Assessment of the effects of cellular therapy on reproduction of the conditioned passive avoidance reflex in rats with quinoline-induced model of Huntington’s disease

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Abstract

Abstract

Introduction. The model involving injection of quinolinic acid (QA) into the rat striatum simulates many clinical and morphological characteristics of Huntington’s disease (HD). Searching for effective treatment methods is rather topical because of the fatality of HD. One of such methods is to create a neuroprotective environment to slow down the current degenerative process and/or replace dead neurons. In particular, this can be performed by transplantation of cells capable of undergoing neuronal differentiation and integration into the proper structural and functional brain networks.

Objective. To assess effectiveness and safety of transplantation of neural progenitors differentiated from induced pluripotent stem cells (iPSCs) harvested from a healthy donor into the striatum with QA-induced model of HD.

Materials and methods. The effects of neurotransplantation on reproduction of the conditioned passive avoidance reflex were studied in rats with the model of HD induced by injection of QA into the caudate nuclei of the striatum. In the study group (n=8), human neural progenitors (1×106 per 10 µl of normal saline unilaterally, on the injured side) derived from iPSCs harvested from a healthy donor were injected into the caudate nuclei as the transplanted material; normal saline was injected in the control group. The conditioned passive avoidance responses were tested using the ShutАvoid 1.8.03 software on a Harvard apparatus (Panlab, Spain).

Results. When testing the reproduction of the passive avoidance responses, we found that injection of QA into the caudate nuclei of the rat brain reliably reduced the conditioned responses. Neurotransplantation of neural progenitors derived from iPSCs had a clear therapeutic effect and reinforced the passive avoidance reflex. During the entire testing period (7 days after exposure to the pain stimulus), the experimental animals either did not visit the dark compartment at all or visited it with a long latency period.

Conclusions. Experimental neurotransplantation using iPSC derivatives allowance to improve storage of trace memory in rats with QA-induced model of HD, which contributes to correction of cognitive impairments caused by administration of the neurotoxin.

About the authors

Alla V. Stavrovskaya

Research Center of Neurology, Moscow

Author for correspondence.
Email: platonova@neurology.ru
Russian Federation

Ekaterina V. Novosadova

Institute of Molecular Genetics of RAS, Moscow

Email: platonova@neurology.ru
Russian Federation

Nina G. Yamshchikova

Research Center of Neurology, Moscow

Email: platonova@neurology.ru
Russian Federation

Artem S. Ol’shansky

Research Center of Neurology, Moscow

Email: platonova@neurology.ru
Russian Federation

A. S. Gushchina

Research Center of Neurology, Moscow

Email: platonova@neurology.ru
Russian Federation

Evgeniya V. Konovalova

Research Center of Neurology, Moscow

Email: platonova@neurology.ru
Russian Federation

Igor' A. Grivennikov

Institute of Molecular Genetics of RAS, Moscow

Email: platonova@neurology.ru
Russian Federation

Sergey N. Illarioshkin

Research Center of Neurology, Moscow

Email: platonova@neurology.ru
Russian Federation

References

  1. The Huntington’s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell. 1993; 72: 971–983. PMID: 8458085
  2. Ivanova-Smolenskaya I.A., Markova E.D., Illarioshkin S.N., Nikol’skaya N.N. Monogenic hereditary diseases of the central nervous system. In: Hereditary diseases of nervous system. Guidelines for doctors. Vel’tishcheva J.E., Temina P.A. (Eds.). Moscow: Meditsina. 1998: 9–104. (in Russ.)
  3. Estrada Sanchez AM, Mejia-Toiber J, Massieu L. Excitotoxic neuronal death and the pathogenesis of Huntington’s disease. Arch Med Res 2008;39:265–276. PMID: 18279698 doi: 10.1016/j.arcmed.2007.11.011
  4. Bachoud-Levi A.-C. Neural grafts in Huntington’s disease: Viability after 10 years. Lancet Neurol. 2009; 8: 979–981. PMID: 19833293 doi: 10.1016/S1474-4422(09)70278-9
  5. Cicchetti F, Saporta S, Hauser RA et al. Neural transplants in patients with Huntington’s disease undergo disease-like neuronal degeneration. Proc. Natl. Acad. Sci. USA. 2009; 106: 12483–12488. PMID: 19620721 doi: 10.1073/pnas.0904239106
  6. Kerkis I., Haddad M, Valverde C., Glosman S. Neural and mesenchymal stem cells in animal models of Huntington’s disease: past experiences and future challenges. Stem Cell Research & Therapy. 2015; 6: 232. PMID: 26667114 doi: 10.1186/s13287-015-0248-1
  7. Maucksch C., Vazey E., Gordon R., Connor B. Stem cell-based therapy for Huntington’s disease. J. Cell. Biochem. 2013; 114: 754–763. PMID: 23097329 doi: 10.1002/jcb.24432
  8. Reuter I, Tai YF, Pavese N et al. Long-term clinical and positron emission tomography out- come of fetal striatal transplantation in Huntington’s disease. J Neurol Neurosurg Psychiatry 2008; 79:948–951.
  9. Nekrasov E.D., Lebedeva O.S., Vasina E.M. et al. [Platform for studying of Huntington's disease on the base of induced pluripotent stem cells]. Annals of Clinical and Experimental Neurology. 2012; 6(4): 30–35. (in Russ.)
  10. Fink K., Crane A. et al., Intrastriatal transplantation of adenovirus-generated induced pluripotent stem cells for treating neuropathological and functional deficits in a rodent model of Huntington’s disease. Stem Cells Translational Medicine. 2014; 3: 620–631. PMID: 24657963 doi: 10.5966/sctm.2013-0151
  11. Fink K., Rossignol J., Lu M. et al. Survival and differentiation of adenovirus-generated induced pluripotent stem cells transplanted into the rat striatum. Cell Transplant. 2013 [Epub ahead of print]. PMID: 23879897 doi: 10.3727/096368913X670958
  12. Peng J., Zeng X. The role of induced pluripotent stem cells in regenerative medicine: neurodegenerative diseases. Stem Cell Res. Ther. 2011; 2: 32. PMID: 21861938 doi: 10.1186/scrt73
  13. Takahashi K., Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006; 126: 663–676. PMID: 16904174 doi: 10.1016/j.cell.2006.07.024
  14. Yamanaka S., Blau H.M. Nuclear reprogramming to a pluripotent state by three approaches. Nature 2010; 465: 704–712. PMID: 20535199 doi: 10.1038/nature09229
  15. Stavrovskaya A.V., Konorova I.L., Illarioshkin S.N. et al. [Technologies of nervous system diseases modeling]. In: Neurology of the 21st century: diagnostic, medical and research technologies. Piradov M.A., Illarioshkin S.N., Tanashyan M.M. (Eds). Мoscow: «АТМО». 2015; 3: 73–133. (in Russ.)
  16. Leavitt B.R., Raamsdonk J.M., Shehadeh J. et al. Wild-type huntingtin protects neurons from excitotoxicity. J Neurochem 2006; 96: 1121-1129. PMID: 16417581 doi: 10.1111/j.1471-4159.2005.03605.x
  17. Paxinos G., Watson C. The Rat Brain in stereotaxic coordinates. Fourth Edition Academic Press 1998. - 456 p.
  18. Miroshnichenko E.V., Stavrovskaya A.V., Shugalev N.P. et al. [Changes of an emotional condition of rats at representation of passive avoidance reactions after neurotensin administration into nucleus accumbens of rat brain]. Zhurnal vysshei nervnoi deyatelnosti im. I.P.Pavlova .2010; 60(6): 704-711. (in Russ.)
  19. Stavrovskaya A.V., Yamshikova N.G., Olshansky A.S. et al. [Neurotensin changes an after-action of a painful stress to behavior of rats with lesion of serotoninergic structures of substancia nigra]. Zhurnal vysshei nervnoi deyatelnosti im. I.P.Pavlova. 2013; 63(3): 384-394. (in Russ.)
  20. Shugalev N.P., Stavrovskaya A.V., Yamshikova N.G. et al. [Representation of of passive avoidance reactions after neurotensin administration into nucleus accumbens of rat brain against the background of Reserpine action]. Zhurnal vysshei nervnoi deyatelnosti im. I.P.Pavlova. 2012; 62(3): 357-363. (in Russ.)
  21. Roberts T.J., Price J., Williams S.C., Modo M. Preservation of striatal tissue and behavioral function after neural stem cell transplantation in a rat model of Huntington’s disease. Neuroscience. 2006;139:1187–1199. PMID: 16517087 doi: 10.1016/j.neuroscience.2006.01.025
  22. Kendall A., Hantraye P., Palfi S. Striatal tissue transplantation in non-human primates. Prog. Brain Res. 2000; 127: 381–404. PMID: 11142037 doi: 10.1016/S0079-6123(00)27018-0
  23. Shen L.H., Li Y., Chen J. et al. Intracarotid transplantation of bone marrow stromal cells increases axon-myelin remodeling after stroke. Neuroscience. 2006;137:393–9. PMID: 16298076 doi: 10.1016/j.neuroscience.2005.08.092
  24. Shyu W.C., Lin S.Z., Chiang M.F. et al. Intracerebral peripheral blood stem cell (CD34z) implantation induces neuroplasticity by enhancing beta1 integrin-mediated angiogenesis in chronic stroke rats. J Neurosci. 2006;26:3444–53. PMID: 16571751, doi: 10.1523/JNEUROSCI.5165-05.2006
  25. Nakao N., Nakayama T., Yahata T. et al. Adipose tissue-derived mesenchymal stem cells facilitate hematopoiesis in vitro and in vivo: advantages over bone marrow-derived mesenchymal stem cells. Am J Pathol. 2010; 177(2): 547–54. PMID: 20558580 doi: 10.2353/ajpath.2010.091042
  26. Ribeiro C.A., Grando V., Dutra Filho C.S. et al. Evidence that quinolinic acid severely impairs energy metabolism through activation of NMDA receptors in striatum from developing rats. J Neurochem 2006; 99: 1531-1542. doi: 10.1111/j.1471-4159.2006.04199.x
  27. McLin J.P., Thompson L.M., Steward O. Differential susceptibility to striatal neurodegeneration induced by quinolinic acid and kainate in inbred, outbred and hybrid mouse strains. Eur J Neurosci 2006; 24: 3134-3140. doi: 10.1111/j.1460-9568.2006.05198.x
  28. Emerich D.F., Thanos C.G., Goddard M. et al. Extensive neuroprotection by choroid plexus transplants in excitotoxin lesioned monkeys. Neurobiol. Dis 2006; 23: 471-480. PMID: 16777422 doi: 10.1016/j.nbd.2006.04.014
  29. Kendall A.L., David F., Rayment G. et al. The influence of excitotoxic basal ganglia lesions on motor performance in the common marmoset. Brain 2000; 123 (Pt 7):1442-1458. PMID: 10869056 doi: 10.1093/brain/123.7.1442
  30. Becker S., Lim J. A computational model of prefrontal control in free recall: strategic memory use in the California Verbal Learning Task. J. Cogn. Neurosci. 2003; 15: 821–832. PMID: 14511535 doi: 10.1162/089892903322370744
  31. Illarioshkin S.N. Huntington's disease as model for studying of neurodegenerative diseases. Byulleten natsional’ogo obshchestva po izucheniyu bolezni Parkinsona i rasstroystvam dvizheniy. 2016; 1: 3–11. (in Russ.)

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Copyright (c) 2017 Stavrovskaya A.V., Novosadova E.V., Yamshchikova N.G., Ol’shansky A.S., Gushchina A.S., Konovalova E.V., Grivennikov I.A., Illarioshkin S.N.

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