Effect of fetal cerebellum tissue transplantation on the spasticity and chronic pain syndrome after spinal cord injury in rats

Home/2017, Vol. 5, No. 1/Effect of fetal cerebellum tissue transplantation on the spasticity and chronic pain syndrome after spinal cord injury in rats

Cell and Organ Transplantology. 2017; 5(1):50-55.
DOI: 10.22494/COT.V5I1.68

Effect of fetal cerebellum tissue transplantation on the spasticity and chronic pain syndrome after spinal cord injury in rats

Medvediev V. V.1, Senchyk Yu. Yu.2, Tatarchuk M. M.3, Draguntsova N. G.3, Dychko S. M.3, Tsymbaliuk V. I.3
1Bogomoletz National Medical University, Kyiv, Ukraine
2Kyiv city clinical emergency hospital, Kyiv, Ukraine
3A. P. Romodanov State Institute of Neurosurgery NAMS Ukraine, Kyiv, Ukraine

The syndromes of spasticity and chronic pain are diagnosed in the majority of patients in different periods of recovering from spinal injury. Current synthetic or semi-synthetic matrixes, tissue and cell transplants, which are used in the treatment of spinal cord injuries, can affect the development of the syndrome of spasticity and chronic pain.
Objective. To examine the effect of fetal cerebellum tissue transplantation (FCTT) on the course of the spasticity and chronic pain syndrome after experimental spinal cord injury.
Materials and methods. Animals – albino outbred male rats (5.5 months, 300 grams, inbred line, the original strain – Wistar); main experimental groups: 1 – spinal cord injury only (n = 16), 2 – spinal cord injury + immediate homotopical implantation of a fragment of the fetal cerebellum tissue (n = 15). Model of injury – left-side spinal cord hemisection at Т11 level; verification of spasticity – by Ashworth scale and electroneuromyography, severe pain syndrome – by autophagy.
Results. FCTT does not affect the frequency of severe neuropathic pain syndrome, is accompanied by early (1st week) debut of spasticity signs, significantly increases the level of spasticity (1st-3rd weeks), which is most likely due to glutamatergic effect of descendants of immature transplant cells – cerebellar granular neurons precursors. The maximum increase of the spasticity in the case of FCTT was observed at the 3rd week, in the control group – within the 1st and 4th weeks; from the 4th week after FCTT till the end of the experiment stabilization of spasticity rate in the range of 1.8-2.1 points was observed, which is probably due to the autoimmune motoneurons loss in the perifocal area. At the 24th week the level of spasticity in the case of FCTT succumbed to 2.1 ± 0.3 points, in the control group – 2.6 ± 0.4 Ashworth’s points (p > 0.05).
Conclusion. Immediate fetal cerebellum tissue transplantation in rats with spinal cord injury causes early pro-spastic effect, in the long term – stabilizes spasticity level.

Key words: spinal cord injury; fetal cerebellum tissue transplantation; motor function recovery; posttraumatic spasticity syndrome; chronic pain syndrome

Full Text PDF (eng) Full Text PDF (ua)


1. Lee BB, Cripps RA, Fitzharris М, et al. The global map for traumatic spinal cord injury epidemiology: update 2011, global incidence rate. Spinal Cord. 2014; 52(2): 110-16.
2. Malhotra S, Pandyan AD, Day CR, et al. Spasticity, an impairment that is poorly defined and poorly measured. Clin Rehabil. 2009; 23(7): 651-58.
3. Hwang M, Zebracki K, Chlan KM, et al. Longitudinal changes in medical complications in adults with pediatric-onset spinal cord injury. J Spinal Cord Med. 2014; 37(2): 171-78.
PMid:24090490 PMCid:PMC4066425
4. Christensen MD, Hulsebosch C. Сhronic central pain after spinal cord injury. J Neurotrauma. 1997; 14(8): 517-37.
5. Finnerup NB, Norrbrink C, Trok K, et al. Phenotypes and predictors of pain following traumatic spinal cord injury: a prospective study. J Pain. 2014; 15(1): 40-48.
6. Wu J, Sun T, Ye C, et al. Clinical observation of fetal olfactory ensheathing glia transplantation (OEGT) in patients with complete chronic spinal cord injury. Cell Transplant. 2012; 21(1): 33-37.
7. Hofstetter CP, Holmström NAV, Lilja JA, et al. Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome. Nature Neurosci. 2005; 8(3): 346-53.
8. Macias MY, Syring MB, Pizzi MA, et al. Pain with no gain: Allodynia following neural stem cell transplantation in spinal cord injury. Exp Neurology. 2006; 201: 335-48.
9. Piltti K, Salazar D, Uchida N, et al. Safety of human neural stem cell transplantation in chronic spinal cord injury. Stem Cell Transl Med. 2013; 2: 961-974. Available: http://dx.doi.org/10.5966/sctm.2013-0064
10. Roh DH, Seo MS, Choi HS, et al. 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.
11. Luo Y, Zou Y, Yang L, et al. Transplantation of NSCs with OECs alleviates neuropathic pain associated with NGF downregulation in rats following spinal cord injury. Neurosci Lett. 2013; 549: 103-108. Available: http://dx.doi.org/10.1016/j.neulet.2013.06.005
12. Yao ZG, Sun XL, Li P, et al. 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): 404-412. Available: www.ijcem.com/ISSN:1940-5901/IJCEM0003074
13. Watanabe S, Uchida K, Nakajima H, et al. 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): 1902-1914.
14. Yousefifard M, Nasirinezhad F, Manaheji HS, et al. 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(36): 1-14.
15. Hua R, Li P, Wang X, et al. Evaluation of somatosensory evoked potential and pain rating index in a patient with spinal cord injury accepted cell therapy. Pain Physician. 2016; 19: 659-666.
16. Tsymbaliuk VI, Medvediev VV. Spinnoy mozg. Elegiya nadezhdy: monografiya [Spinal cord. Elegy of hope: a monograph]. Vinnitsa: Nova Kniga – Vinnitsa: New Book, 2010. 944 p. [in Russian]
17. Marzban H, Del Bigio MR, Alizadeh J, et al. Cellular commitment in the developing cerebellum. Front Cell Neurosci. 2015; 8: 1-26. Available: http://journal.frontiersin.org/article/10.3389/fncel.2014.00450/full
PMid:25628535 PMCid:PMC4290586
18. Kumar M, Csaba Z, Peineau S, et al. Endogenous cerebellar neurogenesis in adult mice with progressive ataxia. Ann Clin Transl Neurol. 2014; 1(12): 968-81.
PMid:25574472 PMCid:PMC4284123
19. Chang JC, Leung M, Gokozan HN, et al. 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.
PMid:25668568 PMCid:PMC4333719
20. Ma M, Wu W, Li Q, et al. N-myc is a key switch regulating the proliferation cycle of postnatal cerebellar granule cell progenitors. Sci Rep. 2015; 5: 1-13. Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4523855/
21. Leffler SR, Legué E, Aristizábal O,•et al. A mathematical model of granule cell generation during mouse cerebellum development. Bull Math Biol. 2016; 78(5): 859-78.
PMid:27125657 PMCid:PMC4911999
22. Zhu T, Tang H, Shen Y, et al. Transplantation of human induced cerebellar granular-like cells improves motor functions in a novel mouse model of cerebellar ataxia. Am J Transl Res. 2016; 8(2): 705-18.
PMid:27158363 PMCid:PMC4846920
24. Medvediev VV, Senchyk YuYu, Draguntsova NG, Dychko SM, Tsymbaliuk VI. Effect of fetal cerebellar tissue transplantation on the restoration of hind limb locomotor function in rats with spinal cord injury. Cell and Organ Transplantology. 2016; 4(2):175-180. doi:10.22494/COT.V4I2.57
25. Dong HW, Wang LH, Zhang M, et al. Han Decreased dynorphin A (1–17) in the spinal cord of spastic rats after the compressive injury. Brain Res Bull. 2005; 67(3): 189-195.
26. Hahm SC, Yoon YW, Kim J. High-frequency transcutaneous electrical nerve stimulation alleviates spasticity after spinal contusion by inhibiting activated microglia in rats. Neurorehabil Neural Repair. 2015; 29(4): 370-381.
27. Palmieri RM, Ingersoll CD, Hoffman MA. The hoffmann reflex: methodologic considerations and applications for use in sports medicine and athletic training research. J Athl Train. 2004; 39(3): 268-277.
PMid:16558683 PMCid:PMC522151
28. Yates C, Garrison K, Reese NB, et al. Novel mechanism for hyper-reflexia and spasticity. Prog Brain Res. 2011; 188: 167-180.
PMid:21333809 PMCid:PMC3646581
29. Tan AM, Chakrabarty S, Kimura H, et al. Selective corticospinal tract injury in the rat induces primary afferent fiber sprouting in the spinal cord and hyperreflexia. J Neurosci. 2012; 32(37): 12896-908.
PMid:22973013 PMCid:PMC3499628
30. Bandaru SP, Liu S, Waxman SG, et al. Dendritic spine dysgenesis contributes to hyperreflexia after spinal cord injury. J Neurophysiol. 2015; 113:1598-615.
PMid:25505110 PMCid:PMC4346729
31. Barakat MI, Elhady W, Gouda M, et al. Surgical management of intractable spasticity. Eur Spine J. 2016; 25(3): 928-935.
33. Christensen MD, Everhart AW, Pickelman JT, et al. Mechanical and thermal allodynia in chronic central pain following spinal cord injury. Pain. 1996; 68(1): 97-107.
34. Sharp KG, Dickson AR, Marchenko SA, et al. Salmon fibrin treatment of spinal cord injury promotes functional recovery and density of serotonergic innervation. Exp Neurol. 2012; 235(1): 345-56.
PMid:22414309 PMCid:PMC3437931
35. Hashimoto M, Hibi M. Development and evolution of cerebellar neural circuits. Dev Growth Differ. 2012; 54(3): 373-89.
36. Hoshino M. Neuronal subtype specification in the cerebellum and dorsal hindbrain. Dev Growth Differ. 2012; 54(3): 317-26.
37. Jankowski J, Miething A, Schilling K, et al. Cell death as a regulator of cerebellar histogenesis and compartmentation. Cerebellum. 2011; 10: 373-92.
39. Casella GTB, Marcillo A, Bunge MB, et al. 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.
40. Garcia E, Aguilar-Cevallos J, Silva-Garcia R, et al. Cytokine and growth factor activation in vivo and in vitro after spinal cord injury. Mediators Inflamm. 2016; 2016: 1–21. Available: https://www.hindawi.com/journals/mi/2016/9476020
41. Kjell J, Olson L. Rat models of spinal cord injury: from pathology to potential therapies. Dis Model Mech. 2016; 9(10): 1125-137.
PMid:27736748 PMCid:PMC5087825
42. Le Blon D, Hoornaert C, Detrez JR, et al. Immune remodelling of stromal cell grafts in the central nervous system: therapeutic inflammation or (harmless) side-effect? J Tissue Eng Regen Med. 2016; doi: 10.1002/term.2188. [Epub ahead of print].
43. Pajer K, Feichtinger G, Márton G, et al. Cytokine signaling by grafted neuroectodermal stem cells rescues motoneurons destined to die. Exp Neurol. 2014; 261:180-189.
44. Centonze D. Advances in the management of multiple sclerosis spasticity: multiple sclerosis spasticity nervous pathways. Eur Neurol. 2014; 72(l): 6-8.
45. Kapadia M, Sakic B. Autoimmune and inflammatory mechanisms of CNS damage. Prog Neurobiol. 2011; 95(3): 301-33.
46. Levite M. Glutamate receptor antibodies in neurological diseases. J Neural Transm. 2014; 121(8): 1029-75.
47. Bakpa OD, Reuber M, Irani SR. Antibody associated epilepsies: clinical features, evidence for immunotherapies and future research questions. Seizure. 2016; 41: 26-41.
PMid:27450643 PMCid:PMC5042290
48. Dalmau J, Geis C, Graus F. Autoantibodies to synaptic receptors and neuronal cell surface proteins in autoimmune diseases of the central nervous system. Physiol Rev. 2017; 97(2): 839-87.
49. D’Amico JM, Condliffe EG, Martins KJB, et al. Recovery of neuronal and network excitability after spinal cord injury and implications for spasticity. Front Int Neurosci. 2014; 8: 1-24. Available: http://journal.frontiersin.org/article/10.3389/fnint.2014.00036/full
50. Crowe MJ, Bresnahan JC, Shuman SL, et al. Apoptosis and delayed degeneration after spinal cord injury in rats and monkeys. Nat Med. 1997; 3(1): 73-76.
51. Liu XZ, Xu XM, Hu R, et al. Neuronal and glial apoptosis after traumatic spinal cord injury. J Neurosci. 1997; 17: 5395-406.
52. Kim P, Haisa T, Kawamoto T, et al. Delayed myelopathy induced by chronic compression in the rat spinal cord. Ann Neurol. 2004; 55(4): 503-11.
53. Moghaddam A, Child C, Bruckner T, et al. Posttraumatic inflammation as a key to neuroregeneration after traumatic spinal cord injury. Int J Mol Sci. 2015; 16(4): 7900-916.
PMid:25860946 PMCid:PMC4425057
54. Shabbir A, Bianchetti E, Cargonja R, et al. Role of HSP70 in motoneuron survival after excitotoxic stress in a rat spinal cord injury model in vitro. Eur J Neurosci. 2015; 42(12): 3054-65.
55. Pajer K, Feichtinger G, Márton G, et al. Cytokine signaling by grafted neuroectodermal stem cells rescues motoneurons destined to die. Exp Neurol. 2014; 261: 180-89.

Medvediev VV, Senchyk YuYu, Tatarchuk MM, Draguntsova NG, Dychko SM, Tsymbaliuk VI. Effect of fetal cerebellum tissue transplantation on the spasticity and chronic pain syndrome after spinal cord injury in rats. Cell and Organ Transplantology. 2017; 5(1):50-55. doi:10.22494/cot.v5i1.68


Creative Commons License
Is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.