrossRef] [PubMed]
34. Luo Y, Zou Y, Yang L, Liu J, Liu S, Liu J, Zhou X, Zhang W, Wang T. Transplantation of NSCs with OECs alleviates neuropathic pain associated with NGF downregulation in rats following spinal cord injury. Neurosci Lett. 2013;549:103-8. [CrossRef] [PubMed]
36. Roh DH, Seo MS, Choi HS, Park SB, Han HJ, Beitz AJ, Kang KS, Lee JH. Transplantation of human umbilical cord blood or amniotic epithelial stem cells alleviates mechanical allodynia after spinal cord injury in rats. Cell Transplant. 2013;22(9):1577-90. [CrossRef] [PubMed]
37. Watanabe S, Uchida K, Nakajima H, Matsuo H, Sugita D, Yoshida A, Honjoh K, Johnson WE, Baba H. Early transplantation of mesenchymal stem cells after spinal cord injury relieves pain hypersensitivity through suppression of pain-related signaling cascades and reduced inflammatory cell recruitment. Stem Cells. 2015;33(6):1902-14. [CrossRef] [PubMed]
38. Yao Z-G, Sun X-L, Li P, Liu H-L, Wu H-L, Xi Z-Q, Zheng Z-H. Neural stem cells transplantation alleviate the hyperalgesia of spinal cord injured (SCI) associated with down-regulation of BDNF. Int J Clin Exp Med. 2015;8(1):404-12. [PubMed]
39. Hua R, Li P, Wang X, Yang J, Zheng P, Niu X, Li Y, An Y. Evaluation of somatosensory evoked potential and pain rating index in a patient with spinal cord injury accepted cell therapy. Pain Physician. 2016;19(4):E659–67. [PubMed]
40. Yousefifard M., Nasirinezhad F., Manaheji HS, Janzadeh A, Hosseini M, Keshavarz M. Human bone marrow-derived and umbilical cord-derived mesenchymal stem cells for alleviating neuropathic pain in a spinal cord injury model. Stem Cell Res Ther. 2016;7(Art.36):1-14. [CrossRef] [PubMed]
41. Myers SA, Bankston AN, Burke DA, Ohri SS, Whittemore SR. Does the preclinical evidence for functional remyelination following engraftment into the injured spinal cord support progression to clinical trials? Exp Neurol. 2016 [Epub ahead of print], Apr. 13: pii: S0014-4886(16)30089-9. [CrossRef] [PubMed]
43. Siebert JR, Eade AM, Osterhout DJ. Biomaterial approaches to enhancing neurorestoration after spinal cord injury: strategies for overcoming inherent biological obstacles. BioMed Res Int. 2015;2015(Art. ID 752572):1-20. [CrossRef] [PubMed]
45. Chang JC, Leung M, Gokozan HN. Gygli PE, Catacutan FP, Czeisler C, Otero JJ. Mitotic events in cerebellar granule progenitor cells that expand cerebellar surface area are critical for normal cerebellar cortical lamination in mice. J Neuropathol Exp Neurol. 2015;74(3):261-72. [CrossRef] [PubMed]
48. Sentilhes L, Michel C, Lecourtois M, Catteau J, Bourgeois P, Laudenbach V, Marret S, Laquerriere A. Vascular endothelial growth factor and its high–affinity receptor (VEGFR–2) are highly expressed in the human forebrain and cerebellum during development. J Neuropathol Exp Neurol. 2010;69(2):111-28. [CrossRef] [PubMed]
53. Eremina V, Quaggina SE. The role of VEGF–A in glomerular development and function. Curr Ohin Nephrol Hypertens. 2004;13(1):9-15. [PubMed]
56. Halt KJ, Parssinen HE, Junttila SM, Saarela U, Sims-Lucas S, Koivunen P, Myllyharju J, Quaggin S, Skovorodkin IN, Vainio SJ. CD146+ cells are essential for kidney vasculature development. Kidney Int. 2016;90(2):311-24. [CrossRef] [PubMed]
57. Hu Y, Gomez A, Sequeira-Lopez MLS. Hemovascular progenitors in the kidney require sphingosine-1-phosphate receptor 1 for vascular development. J Am Soc Nephrol. 2015;27(7):1984-95. [CrossRef] [PubMed]
58. Tsymbaliuk V, Medvediev V, Semenova V, Grydina N, Senchyk Yu, Velychko O, Dychko S, Vaslovych V. [The model of lateral spinal cord hemisection. Part I. The technical, pathomorphological, clinical and experimental peculiarities]. Ukrainian Neurosurgical Journal. 2016;(2):18–27. Ukrainian.
59. Tsymbaliuk VI, Medvediev VV. Ce.re.bellum, abo mozochok [Cerebellum]. Vinnytsa: Nova Knyga; 2010. Ukrainian.
60. Karimi-Abdolrezaee S, Eftekharpour E, Wang J, Schut D, Fehlings MG. Synergistic effects of transplanted adult neural stem/progenitor cells, chondroitinase, and growth factors promote functional repair and plasticity of the chronically injured spinal cord. J Neurosci. 2010;30(5):1657-76. [CrossRef] [PubMed]
63. Casella GTB, Marcillo A, Bunge MB, Wood PM. New vascular tissue rapidly replaces neural parenchyma and vessels destroyed by a contusion injury to the rat spinal cord. Exp Neurol. 2002;173(1):63-76. [CrossRef] [PubMed]
67. Hou Y, Shin Y-J, Han EJ, Choi J-S, Park J-M, Cha J-H, Choi J-Y, Lee M-Y. Distribution of vascular endothelial growth factor receptor–3/Flt4 mRNA in adult rat central nervous system. J Chem Neuroanat. 2011;42(1):56-64. [CrossRef] [PubMed]
68. Muhl L, Moessinger C, Adzemovic MZ, Dijkstra MH, Nilsson I, Zeitelhofer M, Hagberg CE, Huusko J, Falkevall A, Ylд-Herttuala S, Eriksson U. Expression of vascular endothelial growth factor (VEGF)-B and its receptor (VEGFR1) in murine heart, lung and kidney. Cell Tissue Res. 2016;365(1):51-63. [CrossRef] [PubMed]
70. Pajer K, Feichtinger G, Mбrton G, Sabitzer S, Klein D, Redl H, Nуgrбdi A. Cytokine signaling by grafted neuroectodermal stem cells rescues motoneurons destined to die. Exp Neurol. 2014;261:180-9. [CrossRef] [PubMed]
73. Levite M. Glutamate receptor antibodies in neurological diseases: Anti-AMPA-GluR3 antibodies, Anti-NMDA-NR1 antibodies, Anti-NMDA-NR2A/B antibodies, Anti-mGluR1 antibodies or Anti-mGluR5 antibodies are present in subpopulations of patients with either: Epilepsy, Encephalitis, Cerebellar Ataxia, Systemic Lupus Erythematosus (SLE) and Neuropsychiatric SLE, Sjogren’s syndrome, Schizophrenia, Mania or Stroke. These autoimmune anti-glutamate receptor antibodies can bind neurons in few brain regions, activate glutamate receptors, decrease glutamate receptor’s expression, impair glutamate-induced signaling and function, activate Blood Brain Barrier endothelial cells, kill neurons, damage the brain, induce behavioral/psychiatric/cognitive abnormalities and Ataxia in animal models, and can be removed or silenced in some patients by immunotherapy. J Neural Transm. 2014;121(8):1029-75. [CrossRef] [PubMed]
76. Palazzo E, Marabese I, Luongo L, Guida F, de Novellis V, Maione S. Nociception modulation by supraspinal group III metabotropic glutamate receptors. J Neurochem. 2016 [Epub ahead of print]. [CrossRef] [PubMed]
77. Camand E, Morel M-P, Faissner A, Sotelo C, Dusart I. Long-term changes in the molecular composition of the glial scar and progressive increase of serotoninergic fibre sprouting after hemisection of the mouse spinal cord. Eur J Neurosci. 2004;20(5):1161-76. [CrossRef] [PubMed]
GOST Style Citations
Copyright (c) 2017 Volodymyr V. Medvediev
This work is licensed under a Creative Commons Attribution 4.0 International License.