Использование фармабиотика на основе штамма Lactobacillus fermentum U-21 с целью модуляции нейродегенеративного процесса при экспериментальном паркинсонизме

Valery N. Danilenko1, Alla V. Stavrovskaya2, Dmitriy N. Voronkov2, Anastasiya S. Gushchina2, Maria V. Marsova1, Nina G. Yamshchikova2, Аrtyem S. Ol’shansky2, M. V. Ivanov2, Sergey N. Illarioshkin2
1ФГБУН «Институт общей генетики им. Н.И. Вавилова» РАН, Москва, Россия; 2ФГБНУ «Научный центр неврологии», Москва, Россия

Аннотация


Введение. В экспериментальных и клинических исследованиях неоднократно показано взаимное влияние состояния кишечной микробиоты и нервной системы, при этом выявлена четкая связь изменений микробиоты с развитием нейродегенеративного процесса. Предполагается, что нарушение микрофлоры и воспаление провоцируют распространение патологических форм α-синуклеина в нервной системе, что признается основной причиной нейродегенерации при болезни Паркинсона.

Цель исследования: выявление эффектов препарата-фармабиотика на основе штамма Lactobacillus fermentum U-21 при введении крысам Вистар индуктора паркинсонизма — параквата.

Материал и методы. Две группы животных на фоне внутрибрюшинных инъекций параквата (8 доз по 10 мг/кг, через день в течение 15 дней) получали перорально 0,9% NaCl или препарат U-21 ежедневно в течение 15 дней, а контрольные группы получали инъекции 0,9% NaCl и перорально U-21 или 0,9% NaCl в том же режиме. Двигательную активность исследовали в тестах «открытое поле» и «сужающаяся дорожка». Морфологически оценивали изменения позитивных к тирозингидроксилазе волокон энтеральных сплетений и количество бокаловидных клеток ворсин тонкого кишечника.

Результаты. Введение параквата приводило к прогрессирующей гибели животных, но применение U-21 увеличивало их выживаемость и сохраняло двигательную активность на уровне контрольных крыс. Пероральное введение только фармабиотика не влияло на двигательную активность животных. Паракват снижал плотность позитивных к тирозингидроксилазе волокон и увеличивал число бокаловидных клеток, а исследуемый препарат частично ослаблял изменения, выявляемые под действием параквата.

Заключение. Препарат U-21 показал высокую биологическую активность на нейротоксической модели паркинсонизма, что обосновывает дальнейшие расширенные исследования его эффектов.

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Ключевые слова

энтеральная нервная система; паркинсонизм; пробиотик; модели на животных; паракват; Lactobacillus

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Литература

Cacabelos R. Parkinson’s disease: from pathogenesis to pharmacogenomics. Int J Mol Sci 2017; 18: E551. DOI: 10.3390/ijms18030551. PMID: 28273839.

Potashkin J.A., Blume S.R., Runkle N.K. Limitations of animal models of Parkinson’s disease. Parkinsons Dis 2010; 2011: 658083. DOI: 10.4061/2011/658083. PMID: 21209719.

Illarioshkin S.N. [Modern ideas about the etiology of Parkinson's disease]. Nevrologicheskiy zhurnal 2015; 4: 4–13. (In Russ.)

Dauer W., Przedborski S. Parkinson’s disease: mechanisms and models. Neuron 2003; 39: 889–909. DOI: 10.1016/S0896-6273(03)00568-3. PMID: 12971891.

Müller T. Catechol-o-methyltransferase inhibitors in Parkinson’s disease. Drugs 2015; 75:157–174. DOI: 10.1007/s40265-014-0343-0. PMID: 25559423.

Hughes A.J., Daniel S.E., Kilford L., Lees A.J. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinicopathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992; 55: 181–184. DOI: 10.1136/jnnp.55.3.181. PMID: 1564476.

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Milber J.M., Noorigian J.V., Morley J.F. et al. Lewy pathology is not the first sign of degeneration in vulnerable neurons in Parkinson disease. Neurology 2012; 79: 2307–2314. DOI: 10.1212/WNL.0b013e318278fe32. PMID: 23152586.

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Jackson A., Forsyth C.B., Shaikh M. et al. Diet in Parkinson's disease: critical role for the microbiome. Front Neurol 2019; 10: 1245. DOI: 10.3389/fneur.2019.01245. PMID: 31920905.

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Robinson S., Rainwater A.J., Hnasko T.S., Palmiter R.D. Viral restoration of dopamine signaling to the dorsal striatum restores instrumental conditioning to dopamine-deficient mice. Psychopharmacology (Berl) 2007; 191: 567–578. DOI: 10.1007s00213-006-0579-9. PMID: 17093978.

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Klingelhoefer L, Reichmann H. The gut and nonmotor symptoms in Parkinson's disease. Int Rev Neurobiol 2017; 134: 787–809. DOI: 10.1016/bs.irn.2017.05.027. PMID: 28805583.

Braak H., de Vos R.A., Bohl J., Del Tredici K. Gastric alpha-synuclein immunoreactive inclusions in Meissner’s and Auerbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology. Neurosci Lett 2006; 396: 67–72. DOI: 10.1016/j.neulet.2005.11.012. PMID: 16330147.

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Forsyth C.B., Shannon K.M., Kordower J.H. et al. Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson's disease. PLoS One 2011; 6: e28032. DOI: 10.1371/journal.pone.0028032. PMID: 22145021.

O'Donovan S.M., Crowley E.K., Brown J.R. et al. Nigral overexpression of α-synuclein in a rat Parkinson's disease model indicates alterations in the enteric nervous system and the gut microbiome. Neurogastroenterol Motil 2020; 32: e13726. DOI: 10.1111/nmo.13726. PMID: 31576631.

Campos-Acuña J., Elgueta D., Pacheco R. T-cell-driven inflammation as a mediator of the gut-brain axis involved in Parkinson's disease. Front Immunol 2019; 10: 239. DOI: 10.3389/fimmu.2019.00239. PMID: 30828335.

Sharma S., Awasthi A., Singh S. Altered gut microbiota and intestinal permeability in Parkinson's disease: Pathological highlight to management. Neurosci Lett 2019; 712: 134516. DOI: 10.1016/j.neulet.2019.134516. PMID: 31560998.

Barrenschee M., Zorenkov D., Böttner M. et al. Distinct pattern of enteric phospho-alpha-synuclein aggregates and gene expression profiles in patients with Parkinson‘s disease. Acta Neuropathol Commun 2017; 5: 1. DOI: 10.1186/s40478-016-0408-2. PMID: 28057070.

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DOI: http://dx.doi.org/10.25692/ACEN.2020.1.7