Annals of Clinical and Experimental NeurologyAnnals of Clinical and Experimental NeurologyАнналы клинической и экспериментальной неврологии2075-54732409-2533Eco-Vector56410.25692/ACEN.2018.5.9ReviewsОбзорыUnknownCellular models of the nervous system diseasesКлеточные модели заболеваний нервной системыKhaspekovLeonid G.ХаспековЛеонид Георгиевич
Russian Federation
khaspekleon@mail.ruResearch Center of NeurologyФГБНУ «Научный центр неврологии»26122018125S707826122018Copyright ©; 2018, Khaspekov L.G.Copyright ©; 2018, Khaspekov L.G.2018Khaspekov L.G.Khaspekov L.G.https://creativecommons.org/licenses/by/4.0https://annaly-nevrologii.com/pathID/article/view/564

Cellular models are a very important research tool in modern neurobiology. The presented review of Russian and international literature summarizes the main data of experimental studies, conducted over the past 15 years, aimed at modeling in vitro acute and chronic forms of cerebral pathology in order to reveal the mechanisms of their pathogenesis and to develop approaches to their pharmacological correction. The results of modeling of ischemic neurodestructive processes, epilepsy, Parkinson's disease, Alzheimer's disease and Huntington's disease, obtained using modern cellular research methods, such as cell cultivation in a multielectrode system and technology of induced pluripotent stem cells, are presented. A number of key concepts related to this problem are illustrated with the data obtained by the author and his laboratory. In conclusion, the short-term goals and prospects of in vitro studies of pathogenic mechanisms of neurological diseases and of the search for new neuroprotectors are formulated.

Клеточные модели являются важнейшим исследовательским инструментом в современной нейробиологии. Представленный обзор отечественной и зарубежной литературы обобщает основные данные экспериментальных исследований последних 15 лет, направленных на моделирование in vitro острых и хронических форм церебральной патологии с целью выяснения механизмов их патогенеза и поиска способов их фармакологической коррекции. Представлены результаты моделирования ишемических нейродеструктивных процессов, эпилепсии, болезней Паркинсона, Альцгеймера, Гентингтона, полученные с использованием современных клеточных методов исследования, таких как культивирование клеток в мультиэлектродной системе и технология индуцированных плюрипотентных стволовых клеток. Ряд ключевых положений по данной проблеме проиллюстрирован собственными приоритетными результатами автора и его лаборатории. Сформулированы ближайшие цели и перспективы исследований in vitro патогенетических механизмов заболеваний нервной системы и поиска новых нейропротекторов.

nerve cell culturemodeling of neurological diseasesneuroprotectorsmodern cellular technologiesкультура клеток нервной системымоделирование неврологических заболеванийнейропротекциясовременные клеточные технологииPanula P., Rechardt L. The development of histochemically demonstrable cholinesterases in the rat neostriatum in vivo and in vitro. Histochemistry 1979; 64: 35–50. PMID: 521314.Berger B., Di Porzio U., Dagnet M.C. Long-term development of mesencephalic dopaminergic neurons of mouse embryos in dissociated primary cultures: morphological and histochemical characteristics. Neuroscience 1982; 7: 193–205. PMID: 6123092.Victorov I.V. Razvitiye i plastichnost’ neyronov v tkanevykh i kletochnykh kul’turakh. Dis. ... dokt. biol. nauk. [The development and plastisicity of neurons in tissue and cell cultures. D.Sci.(Biol.) diss.]. Мoscow. 1987. (In Russ.)Викторов И.В. Развитие и пластичность нейронов в тканевых и клеточных культурах. Дис. ...докт. биол. наук. Москва. 1987.Sommer S.J. Ischemic stroke: experimental models and reality. Acta Neuropathol 2017; 133: 245–261. DOI: 10.1007/s00401-017-1667-0. PMID: 28064357.Holloway P.M., Gavins F.N. Modeling ischemic stroke in vitro: status quo and future perspectives. Stroke 2016; 47: 561-569. DOI: 10.1161/STROKEAHA. 115.011932.Holloway P.M., Gavins F.N. Modeling ischemic stroke in vitro: status quo and future perspectives. Stroke 2016; 47: 561-569. DOI: 10.1161/STROKEAHA. 115.011932Choi D.W., Maulucci-Gedde M., Kriegstein A.R. Glutamate neurotoxicity in cortical cell culture. J Neurosci 1987; 7: 357–368. PMID: 2880937.Choi D.W., Maulucci-Gedde M., Kriegstein A.R. Glutamate neurotoxicity in cortical cell culture. J Neurosci 1987; 7: 357–368. PMID: 2880937Huang R., Sochoka E., Hertz L. Cell culture studies of the role of elevated extracellular glutamate and K+ in neuronal cell death during and after anoxia/ ischemia. Neurosci Behav Rev 1997; 21: 129–134. PMID: 9062935.Huang R., Sochoka E., Hertz L. Cell culture studies of the role of elevated extracellular glutamate and K+ in neuronal cell death during and after anoxia/ ischemia. Neurosci Behav Rev 1997; 21: 129–134. PMID: 9062935Khodorov B. Glutamate induced deregulation of calcium homeostasis and mitochondrial disfunction in mammalian central neurones. Prog Biophys Mol Biol 2004; 2: 279–351. PMID: 15288761.Khodorov B. Glutamate induced deregulation of calcium homeostasis and mitochondrial disfunction in mammalian central neurones. Prog Biophys Mol Biol 2004; 2: 279–351. PMID: 15288761Surin A.M. Mekhanizmy disfunktsii mitokhondriy i narusheniy ionnogo gomeostaza pri glutamatnoy neyrotoksichnosti: Dis. … dokt. biol. nauk. [Mechanisms of mitochondrial disfunction and ion homeostasis disturbances as consequences of glutamate neurotoxicity. D.Sci.(Biol.) diss.]. Мoscow. 2014. (In Russ.)Сурин А.М. Механизмы дисфункции митохондрий и нарушений ионного гомеостаза при глутаматной нейротоксичности: Дис. … докт. биол. наук. Москва. 2014.Woodruff T.M., Thundyil J., Tang S.-C. et al. Pathophysiology, treatment, and animal and cellular models of human ischemic stroke. Mol Neurodegener 2011; 6: 11. DOI: 10.1186/1750-1326-6-11. PMID: 21266064.Stelmashook E.V., Isaev N.K., Lozier E.R. et al. Role of glutamine in neuronal survival and death during brain ischemia and hypoglycemia. Int J Neurosci 2011; 121: 415–422. DOI: 10.3109/00207454.2011.570464. PMID: 21574892.Stelmashook E.V., Isaev N.K., Plotnikov E.Y. et al. Effect of transitory glucose deprivation on mitochondrial structure and functions in cultured cerebellar granule neurons. Neurosci Lett 2009; 461: 140-144. DOI: 10.1016/j. neulet.2009.05.073. PMID: 19500653.Stelmashook E.V., Isaev N.K., Zorov D.B. Paraquat potentiates glutamate toxicity in immature cultures of cerebellar granule neurons. Toxicol Lett 2007; 174: 82–88. DOI: 10.1016/j.toxlet. 2007.08.012. PMID: 17919854.Kapay N.A., Popova O.V., Isaev N.K. et al. Mitochondria-targeted plastoquinone antioxidant SkQ1 prevents amyloid-β-induced impairment of long-term potentiation in rat hippocampal slices. J Alzheim Dis 2013; 36: 377-383. DOI: 10.3233/JAD-122428. PMID: 23735258.Isaev N.K., Lozier E.R., Novikova S.V. et al. Glucose starvation stimulates Zn2+ toxicity in cultures of cerebellar granule neurons. Brain Res Bull 2012; 87: 80-84. DOI: 10.1016/ j.brainresbull.2011.10.017. PMID: 2207950377Isaev N.K., Lozier E.R., Novikova S.V. et al. Glucose starvation stimulates Zn2+ toxicity in cultures of cerebellar granule neurons. Brain Res Bull 2012; 87: 80-84. DOI: 10.1016/ j.brainresbull.2011.10.017. PMID: 22079503Losier E.R., Stelmashook E.V., Uzbekov R.E. et al. Stimulation of kainite toxicity by zinc in cultured cerebellar granule neurons and the role of mitochondria in this process. Toxicol Lett 2012; 208: 36-40. DOI: 10.1016/j. toxlet.2011.10.003. PMID: 22008730.Stelmashook E.V., Novikova S.V., Amelkina G.A. et al. [Acidosis and 5-(N-ethyl-N-isopropyl)amiloride (EIPA) attenuate zinc/kainate toxicity in cultured cerebellar granule neurons]. Biokhimiya 2015; 80: 1282-1288. (In Russ.)Стельмашук Е.В., Новикова С.В., Амелькина Г.А. и др. Ацидоз и 5-(N-этил-N-изопропил)амилорид (EIPA) снижают цинк/каинатную токсичность в культурах зернистых нейронов мозжечка крыс. Биохимия 2015; 80: 1282-1288.Isaev N.K., Golyshev S.A., Avilkina S . et al. N-acetyl-L-cysteine and Mn2+ attenuate Cd2+-induced disturbance of the intracellular free calcium homeostasis in cultured cerebellar granule neurons. Toxicology 2018; 393: 1-8. DOI: 10.1016/j.tox.2017.10.017. PMID: 29100878.Isaev N.K., Golyshev S.A., Avilkina S . et al. N-acetyl-L-cysteine and Mn2+attenuate Cd2+-induced disturbance of the intracellular free calcium homeostasis in cultured cerebellar granule neurons. Toxicology 2018; 393: 1-8. DOI: 10.1016/j.tox.2017.10.017. PMID: 29100878.Gromova O.A., Torshin I.Yu., Gogoleva I.V. et al. [Pharmacokinetic and pharmacodynamic sinergy between neuropeptides and lithium in realization of neurotrophic and neuroprotective effects of cerebrolysinum]. Zhurnal nevrologii I psikhiatrii im. S.S. Korsakova 2015; 15: 65-72. (In Russ.)Громова О.А., Торшин И.Ю., Гоголева И.В. и др. Фармакокинетический и фармакодинамический синергизм между нейропептидами и литием в реализации нейротрофического и нейропротективного действия церебролизина. Журнал неврологии и психиатрии им. С.С. Корсакова 2015; 15: 65-72.Yakovlev A.A., Lyzhin A.A., Khaspekov L.G. et al. [Peptide drug cortexin inhibits brain caspase-8]. Biomeditsinskaya Khimiya 2017; 63(1): 27-31. (In Russ.)Яковлев А.А., Лыжин А.А., Хаспеков Л.Г. и др. Пептидный препарат кортексин ингибирует каспазу-8 мозга. Биомедицнская химия 2017; 63(1): 27-31.Khaspekov L.G., Brenz Verca M.S., Frumkina L.E. et al. Involvement of brain-derived neurotrophic factor in cannabinoid receptor-dependent protection against excitotoxicity. Eur J Neurosci 2004; 19: 1691-1698. DOI: 10.1111/j.1460-9568.2004.03285.x. PMID: 15078543.Genrikhs E.E., Bobrov M.Yu., Andrianova E.L. et al. [Modulators of endogenous cannabinoid system as neuroprotectants]. Annals of Clinical and Experimental Neurology 2010; 4: 37–42. (In Russ.)Генрихс Е.Е., Бобров М.Ю., Андрианова Е.Л. и др. Модуляторы эндогенной каннабиноидной системы как нейропротекторы. Анналы клинической и экспериментальной неврологии 2010; 4: 37–42.Rzeczinski S., Victorov I.V., Lyjin A.A. et al. Roller culture of free-floating retinal slices: a new system of organotypic cultures of adult rat retina. Ophthalmic Res 2006; 38: 263-269. DOI: 10.1159/000095768. PMID: 16974126Rzeczinski S., Victorov I.V., Lyjin A.A. et al. Roller culture of free-floating retinal slices: a new system of organotypic cultures of adult rat retina. OphthalmicRes 2006; 38: 263-269. DOI: 10.1159/000095768. PMID: 16974126.Mukhina I.V., Khaspekov L.G. [New technologies in experimental nevrology: neuronal networks on multielectrode array]. Annals of Clinical and Experimental Neurology 2010; 2: 44–51. (In Russ.)Мухина И.В., Хаспеков Л.Г. Новые технологии в экспериментальной нейробиологии: нейронные сети на мультиэлектродной матрице. Анналы клинической и экспериментальной неврологии 2010; 2: 44–51.Shimono K., Baudry M., Panchenko V., Taketani M. Chronic multichannel recordings from organotypic hippocampal slice cultures: protection from excitotoxic effects of NMDA by noncompetitive NMDA antagonists. J Neurosci Meth 2002; 120: 193–202. PMID: 12385769.Wahl A.-S., Buchthal B., Rode F. Hypoxic/ischemic conditions induce expression of the putative pro-death gene Clca1 via activation of extrasynaptic N-methyl-D-aspartate receptors. Neuroscience 2009; 158: 344–352. DOI: 10.1016/j.neuroscience.2008.06.018. PMID: 18616968.Linke S., Goertz P., Baader S.L. et al. Aldolase C/Zebrin II is released to the extracellular space after stroke and inhibits the network activity of cortical neurons. Neurochem Res 2006; 31: 1297–1303. DOI: 10.1007/s11064-006-9169-9. PMID: 17053973.Vishwakarma S.K., Bardia A., Tiwari S.K. et al. Current concept in neural regeneration research: NSCs isolation, characterization and transplantation in various neurodegenerative diseases and stroke: a review. J Adv Res 2014; 5: 277–294. DOI: 10.1016/j.jare.2013.04.005. PMID: 25685495.DeLorenzo R.J., Sun D.A., Blair R.E., Sombati S. An in vitro model of stroke-induced epilepsy: elucidation of the roles of glutamate and calcium in the induction and maintenance of stroke-induced epileptogenesis. Int Rev Neurobiol 2007; 81: 59–84. DOI: 10.1016/S0074-7742(06) 81005-6. PMID: 17433918.Noraberg J., Poulsen F.R., Blaabjerg M. et al. Organotypic hippocampal slice cultures for studies of brain damage, neuroprotection and neurorepair. Curr Drug Targets CNS Neurol Disord 2005; 4: 435-452. PMID: 16101559.Jones N.A., Hill A.J., Smith I. et al. Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo. J Pharm Exp Ther 2010; 332: 569–577. DOI: 10.1124/ jpet.109.159145. PMID: 19906779.Jones N.A., Hill A.J., Smith I. et al. Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo. J Pharm Exp Ther 2010; 332: 569– 577. DOI: 10.1124/ jpet.109.159145. PMID: 19906779.Sun D.A., Sombati S., Blair R.E., DeLorenzo R.J. Long-lasting alterations in neuronal calcium homeostasis in an in vitro model of stroke induced epilepsy. Cell Calcium 2004; 35: 155–163. PMID: 14706289.Corti S., Faravelli I., Cardano M., Conti L. Human pluripotent stem cells as tools for neurodegenerative and neurodevelopmental disease modeling and drug discovery. Expert Opin Drug Discov 2015; 10: 615–629. DOI: 10.1517/17460441.2015.1037737. PMID: 25891144.Tonges L., Frank T., Tatenhorst L. et al. Inhibition of rho kinase enhances survival of dopaminergic neurons and attenuates axonal loss in a mouse model of Parkinson’s disease. Brain 2012; 135: 3355–3370. DOI: 10.1093/brain/aws254. PMID: 23087045.Desplats P., Lee H.J., Bae E.J. et al. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci USA 2009; 106: 13010–13015. DOI: 10.1073/pnas.0903691106. PMID: 19651612.Hargus G., Cooper O., Deleidi M. et al. Differentiated parkinson patient-derived induced pluripotent stem cells grow in the adult rodent brain and reduce motor asymmetry in parkinsonian rats. Proc Natl Acad Sci USA 2010; 107:15921–15926. DOI: 10.1073/pnas. 1010209107. PMID: 20798034.Hargus G., Cooper O., Deleidi M. et al. Differentiated parkinson patient-derived induced pluripotent stem cells grow in the adult rodent brain and reduce motor asymmetry in parkinsonian rats. Proc Natl Acad Sci USA 2010; 107: 15921–15926. DOI: 10.1073/pnas. 1010209107. PMID: 20798034.Hargus G., Ehrlich M., Hallmann A.-L., Kuhlmann T. Human stem cell models of neurodegeneration: a novel approach to study mechanisms of disease development. Acta Neuropathol 2014; 127: 151–173. DOI: 10.1007/s00401-013-1222-6. PMID: 24306942.Hargus G., Ehrlich M., Hallmann A.-L., Kuhlmann T. Human stem cell models of neurodegeneration: a novel approach to study mechanisms of disease development. Acta Neuropathol 2014; 127: 151–173. DOI: 10.1007/s00401-0131222-6. PMID: 24306942.Lebedeva O.S., Lagar’kova M.A., Kiselev S.L. et al. [The morphofunctional properties of induced pluripotent stem cells derived from human skin fibroblasts and differentiated to dopaminergic neurons]. Neyrokhimiya 2013; 30: 233-241.(In Russ.)Лебедева О.С., Лагарькова М.А., Киселев С.Л. и др. Морфофункциональные свойства индуцированных плюрипотентных стволовых клеток, полученных из фибробластов кожи человека и дифференцированных в дофаминергические нейроны. Нейрохимия 2013; 30: 233–241.78 Специальный выпуск к 90-летию со дня основания Института мозга www.annaly-nevrologii.comStavrovskaya A.V., Voronkov D.N., Yamschikova N.G. et al. [Morphochemical evaluation of the results of neurotransplantation in experimental parkisonism]. Annals of Clinical and Experim Neurol 2015; 2: 28–32. (In Russ.)Ставровская А.В., Воронков Д.Н., Ямщикова Н.Г. и др. Морфохимическая оценка результатов нейротрансплантации при экспериментальном паркинсонизме. Анналы клинической экспериментальной неврологии 2015; 2: 28–32.Konovalova E.V., Lopacheva O.M., Grivennikov I.A. et al. Mutations in the Parkinson’s disease-associated PARK2 gene are accompanied by imbalance in programmed cell death Systems. Acta Naturae 2015; 7: 146-149. PMID: 26798503.Konovalova E.V., Lopacheva O.M., Grivennikov I.A. et al. Mutations in the Parkinson’s disease-associated PARK2 gene are accompanied by imbalance in programmed cell death systems. Acta Naturae 2015; 7: 146-149. PMID: 26798503.Konovalova E.V., Illarioshkin S.N., Novosadova E.V., Grivennikov I.A. [Phenotypical differences in neuronal cultures derived via reprogramming the fibroblasts from patients carrying mutations in parkinsonian genes LRRK2 and PARK2]. Bull Exp Biol Med 2015; 159: 749-753. (In Russ.)Коновалова Е.В., Новосадова Е.В., Гривенников И.А., Иллариошкин С.Н. Фенотипические различия культур нейронов, получаемых путем репрограммирования фибробластов пациентов с мутациями в генах паркинсонизма LRRK2 и PARK2. Бюллетень экспериментальной биологии и медицины 2015; 159: 749–753.Stansley B., Post J., Hensley K. A comparative review of cell c ulture systems for the study of microglial biology in Alzheimer’s disease. J Neuroinflammation 2012; 9: 115. DOI: 10.1186/ 742-2094-9-115. PMID: 22651808.Stansley B., Post J., Hensley K. A comparative review of cell culture systems for the study of microglial biology in Alzheimer’s disease. J Neuroinflammation 2012; 9: 115. DOI: 10.1186/ 742-2094-9-115. PMID: 22651808.Varghese K., Molnar P., Das M. et al. A new target for amyloid beta toxicity validated by standard and high-throughput electrophysiology. PLoS One 2010; 5: e8643. DOI: 10.1371/ journal.pone.0008643. PMID: 20062810.Ahuja T.K., Mielke J.G., Comas T. et al. Hippocampal slice cultures integrated with multielectrode arrays: a model for study of long-term drug effects on synaptic activity. Drug Devel Res 2007; 68: 84–93. DOI: org/10.1002/ddr.20170.Choi S.H., Kim Y.H., Hebisch M. et al. A three-dimensional human neural cell culture model of Alzheimer’s disease. Nature 2014; 515: 274–278. DOI: 10.1038/nature13800. PMID: 25307057.Xie Y. Z., Zhang R. X. Neurodegenerative diseases in a dish: the promise of IPSC technology in disease modeling and therapeutic discovery. Neurol Sci 2015; 36: 21–27. DOI: 10.1007/s10072-014-1989-9. PMID: 25354658.Xie Y. Z., Zhang R. X. Neurodegenerative diseases in a dish: the promise of IPSC technology in disease modeling and therapeutic discovery. Neurol Sci 2015; 36: 21–27. doi: 10.1007/s10072-014-1989-9. PMID: 25354658.Millet L.J., Gillette M.U. New perspectives on neuronal development via microfluidic environments. Trends Neurosci 2012; 32: 752–761. DOI: 10.1016/j. tins.2012.09.001. PMID: 23031246Millet L.J., Gillette M.U. New perspectives on neuronal development via microfluidic environments. Trends Neurosci 2012; 32: 752–761. DOI: 10.1016/j. tins.2012.09.001. PMID: 23031246.Daviaud N., Garbayo E., Schiller P.C. et al. Organotypic cultures as tools for optimizing central nervous system cell therapies. Exp Neurol 2013; 248: 429–440.Daviaud N., Garbayo E., Schiller P.C. et al. Organotypic cultures as tools for optimizing central nervous system cell therapies. Exp Neurol 2013; 248: 429–440. DOI: 10.1016/j.expneurol. 2013.07.012. PMID: 23899655.DOI: 10.1016/j.expneurol. 2013.07.012. PMID: 23899655.Corti S., Faravelli I., Cardano M., Conti L. Human pluripotent stem cells as tools for neurodegenerative and neurodevelopmental disease modeling and drug discovery. Expert Opin Drug Discov 2015; 10: 615–629. DOI: 10.1517/17460441.2015.1037737. PMID: 25891144Corti S., Faravelli I., Cardano M., Conti L. Human pluripotent stem cells as tools for neurodegenerative and neurodevelopmental disease modeling and drug discovery. Expert Opin Drug Discov 2015; 10: 615–629. DOI:10.1517/17460441.2015.1037737. PMID: 25891144.