ISSN 2415-3060 (print), ISSN 2522-4972 (online)
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УЖМБС 2021, 6(3): 78–84
Medicine. Reviews

Toxic Models of Parkinson's Disease: History and Prospects

Yaroshenko D. S.

The review article presents data on the history of research of extrapyramidal system dysfunctions, modern ideas about the etiology and diagnosis of Parkinson's disease, as the most common disease of the group of extrapyramidal disorders. Currently, no concept of effective therapy for patients with extrapyramidal system dysfunction has been developed, but it has been proven that the probability of developing the disease largely depends on the genetic predisposition and the level of environmental pollution. In the early stages, the disease is slow and asymptomatic, but gradually more than half of patients with Parkinson's disease die, and others need outside care. According to experts, in the near future, Parkinson's disease will become a problem for a significant part of people, because today it affects more and more people of working age. Under such conditions, reliable and early diagnosis of the disease is of great importance, which guarantees timely and most effective treatment. Modern therapies fail to stop the progressive death of the dopaminergic neurons of the substantia nigra, but traditional treatment can achieve symptomatic relief. Currently, it is known that the probability of developing Parkinson's disease depends on the genetic predisposition and the level of man-made environmental stress. The researchers consider that the pathological development of Parkinson's disease in the brain begins in the lower structures of the brain stem with the involvement of the caudal-Rostral nuclei, as well as the involvement of the cortico-basal ganglia-cerebellar pathways. The pathological process affects the ascending pathways and gradually passes to the midbrain, directly to the black substance, spreads from there and weakens the mesocortex and neocortex. Injuries in the brain stem lead to disorganization of the cortico-basal ganglia and cerebellar pathways, followed by the formation of alternative pathways to compensate for the initial disorders in the early stages of the disease. In addition, in Parkinson's disease, intracellular Lewy bodies and neurites formed by the protein alpha-synuclein are created, which are found in the autopsy material of most patients. Poor results of diagnostic evaluation and treatment of Parkinson's disease are usually associated with a lack of understanding of the pathogenesis of Parkinson's disease. The study of the biological basis and pathogenesis of Parkinson's disease is an important task of a whole complex of scientific studies of extrapyramidal system dysfunction. Conclusion. The article discusses the creation of toxic models of Parkinson's disease in vivo and in vitro, which help to recreate the pathogenesis of the disease for early diagnosis and the development of new ways to treat neurodegenerative diseases. In toxic models of Parkinsonism, not only deficits of motor functions such as bradykinesia, tremor, and posture disorders are actively studied, but also non-motor symptoms such as sleep disorders, neuropsychiatric and cognitive abnormalities

Keywords: extrapyramidal system, models of Parkinson’s disease, tremor, Lewy bodies

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  1. Van der Merwe PL, Kalis NN. Sydenham's chorea-analysis of 27 patients and a review of the literature. S Afr Med J. 1997 Jun; 87(Suppl 3): 157-60.
  2. Keener AM, Bordelon YM. Parkinsonism. Semin Neurol. 2016 Aug; 36(4): 330-4. PMid: 27643900.
  3. Kalyan B. Bhattacharyya. The story of George Huntington and his disease. Ann Indian Acad Neurol. 2016 Jan-Mar; 19(1): 25-28. PMid: 27011624. PMCid: PMC4782548.
  4. Ma YL, Li ZP. Jean-Martin Charcot, discovery and nomenclature of amyotrophic lateral sclerosis. Zhonghua Yi Shi Za Zhi. 2019 Jun 28; 49(1): 14-18.
  5. Bozhkova E. Vladimir Mikhailovich Bekhterev. Lancet Neurol. 2018 Sep; 17(9): 744.
  6. Vein AA. Lazar Solomonovich Minor (1855-1942). J Neurol. 2011 Jul; 258(7): 1371-1372. PMid: 21286742. PMCid: PMC3132283.
  7. Marco M. Sergei Davidenkov, the father of Soviet neurogenetics. Neurosciences and History. 2018; 6(1): 21-27.
  8. Zileli M, Sharif S, Fornari M, Ramani P, Jian F, Fessler R, et al. History of Spinal Neurosurgery and Spine Societies. Neurospine. 2020 Dec; 17(4): 675-694. PMID: 33401848.
  9. Yakhno NN. Sovremennye podkhody k lekarstvennomu lechenyyu bolezny Parkynsona [Modern approaches to the medicinal treatment of Parkinson's disease]. Klynycheskaya farmakologyya y terapyya. 1994; 3-4: 92-97. [Russian]
  10. Postuma R, Berg D, Stern M, Poewe W, Olanow C, Oertel W, et al. MDS clinical diagnostic criteria for Parkinson's disease. Mov Disord. 2015 Oct; 30(12): 1591-601. PMid: 26474316.
  11. Braak H, Del Tredici K, Rub U, De Vos R, Jansen Steur E, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol. 2003 Aug; 24: 197-211.
  12. Quartarone A, Cacciola A, Milardi D, Ghilardi MF, Calamuneri A, Chillemi G, et al. New insights into cortico-basal-cerebellar connectome: clinical and physiological considerations. Brain. 2020; 143: 396-406. PMid: 31628799.
  13. Caligiore D, Pezzulo G, Baldassarre G, Bostan AC, Strick PL, Doya K, et al. Consensus paper: towards a systems-level view of cerebellar function: the interplay between cerebellum, basal ganglia and cortex. Cerebellum. 2017; 16: 203-229. PMid: 26873754. PMCid: PMC5243918.
  14. Wu T, Hallett M. The cerebellum in Parkinson's disease. Brain. 2013; 136: 696-709. PMid: 23404337. PMCid: PMC7273201.
  15. Fearnley J., Lees, A. Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain. 1991; 114: 2283-2301. PMid: 1933245.
  16. Pat S, Gerhard L. Golgi study of human locus coeruleus in normal brains and in Parkinson's disease. Neuropathol Appl Neurobiol. 1993; 19: 519-523. PMid: 8121544.
  17. Shin E, Rogers J, Devoto P, Björklund A, Carta M. Noradrenaline neuron degeneration contributes to motor impairments and development of L-DOPA-induced dyskinesia in a rat model of Parkinson's disease. Exp Neurol. 2014 Jul; 257: 25-38. PMid: 24747357.
  18. Obeso JA, Rodriguez-Oroz MC, Goetz CG, Marin C, Kordower JH, Rodriguez M, et al. Missing pieces in the Parkinson's disease puzzle. Nat Med. 2010; 16: 653-661. PMid: 20495568.
  19. Alberio T, Lopiano L, Fasano M. Cellular models to investigate biochemical pathways in Parkinson's disease. FEBS J. 2012; 279: 1146-1155. PMid: 22314200.
  20. Ahlskog J. E. Challenging conventional wisdom: the etiologic role of dopamine oxidative stress in Parkinson's disease. Mov Disord. 2005; 20: 271-282. PMid: 15580550.
  21. Lindqvist D, Hall S, Surova Y, Nielsen HM, Janelidze S, Brundin L, et al. Cerebrospinal fluid inflammatory markers in Parkinson's disease -associations with depression, fatigue and cognitive impairment. Brain Behav Immun. 2013; 33: 183-189. PMid: 23911592.
  22. Thomas B, Beal MF. Parkinson's disease. Hum Mol Genet. 2007; 2: 183-94.
  23. Terzioglu M., Galter D. Parkinson's disease: genetic versus toxin‐induced rodent models. FEBS Journal. 2008; 275: 1384-1391. PMid: 18279376.
  24. Slomynskyy PA, Myloserdova OV, Popova SN. Analyz deletsyy mutatsyy v gene PARK2 pry ydyopatycheskoy formoy bolezny Parkynsona [Analysis of the deletion of mutation in the Park2 gene with an idiopathic form of Parkinson's disease]. Genetyka. 2003; 2: 223- 228. [Russian]
  25. Ross OA, Braithwhaite AT, Farrer MJ. Genetics of Parkinson's disease. Parkinson's disease: molecular and therapeutic insights from model systems. Eds R Nass, S Przedborski. Amsterdam: Elsevier; 2008. p. 9-33.
  27. Levyn O, Fedorova N. Bolezn Parkinsona [Parkinson's disease]. Monografyya. 2‐e yzd. M: MEDpress‐inform; 2012. 352 p. [Russian]
  28. Ershova M, Yvanova E, Yllaryoshkyn S. Bolezn Parkynsona y neyrotrofycheskyy gomeostaz [Parkinson's disease and neurotrophic homeostasis]. Nervnye bolezny. 2018; 1: 3-9. [Russian].
  29. Lu B, Nagappan G, Guan X, Nathan P, Wren P. BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases. Nat Rev Neurosci. 2013; 14(6): 401-16. PMid: 23674053.
  30. Pasquini J, Ceravolo R, Qamhawi Z, Lee JY, Deuschl G, Brooks DJ, et al. Progression of tremor in early stages of Parkinson's disease: a clinical and neuroimaging study. Brain. 2018; 141: 811-21. PMid: 29365117.
  31. Leão A, Sarmento-Silva A, Santos J, Ribeiro A, Silva R. Molecular, Neurochemical, and Behavioral Hallmarks of Reserpine as a Model for Parkinson's Disease: New Perspectives to a Long-Standing Model. Brain Pathol. 2015 Jul; 25(4): 377-90. PMid: 25726735.
  32. Ikram H, Haleem D. Repeated treatment with a low dose of reserpine as a progressive model of Parkinson's dementia. Pak J Pharm Sci. 2019. Mar; 32(2): 555-562.
  33. Langston J, Ballard P, Tetrud J, Irwin I. Chronic Parkinsonism in humans due to a product of meperidine‐analog synthesis. Science. 1983; 219: 979-980. PMid: 6823561.
  34. Sedelis M, Hofele K, Auburger G, Morgan S, Huston J, Schwarting R. MPTP susceptibility in the mouse: behavioral, neurochemical, and histological analysis of gender and strain differences. Behav Genet. 2000; 30: 171-182. PMid: 11105391.
  35. Betarbet R, Sherer T, Greenamyre J. Animal models of Parkinson's disease. BioEssays 2002; 24(4): 308-18. PMid: 11948617.
  36. Chia S, Tan E, Chao Y. Historical Perspective: Models of Parkinson's Disease. Int J Mol Sci. 2020; 21(7): 2464. PMid: 32252301. PMCid: PMC7177377.
  37. Tanner C, Kamel F, Ross GW, Hoppin JA, Goldman SM, Korell M, et al. Rotenone, paraquat and Parkinson's disease. Environ. Health Perspect. 2011; 119: 866-872. PMid: 21269927. PMCid: PMC3114824.
  38. Kang M, Gil S, Koh H. Paraquat induces alternation of the dopamine catabolic pathways and glutathione levels in the substantia nigra of mice. Toxicol Lett. 2009; 188: 148-152. PMid: 19446248.
  39. Sandström J, Broyer A, Schilt C, Greggio C, Fournier M, Do KQ, et al. Potential mechanisms of development-dependent adverse effects of the herbicide paraquat in 3D rat brain cell cultures. Neurotoxicology. 2017; 60: 116-124. PMid: 28467894.
  40. Betarbet R, Canet‐Aviles R, Sherer T, Mastroberardino P, McLendon C, Kim J, et al. Intersecting pathways to neurodegeneration in Parkinson's. disease: effects of the pesticide rotenone on DJ‐1, alpha‐synuclein, and the ubiquitin-proteasome system. Neurobiol Dis. 2006; 22: 404-420. PMid: 16439141.
  41. Boyko A, Gladkova Z, Kuznetsova T, Ponomarev V. Modelyrovanye syndroma parkynsonyzma u krys vvedenyem lypopolysakharyda [Simulation of Parkinsonism Syndrome in Rats by the introduction of lipopolysaccharide]. Zhurnal Grodnenskogo gosudarstvennogo medytsynskogo unyversyteta. 2018; 16(6): 690-696. [Russian].
  42. Zhou H. Triptolide protects dopaminergic neurons from inflammation- mediated damage induced by lipopolysaccharide intranigral injection. Neurobiol Dis. 2005; 18 (3): 441-449. PMid: 15755670.
  43. Hunter RL. Intrastriatal lipopolysaccharide injection induces parkinsonism in C57/B6 mice. J Neurosci Res. 2009; 87(8): 1913-1921. PMid: 19224579. PMCid: PMC2692550.
  44. Tieu K. A guide to neurotoxic animal models of Parkinson's disease. Cold Spring Harb Perspect Med. 2011; 1(1): a009316. PMid: 22229125. PMCid: PMC3234449.
  45. Karymova O, Morozova A, Zorkyna Y, Zubkov E, Ushakova V, Abramova O, et al. Prodepressyvnyy effekt levodopy v modely 6-OHDA-yndutsyrovannogo gemyparkynsonyzma u krys [The processive effect of Levodopa in the model of 6- OHDA -induced hemoparkinsonism in rats]. Almanakh klynycheskoy medytsyny. 2020; 48(1): 22-33. [Russian].
  46. Perlbarg V, Lambert J, Butler B, Felfli M, Valabrègue R, Privat A, et al. Alterations of the nigrostriatal pathway in a 6-OHDA rat model of Parkinson's disease evaluated with multimodal MRI. PLoS One. 2018 Sep 6; 13(9): e02025. PMid: 30188909. PMCid: PMC6126820.
  47. Vieira J, Bassani T, Santiago R, Guaita G, Zanoveli J, Cunha C, et al. Anxiety-like behavior induced by 6-OHDA animal model of Parkinson's disease may be related to a dysregulation of neurotransmitter systems in brain areas related to. anxiety. Behav Brain Res. 2019 Oct 3; 371: 111981. PMid: 31141725.