The use of a pharmabiotic based on the Lactobacillus fermentum U-21 strain to modulate the neurodegenerative process in an experimental model of Parkinson disease

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Abstract

Introduction. Experimental and clinical studies have repeatedly shown the interplay between the intestinal microbiota properties and the nervous system, with a clear link established between changes in microbiota and the development of a neurodegenerative process. It is thought that inflammation and microbiota disturbances provoke the spread of pathological forms of a-synuclein in the nervous system, which is recognized as the main cause of neurodegeneration in Parkinson disease (PD).

Aim of the study: to identify the effect of a pharmabiotic based on a Lactobacillus fermentum U-21 strain in Wistar rats with paraquat-induced parkinsonism.

Materials and methods. Two groups of animals received intra-abdominal paraquat injections (8 doses of 10 mg/kg, every second day for 15 days) and then received orally either a 0.9% NaCl solution, or the U-21 preparation daily for 15 days. The control groups received 0.9% NaCl injections and either a U-21 preparation, or a 0.9% NaCl solution orally under the same regimen. Motor activity was tested in the open field and narrowing beam walking tests. Changes in tyrosine hydroxylase positive enteric plexus fibers and the in quantity of intestinal villi goblet cells were measured morphologically.

Results. Paraquat administration led to a gradual animal death, however, administration of the U-21 increased their survival rate and preserved their motor activity at the level of the control rats. Oral administration of the pharmabiotic only did not alter the animals’ motor activity. Paraquat reduced density of the tyrosine hydroxylase positive fibers and increased the number of goblet cells, while the study drug partially diminished the changes induced by paraquat.

Conclusion. The U-21 preparation demonstrated high biological activity in the neurotoxin-induced model of PD, which justifies further, extended studies of its effects.

About the authors

Valery N. Danilenko

Vavilov Institute of General Genetics, Russian Academy of Sciences

Email: alla_stav@mail.ru
Russian Federation, Moscow

Alla V. Stavrovskaya

Research Center of Neurology

Author for correspondence.
Email: alla_stav@mail.ru
Russian Federation, Moscow

Dmitriy N. Voronkov

Research Center of Neurology

Email: alla_stav@mail.ru
Russian Federation, Moscow

Anastasiya S. Gushchina

Research Center of Neurology

Email: alla_stav@mail.ru
Russian Federation, Moscow

Maria V. Marsova

Vavilov Institute of General Genetics, Russian Academy of Sciences

Email: alla_stav@mail.ru
Russian Federation, Moscow

Nina G. Yamshchikova

Research Center of Neurology

Email: alla_stav@mail.ru
Russian Federation, Moscow

Аrtyem S. Ol'shansky

Research Center of Neurology

Email: alla_stav@mail.ru
Russian Federation, Moscow

M. V. Ivanov

Research Center of Neurology

Email: alla_stav@mail.ru
Russian Federation, Moscow

Sergey N. Illarioshkin

Research Center of Neurology

Email: alla_stav@mail.ru
Russian Federation, Moscow

References

  1. Cacabelos R. Parkinson’s disease: from pathogenesis to pharmacogenomics. Int J Mol Sci 2017; 18: E551. doi: 10.3390/ijms18030551. PMID: 28273839.
  2. 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.
  3. Illarioshkin S.N. [Modern ideas about the etiology of Parkinson's disease]. Nevrologicheskiy zhurnal 2015; 4: 4–13. (In Russ.)
  4. 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.
  5. Müller T. Catechol-o-methyltransferase inhibitors in Parkinson’s disease. Drugs 2015; 75:157–174. doi: 10.1007/s40265-014-0343-0. PMID: 25559423.
  6. 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.
  7. Mink J.W. The basal ganglia: focused selection and inhibition of competing motor programs. Progr Neurobiol 1996; 50: 381–425. doi: 10.1016/S0301-0082(96)00042-1. PMID: 9004351.
  8. 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.
  9. Scheperjans F., Aho V., Pereira P.A. et al. Gut microbiota are related to Parkinson’s disease and clinical phenotype. Mov Disord 2015; 30: 350–358. doi: 10.1002/mds.26069. PMID: 25476529.
  10. Keshavarzian A., Green S.J., Engen P.A. et al. Colonic bacterial composition in Parkinson’s disease. Mov Disord 2015; 30: 1351–1360. doi: 10.1002/mds.26307. PMID: 26179554.
  11. 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.
  12. Leclair-Visonneau L., Neunlist M., Derkinderen P., Lebouvier T. The gut in Parkinson's disease: bottom-up, top-down, or neither? Neurogastroenterol Motil 2020; 32: e13777. doi: 10.1111/nmo.13777. PMID: 31854093.
  13. Petrov V.A., Saltykova I.V., Zhukova I.A. et al. Analysis of gut microbiota in patients with Parkinson's disease. Bull Exp Biol Med 2017; 162: 734–737. doi: 10.1007/s10517-017-3700-7. PMID: 28429209.
  14. Heiss C.N., Olofsson L.E. The role of the gut microbiota in development, function and disorders of the central nervous system and the enteric nervous system. J Neuroendocrinol 2019; 31: e12684. doi: 10.1111/jne.12684. PMID: 30614568.
  15. Dutta S.K., Verma S., Jain V. et al. Parkinson's disease: the emerging role of gut dysbiosis, antibiotics, probiotics, and fecal microbiota transplantation. J Neurogastroenterol Motil 2019; 25: 363–376. doi: 10.5056/jnm19044. PMID: 31327219.
  16. Poewe W., Seppi K., Tanner C.M. et al. Parkinson disease. Nat Rev Dis Primers 2017; 3: 17013. doi: 10.1038/nrdp.2017.13. PMID: 28332488.
  17. Tulisiak C.T., Mercado G., Peelaerts W. et al. Can infections trigger alpha-synucleinopathies? Prog Mol Biol Transl Sci 2019; 168: 299–322. doi: 10.1016/bs.pmbts.2019.06.002. PMID: 31699323.
  18. Endres K., Schäfer K.H. Influence of commensal microbiota on the enteric nervous system and its role in neurodegenerative diseases. J Innate Immun 2018; 10: 172–180. doi: 10.1159/000488629. PMID: 29742516.
  19. Yunes R.A., Poluektova E.U., Vasileva E.V. et al. A multi-strain potential probiotic formulation of GABA-producing Lactobacillus plantarum 90sk and Bifidobacterium adolescentis 150 with antidepressant effects. Probiotics Antimicrob Proteins 2019. doi: 10.1007/s12602-019-09601-1. PMID: 31677091.
  20. Meredith G.E., Sonsalla P., Chesselet M.F. Animal models of Parkinson’s disease progression. Acta Neuropathol 2008; 115: 385–398. doi: 10.1007/s00401-008-0350-x. PMID: 18273623.
  21. Fahim M.A., Shehab S., Nemmar A. et al. Daily subacute paraquat exposure decreases muscle function and substantia nigra dopamine level. Physiol Res 2013; 62: 313–321. PMID: 23489189.
  22. Marsova M.V., Abilev S.K., Poluektova E.U., Danilenko V.N. A bioluminescent test system reveals valuable antioxidant properties of lactobacillus strains from human microbiota. World J Microbiol Biotechnol 2018; 34: 27. doi: 10.1007/s11274-018-2410-2. PMID: 29344877.
  23. Danilenko V.N., Marsova M.V., Poluektova E.U. et al. The strain Lactobacillus fermentum U-21, producing a complex of biologically active substances that neutralize the superoxide anion induced by chemical agents. Patent No. 2705250 dated 05.02.2018. (In Russ.)
  24. Attia H.N., Maklad Y.A. Neuroprotective effects of coenzyme Q10 on paraquat-induced Parkinson’s disease in experimental animals. Behav Pharmacol 2018; 29: 79–86. doi: 10.1097/FBP.0000000000000342. PMID: 28902670.
  25. Karkishchenko N.N., Gracheva S.V. (eds.) [Guide to laboratory animals and alternative models in biomedical research]. Мoscow, 2010. 358 p. (In Russ.)
  26. Litvinenko I.V., Krasakov I.V., Bisaga G.N. et al. [The modern concept of the pathogenesis of neurodegenerative diseases and the treatment strategy]. S.S. Korsakov zhurnal nevrologii i psikhiatrii 2017; 6(2): 3–10. doi: 10.17116/jnevro2017117623-10. (In Russ.)
  27. 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.
  28. Siderowf A., Lang A.E. Premotor Parkinson’s disease: concepts and definitions. Mov Disord 2012; 27: 608–616. doi: 10.1002/mds.24954. PMID: 22508279.
  29. 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.
  30. 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.
  31. Beach T.G., Adler C.H., Sue L.I. et al. Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol 2010; 119: 689–702. doi: 10.1007/s00401-010-0664-3. PMID: 20306269.
  32. 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.
  33. 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.
  34. 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.
  35. 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.
  36. 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.
  37. Breen D.P., Halliday G.M., Lang A.E. Gut-brain axis and the spread of α-synuclein pathology: vagal highway or dead end? Mov Disord 2019; 34: 307–316. doi: 10.1002/mds.27556. PMID: 30653258.
  38. Sampson T.R., Debelius J.W., Thron T. et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell 2016; 167: 1469–1480.e12. doi: 10.1016/j.cell.2016.11.018. PMID: 27912057.
  39. Borghammer P., Van Den Berge N. Brain-first versus gut-first Parkinson's disease: a hypothesis. J Parkinsons Dis 2019; 9: S281–S295. doi: 10.3233/JPD-191721. PMID: 31498132.
  40. Westfall S., Lomis N., Kahouli I. et al. Microbiome, probiotics and neurodegenerative diseases: deciphering the gut brain axis. Cell Mol Life Sci 2017; 74: 3769–3787. doi: 10.1007/s00018-017-2550-9. PMID: 28643167
  41. Fung T.C. The microbiota-immune axis as a central mediator of gut-brain communication. Neurobiol Dis 2019; 136: 104714.doi: 10.1016/j.nbd.2019.104714. PMID: 31846737.
  42. Zheng W., He R., Yan Z. et al. Regulation of immune-driven pathogenesis in Parkinson's disease by gut microbiota. Brain Behav Immun 2020: S0889–S1591(19)30526–4. doi: 10.1016/j.bbi.2020.01.009. PMID: 31931152.
  43. Dinan T.G., Cryan J.F. Gut instincts: microbiota as a key regulator of brain development, ageing and neurodegeneration. J Physiol 2017; 595: 489–503. doi: 10.1113/JP273106. PMID: 27641441.
  44. Sadler R., Cramer J.V., Heindl S. et al. Short-chain fatty acids improve post-stroke recovery via immunological mechanisms. J Neurosci 2019; 40: 1162–1173. doi: 10.1523/JNEUROSCI.1359-19.2019. PMID: 31889008.
  45. Musgrove R.E., Helwig M., Bae E.J. et al. Oxidative stress in vagal neurons promotes parkinsonian pathology and intercellular α-synuclein transfer. J Clin Invest 2019; 130: 3738–3753. doi: 10.1172/JCI127330. PMID: 31194700.
  46. Luczynski P., McVey Neufeld K.A., Oriach C.S. et al. Growing up in a bubble: using germ-free animals to assess the influence of the gut microbiota on brain and behavior. Int J Neuropsychopharmacol 2016; 19: 11–17. doi: 10.1093/ijnp/pyw020. PMID: 26912607.
  47. Cerdó T., Diéguez E., Campoy C. Impact of gut microbiota on neurogenesis and neurological diseases during infancy. Curr Opin Pharmacol 2019; 18: 33–37. doi: 10.1016/j.coph.2019.11.006. PMID: 31864102.
  48. Lombardi V.C., De Meirleir K.L., Subramanian K. et al. Nutritional modulation of the intestinal microbiota; future opportunities for the prevention and treatment of neuroimmune and neuroinflammatory disease. J Nutr Biochem 2018; 61: 1–16. doi: 10.1016/j.jnutbio.2018.04.004. PMID: 29886183.
  49. Bulatova E.M., Bogdanova N.M., Lobanova E.A., Gabrusskaya T.V. [Probiotics: clinical and nutritional aspects of the application]. Pediatriya 2010; 89(3): 84−90. (In Russ.)
  50. Johnson M.E., Stringer A., Bobrovskaya L. Rotenone induces gastrointestinal pathology and microbiota alterations in a rat model of Parkinson’s disease. Neurotoxicology 2018; 65: 174–185. doi: 10.1016/j.neuro.2018.02.013. PMID: 29471018.
  51. Li Y., Zhang Y., Zhang X.L. et al. Dopamine promotes colonic mucus secretion through dopamine D 5 receptor in rats. Am J Physiol Cell Physiol 2019; 316: C393–C403. doi: 10.1152/ajpcell.00261.2017. PMID: 30624983.
  52. Naudet N., Antier E., Gaillard D. et al. Oral exposure to paraquat triggers earlier expression of phosphorylated α-synuclein in the enteric nervous system of A53T mutant human α-synuclein transgenic mice. J Neuropathol Exp Neurol 2017; 76: 1046–1057. doi: 10.1093/jnen/nlx092. PMID: 29040593.
  53. Anselmi L., Bove C., Coleman F.H. et al. Ingestion of subthreshold doses of environmental toxins induces ascending Parkinsonism in the rat. NPJ Parkinsons Disease 2018; 4: 30. doi: 10.1038/s41531-018-0066-0. PMID: 30302391.

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Copyright (c) 2020 Danilenko V.N., Stavrovskaya A.V., Voronkov D.N., Gushchina A.S., Marsova M.V., Yamshchikova N.G., Ol’shansky А.S., Ivanov M.V., Illarioshkin S.N.

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