Preview

Epilepsia and paroxysmal conditions

Advanced search

CELL THERAPY OF EPILEPSIA. CLINICAL AND IMMUNOLOGICAL ASPECTS

https://doi.org/10.17749/2077-8333.2018.10.1.035-051

Full Text:

Abstract

The aim is to develop and implement a method for the treatment of drug-resistant epilepsy using autologous mesenchymal stem cells and the neuroimaging, immunological and neurophysiological predictors of the brain function.

Material and Methods. Twenty patients (12 males and 8 females) with symptomatic drug-resistant epilepsy participated in the study. The patient age varied from 23 to 46 years; and the duration of epilepsy was 7-29 years. Autologous mesenchymal stem cells of the bone marrow were characterized using cultural, morphological, immunological, molecular-genetic, clinical-functional, laboratory, pathopsychological, and neurophysiological methods. The standard parametric and nonparametric statistical tests were used to evaluate the results.

Results. The study resulted in producing of cultured autologous mesenchymal stem cells of the bone marrow (AMSCBM) sufficient to conduct 20 courses of cell therapy. In total, 40 transplantation procedures using AMSCBM were performed (20 intravenous and 20 endolumbar injections). Cellularity index in the intravenous inoculate ranged from 39.5 to 110.0 million and that for the endolumbar injection – from 5.1 to 10.0 million with viability not less than 95%. The distribution of AMSCBM by key surface markers (CD105+, CD90+, CD45-, CD34-) matched the criteria of the International Association for cell therapy (ISCT). The cell injections were well tolerated and did not cause any severe adverse effects. To monitor the process of neurogenic differentiation, the expression of the surface markers was determined. In most samples with confirmed neural differentiation, a significant increase in the expression of neuron-specific enolase, nestin and MAR-2 was detected. In patients with symptomatic epilepsy, the most significant deviations from normal values were found for the numbers of cytotoxic and activated cells, natural killer (NK) cells, and T-cells with the NK activity. After a course of cell therapy, a significant decrease in CD4+CD8+, CD3+CD8+, CD3+CD95+, and CD8+CD25+ cells was noted. Also decreased were the numbers of NK cells and T-cells with the NK activity, however, their levels remained relatively high as compared with the control group. Following the treatment, we continued to monitor the patients for 3, 6, and 12 months after the cell administration as well as the patients from the group of comparison.

Conclusion. For the first time in the Republic of Belarus, cell therapy in patients with epilepsy was conducted. An intravenous injection of AMSCBM and endolumbar administration of neuro-induced AMSCBM can serve an effective additional therapy of choice in patients with drug-resistant epilepsy. 

About the Authors

T. V. Dokukina
Republican Scientific and Practical Center of Mental Health
Belarus

MD, Deputy Director for Research,

152 Dolginovsky tract, Minsk 220053



M. P. Potapnev
Belarusian State Medical University
Belarus

MD, Professor,

83 prospekt Dzerzhinskogo, Minsk 220116



S. M. Kosmacheva
Republican Scientific and Practical Center of Transfusiology and Medical Biotechnologies
Belarus

MD, PhD, Head, Laboratory of Biology and Genetics of Stem Cells,

160 Dolginovsky tract, Minsk 220053



F. P. Hlebokazov
Republican Scientific and Practical Center of Mental Health
Belarus

MD, PhD, Head, Department for the Treatment of Epilepsy Associated Mental Disorders,

152 Dolginovsky tract, Minsk 220053



E. L. Slobina
Russian Scientific Center of X-ray Radiology of the Ministry of Health of the Russian Federation
Belarus

MD, PhD, Leading Researcher,

86 Profsoyuznaya ul., GSP-7, Moscow 117997



T. S. Golubeva
Republican Scientific and Practical Center of Mental Health
Belarus

PhD, Leading Researcher, Department of Mental and Behavioral Disorders,

152 Dolginovsky tract, Minsk 220053



N. N. Misjuk
Republican Scientific and Practical Center of Mental Health
Belarus

MD, PhD (Functional diagnostics),

152 Dolginovsky tract, Minsk 220053



M. V. Mahrov
Republican Scientific and Practical Center of Mental Health
Belarus

Researcher, Department of Mental and Behavioral Disorders,

152 Dolginovsky tract, Minsk 220053



I. V. Shamruk
Republican Scientific and Practical Center of Mental Health
Belarus

Researcher, Department of Mental and Behavioral Disorders,

152 Dolginovsky tract, Minsk 220053



P. P. Korolevich
Republican Scientific and Practical Center of Mental Health
Belarus

Researcher, Department of Mental and Behavioral Disorders,

152 Dolginovsky tract, Minsk 220053



A. I. Martynenko
Republican Scientific and Practical Center of Mental Health
Belarus

Laboratory Assistant, Department of Mental and Behavioral Disorders,

152 Dolginovsky tract, Minsk 220053



I. V. Bychenko
Republican Scientific and Practical Center of Mental Health
Belarus

Laboratory Assistant, Department of Mental and Behavioral Disorders,

152 Dolginovsky tract, Minsk 220053



T. O. Bud’ko
Republican Scientific and Practical Center of Mental Health
Belarus

Junior Researcher, Department of Mental and Behavioral Disorders,

152 Dolginovsky tract, Minsk 220053



References

1. Hauser W.A., Kurland L. T. The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1967. Epilepsia. 1975; 16 (1): 1-66.

2. Fisher R.S., van Emde Boas W., Blume W. et al. Epileptic seizures and epilepsy: definitions proposed by the International League Against Epi-lepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia. 2005; 46 (4): 470-472.

3. Fisher R.S., Acevedo C., Arzimanoglou A. et al. ILAE Official Report: A practical clinical definition of epilepsy. Epilepsia. 2014; 55 (4): 475-482. DOI: 10.1111/epi.12550.

4. Jobst B.C., Cascino G.D. Resective epilepsy surgery for drug-resistant focal epilepsy: a review. JAMA. 2015; 313 (3): 285-293.

5. Report on the global situation of noncommunicable diseases 2014 by who. 19 January 2015 [Doklad o situatsii v oblasti neinfektsionnykh zabolevanii v mire 2014 g. VOZ. 19 yanvarya 2015 (in Russian)].

6. Mason C., Dunnill P. A brief definition of regenerative medicine. Regen Med. 2008; 3 (1): 1-5.

7. Turner L.P., Selling Stem Cells in the USA: Assessing the Direct-to-Consumer Industry. CellStemCell. 2016; 19 (2): 154-7.

8. Pyadushkina E.A., Frolov M.Yu. FARMAKOEKONOMIKA. Sovremennaya farmakoekonomika i farmakoepidemiologiya / FARMAKOEKONOMIKA. Modern pharmacoeconomics and pharmacoepidemiology (in Russian). 2016; 9 (3): 38-47. DOI:10.17749/2070-4909.2016.9.3.038-047.

9. Dokukina T.V., Golubeva T.S., Matveichuk I.V., Makhrov M.V., Loseva V.M., Krupen’kina E.V., Marchuk S.A. FARMAKOEKONOMIKA. Sovremennaya farmakoekonomika i farmakoepidemiologiya / FARMAKOEKONOMIKA. Modern pharmacoeconomics and pharmacoepidemiology (in Russian). 2014; 7 (2): 33-37.

10. Odintsova G.V., Kuralbaev A.K., Nezdorovina V.G., Abramov K.B., Pavlovskaya M. E., Telegina A.A., Bersnev V.P. Epilepsiya i paroksizmal’nye sostoyaniya / Epilepsy and paroxysmal conditions (in Russian). 2017; 9 (2): 41-49. DOI: 10.17749/2077-8333.2017.9.2.041-049.

11. Mkrtchyan V.R., Sergeev A.M., Pochigaeva K. I., Shpak I.A. FARMAKOEKONOMIKA. Sovremennaya farmakoekonomika i farmakoepidemiologiya / FARMAKOEKONOMIKA. Modern pharmacoeconomics and pharmacoepidemiology (in Russian). 2016; 9 (2): 28-37. DOI: 10.17749/2070-4909.2016.9.2.028-037

12. Voronina T.A., Avakyan G.G., Nerobkova L.N., Litvinova S.A., Avakyan G.N. Epilepsiya i paroksizmal’nye sostoyaniya / Epilepsy and paroxysmal conditions (in Russian). 2015; 7 (4): 59-65. DOI: 10.17749/2077-8333.2015.7.4.059-065.

13. Mazina N.K., Mazin P.V., Kislitsyn Yu.V., Markova E.M. FARMAKOEKONOMIKA. Sovremennaya farmakoekonomika i farmakoepidemiologiya / FARMAKOEKONOMIKA. Modern pharmacoeconomics and pharmacoepidemiology (in Russian). 2016; 9 (1): 15-22. DOI: 10.17749/2070-4909.2016.9.1.015-022.

14. Asatryan E.A., Abramov K.B., Mamatkhanov M.R., Lebedev K. E., Efimtsev A. Yu., Zabrodskaya Yu.M., Sebelev K. I., Ryzhkova D.V., Trufanov G. E., Khachatryan V.A. Epilepsiya i paroksizmal’nye sostoyaniya / Epilepsy and paroxysmal conditions (in Russian). 2017; 9 (1): 40-50. DOI: 10.17749/2077-8333.2017.9.1.040-050.

15. Khlebokazov F.P., Dokukina T.V., Ignatenko S. I., Kosmacheva S.M., Goncharova N.V., Potapnev M.P., Makhrov M.V., Korolevich P.P., Misyuk N.N., Grigor’eva I.V., Marchuk S.A. Epilepsiya i paroksizmal’nye sostoyaniya / Epilepsy and paroxysmal conditions (in Russian). 2014; 6 (1): 6-14.

16. Chu K., Kim M., Jung K.H. et al. Human neural stem cell transplantation reduces spontaneous recurrent seizures following pilocarpine-induced status epilepticus in adult rats. Brain Res. 2004; 1023 (2): 213-221.

17. Shetty A.K., Upadhya D. GABA-ergic cell therapy for epilepsy: Advances, limitations and challenges. Neurosci Biobehav Rev. 2016; 62: 35-47.

18. Waldau B., Hattiangady B., Kuruba R., Shetty A.K. Medial Ganglionic Eminencederived Neural Stem Cell Grafts Ease Spontaneous Seizures and Restore GDNF Expression in a Rat Model of Chronic Temporal Lobe Epilepsy. Stem Cells. 2010; 28 (7): 1153-1164.

19. Huang P.Y., Shih Y.H., Tseng Y. J., Ko T. L., Fu Y.S., Lin Y.Y. Xenograft of human umbilical mesenchymal stem cells from Wharton’s jelly as a potential therapy for rat pilocarpineinduced epilepsy. Brain Behav Immun. 2016; 54: 45-58.

20. Long Q., Qiu B., Wang K., Yang J., Jia C., Xin W. et al. Genetically engineered bone marrow mesenchymal stem cells improve functional outcome in a rat model of epilepsy. Brain Res. 2013; 1532: 1-13.

21. Acharya M.M., Hattiangady B., Shetty A.K. Progress in neuroprotective strategies for preventing epilepsy. Prog Neurobiol. 2008; 84: 363-404.

22. Shetty A.K., Hattiangady B. Concise review: prospects of stem cell therapy for temporal lobe epilepsy. Stem Cells. 2007; 25: 2396-407.

23. Roper S.N., Steindler D.A. Stem cells as a potential therapy for epilepsy. Exp Neurol. 2013; 244: 59-66.

24. Abdanipour A., Tiraihi T., Delshad A. Transdifferentiation of the adipose tissue-derived stem cells into neuron-like cells expressing neurotrophins by selegiline. Iran Biomed J. 2011; 15: 113-21.

25. Huicong K., Zheng X., Furong W., Zhouping T., Feng X., Qi H. et al. The imbalanced expression of adenosine receptors in an epilepsy model corrected using targeted mesenchymal stem cell transplantation. Mol Neurobiol. 2013; 48: 921-30.

26. Leal M.M., Costa-Ferro Z.S., Souza B.S., Azevedo C.M., Carvalho T.M., Kaneto C.M. et al. Early transplantation of bone marrow mononuclear cells promotes neuroprotection and modulation of inflammation after status epilepticus in mice by paracrine mechanisms. Neurochem Res. 2014; 39: 259-68.

27. Costa-Ferro Z.S., Vitola A.S., Pedroso M. F., Cunha F.B., Xavier L. L., Machado D.C. et al. Prevention of seizures and reorganization of hippocampal functions by transplantation of bone marrow cells in the acute phase of experimental epilepsy. Seizure. 2010; 19: 84-92.

28. Costa-Ferro Z.S., Souza B.S., Leal M.M., Kaneto C.M., Azevedo C.M., da Silva I.C. et al. Transplantation of bone marrow mononuclear cells decreases seizure incidence, mitigates neuronal loss and modulates pro-inflammatory cytokine production in epileptic rats. Neurobiol Dis. 2012; 46: 302-13.

29. Costa-Ferro Z.S., de Borba C. F., de Freitas Souza B.S., Leal M.M., da Silva A.A., de Bellis Kuhn T. I. et al. Antiepileptic and neuroprotective effects of human umbilical cord blood mononuclear cells in a pilocarpine-induced epilepsy model. Cytotechnology. 2014; 66: 193-9.

30. Agadi S., Shetty A.K. Concise review: prospects of bone marrow mononuclear cells and mesenchymal stem cells for treating status epilepticus and chronic epilepsy. Stem Cells. 2015; 33: 2093-103.

31. Abdanipour A., Tiraihi T., Mirnajafi-Zadeh J. Improvement of the pilocarpine epilepsy model in rat using bone marrow stromal cell therapy. Neurol Res. 2011; 33: 625-32.

32. Voulgari-Kokota A., Fairless R., Karamita M., Kyrargyri V., Tseveleki V., Evangelidou M. et al. Mesenchymal stem cells protect CNS neurons against glutamate excitotoxicity by inhibiting glutamate receptor expression and function. Exp Neurol. 2012; 236: 161-70.

33. Hunt R. F., Girskis K.M., Rubenstein J. L., Alvarez-Buylla A., Baraban S.C. GABA progenitors grafted into the adult epileptic brain control seizures and abnormal behavior. Nat Neurosci. 2013; 16: 692-7.

34. Cunningham M., Cho J.H., Leung A, Savvidis G., Ahn S., Moon M. et al. hPSC-derived maturing GABAergic interneurons ameliorate seizures and abnormal behavior in epileptic mice. Cell Stem Cell. 2014; 15: 559-73.

35. Lee H., Yun S., Kim I.S, Lee I.S., Shin J. E., Park S.C. et al. Human fetal brain-derived neural stem/progenitor cells grafted into the adult epileptic brain restrain seizures in rat models of temporal lobe epilepsy. PLoS ONE. 2014; 9: e104092.

36. Li T., Ren G., Kaplan D. L., Boison D. Human mesenchymal stem cell grafts engineered to release adenosine reduce chronic seizures in a mouse model of CA3-selective epileptogenesis. Epilepsy Res. 2009; 84: 238-41.

37. Yang C.C., Shih Y.H., Ko M.H., Hsu S.Y., Cheng H., Fu Y.S. Transplantation of human umbilical mesenchymal stem cells from Wharton’s jelly after complete transection of the rat spinal cord. PLoS ONE. 2008; 3: e3336.

38. Takahashi K., Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006; 126 (4): 663-676.

39. Shi Z., Zhang J., Chen S. et al. Conversion of fibroblasts to parvalbumin neurons by one transcription factor, Ascl1, and the chemical compound forskolin. J Biol Chem. 2016; 291 (26): 13560-70.

40. Shakhbazau A., Mishra M., Chu T.H., Brideau C., Cummins K., Tsutsui S. Fluorescent phosphorus dendrimer as a spectral nanosensor for macrophage polarization and fate tracking in spinal cord injury. Macromol Biosci. 2015; 15: 1523-34.

41. Rao G., Mashkouri S., Aum D., Marcet P., Borlongan C.V. Contemplating stem cell therapy for epilepsy-induced neuropsychiatric symptoms. Neuropsychiatric Disease and Treatment. 2017; 13: 585-596.

42. Lipatova L.V. Neuro-immune mechanism of epilepsy as a key to pathogenetic treatment of the disease. Epilepsiya i paroksizmal’nye sostoyaniya / Epilepsy and paroxysmal conditions (in Russian). 2010; 2 (3): 20-27.

43. Blinov D.V. Patsienty s nevrologicheskimi rasstroĬstvami: obosnovanie neobkhodimosti farmakoekonomicheskoĬ otsenki optimizatsii zatrat na vedenie s ispol’zovaniem neĬrospetsificheskikh belkov v kachestve markerov povysheniya pronitsaemosti gematoentsefalicheskogo bar’era. FARMAKOEKONOMIKA. Sovremennaya farmakoekonomika i farmakoepidemiologiya / FARMAKOEKONOMIKA. Modern pharmacoeconomics and pharmacoepidemiology. 2014; 7 (1): 40-45.

44. Blinov D.V. Akusherstvo, ginekologiya i reproduktsiya / Obstetrics, gynecology and reproduction. 2016; 10 (2): 55-63. DOI: 10.17749/2313-7347.2016.10.2.055- 063.

45. Madzhidova E.N., Rakhimbaeva G.S., Azizova R.B. Epilepsiya i paroksizmal’nye sostoyaniya / Epilepsy and paroxysmal conditions (in Russian). 2014; 6 (1): 15-18.


For citation:


Dokukina T.V., Potapnev M.P., Kosmacheva S.M., Hlebokazov F.P., Slobina E.L., Golubeva T.S., Misjuk N.N., Mahrov M.V., Shamruk I.V., Korolevich P.P., Martynenko A.I., Bychenko I.V., Bud’ko T.O. CELL THERAPY OF EPILEPSIA. CLINICAL AND IMMUNOLOGICAL ASPECTS. Epilepsia and paroxysmal conditions. 2018;10(1):35-51. (In Russ.) https://doi.org/10.17749/2077-8333.2018.10.1.035-051

Views: 196


ISSN 2077-8333 (Print)
ISSN 2311-4088 (Online)