Временной ход развития дисфункции диафрагмальной мышцы мышей с генетической моделью бокового амиотрофического склероза

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Боковой амиотрофический склероз (БАС) – неизлечимое фатальное нейродегенеративное заболевание, характеризующееся прогрессирующей гибелью верхних (моторная кора головного мозга) и нижних (передние рога спинного мозга и ядра черепно-мозговых нервов) мотонейронов, развитием атрофий, фасцикуляций и параличей скелетных мышц (Brodie et al., 1999, Siklos et al., 1999). Дыхательная недостаточность вследствие пареза и паралича дыхательных мышц является главной причиной смерти при БАС, при этом основное значение в ее развитии имеет патология нижнего мотонейрона (Hanley et al., 1999). Хотя дыхательная недостаточность, как правило, и является причиной смерти при БАС, мало известно о влиянии этого заболевания на «дыхательные» мотонейроны, о последствиях гибели мотонейронов, или о способности системы управления дыханием сопротивляться болезни, с помощью компенсаторных механизмов.

Оглавление

СПИСОК СОКРАЩЕНИЙ............................................................................. 4

ВВЕДЕНИЕ..................................................................................................... 5

ОБЗОР ЛИТЕРАТУРЫ................................................................................... 7

1.1 Боковой амиотрофический склероз....................................................... 7

1.2. Формы бокового амиотрофического склероза..................................... 7

1.3 Этапы развития бокового амиотрофического склероза........................ 9

1.3.1 Продромальный период................................................................... 9

1.3.2 Первые (локальные) симптомы...................................................... 10

1.3.3 Развернутая стадия (стадия генерализации)................................... 10

1.3.4 Финальная стадия............................................................................ 11

1.3.5 Этап продленной жизни................................................................. 12

1.4 Патофизиологические механизмы бокового амиотрофического склероза

.............................................................................................................................. 12

1.5 Причины возникновения бокового амиотрофического склероза: современные гипотезы............................................................................... 13

1.6 Клиническая картина бокового амиотрофического склероза.............. 15

1.6.1 Синдромы верхнего и нижнего мотонейронов.............................. 15

1.6.2 Бульбарные и псевдобульбарные симптомы.................................. 16

1.6.3 Дыхательные нарушения................................................................ 17

1.6.4 Слабость дыхательных мышц........................................................ 19

1.6.5 Механизмы компенсаторной дыхательной пластичности при боковом амиотрофическом склерозе..................................................................... 23

1.7 Нервно-мышечное соединение в качестве уязвимой мишени бокового амиотрофического склероза....................................................................... 24

1.8 Фермент SOD1, как фактор развития болезни..................................... 27

1.9 Трансгенные животные, как удобные и адекватные модели бокового амиотрофического склероза....................................................................... 28

ЭКСПЕРИМЕНТАЛЬНАЯ ЧАСТЬ.............................................................. 29

2    МАТЕРИАЛЫ И МЕТОДЫ..................................................................... 29

2.1   Объекты исследования......................................................................... 29

2.2   Растворы............................................................................................... 29

2.3   Модель бокового амиотрофического склероза.................................. 29

2.4 Миография............................................................................................ 30

2.5 Электрофизиология.............................................................................. 31

2.5.1 Методы регистрации синаптических сигналов............................... 31

2.5.1.1 Изготовление электродов............................................................ 32

2.5.1.2 Изготовление микроэлектродов из стеклянной трубочки          33

2.5.2 Стимуляция двигательного нерва.................................................. 34

2.5.3 Анализ синаптических сигналов..................................................... 34

3 РЕЗУЛЬТАТЫ И ОБСУЖДЕНИЕ............................................................. 35

3.1.1 Сократительные параметры мышцы в группе мышей дикого типа. 35

3.1.2 Сократительные параметры мышцы у mSOD1 на досимптомной, симптомной и терминальной стадиях болезни.......................................... 39

3.2 Результаты электрофизиологических исследований........................... 53

3.3                        Обсуждение результатов............................................................. 63

ВЫВОДЫ...................................................................................................... 66

ЗАКЛЮЧЕНИЕ............................................................................................. 67

СПИСОК ИСПОЛЬЗОВАННОЙ ЛИТЕРАТУРЫ....................................... 69

1.    Завалишин, И.А. Боковой амиотрофический склероз: руководство для врачей

/И.А. Завалишин // М.- ООО «ИИА «Евразия+»».- 2007.- C. 66-250.

2.    Попова, Л.М. Амиотрофический боковой склероз в условиях продленной жизни /Л.М. Попова // М.- Медицина.- 1998.- 144.

3.    Хондкариан, О.А. Боковой амиотрофический склероз / О.А. Хондкариан, Т.Л. Бунина, И.А. Завалишин // М.- Медицина.- 1978.- C. 264.

4.    Хондкариан, О.А. К вопросу о классификации бокового амиотрофического склероза (клинико-электромиографическое исследование) / О.А. Хондкариан, И.А. Завалишин, В.П. Новикова // Журнал неврологии и психиатрии им. С.С. Корсакова.- 1983.- 6.- C. 877-880

5.     Amano, T. Production of nerve growth factor in rat skeletal muscle /T. Amano // Neurosci Lett. - 1991. - V. 132. - P. 5-7

6.    Andersen, P.M. Sixteen novel mutations in the Cu/Zn superoxide dismutase gene in amyotrophic lateral sclerosis: a decade of discoveries, defects and disputes /P.M. Andersen // Amyotroph Lateral Scler Other Motor Neuron Disord. - 2003. - V. 4. - P. 62-73

7.    Belli, S. Proportionate mortality of Italian soccer players: is amyotrophic lateral sclerosis an occupational disease? / S. Belli, N. Vanacore // Eur. J. Epidemiol.- 2005.- V. 20.- 237-242

8.    Benditt, J.O. The neuromuscular respiratory system: physiology, pathophysiology, and a respiratory care approach to patients /J.O. Benditt // Respir Care. - 2006. - V. 51. - P. 829-837; discussion 837-829

9.    Brodie, M.S. Ethanol directly excites dopaminergic ventral tegmental area reward neurons /M.S. Brodie, C. Pesold and S.B. Appel // Alcohol Clin Exp Res. - 1999. - V. 23. - P. 1848-1852

10. Brooks, B.R. Natural history of amyotrophic lateral sclerosis. Quantification of symptoms, signs, strength, and function /B.R. Brooks // Adv Neurol. - 1995. - V. 68. - P. 163-184

11. Brooks, B.R. The role of axonal transport in neurodegenerative disease spread: a meta-analysis of experimental and clinical poliomyelitis compares with amyotrophic lateral sclerosis /B.R. Brooks // Can J Neurol Sci. - 1991. - V. 18. - P. 435-438

12.       Brown, M. Motor nerver sprouting /M. Brown, R. Holland, W. Hopkins // Ann.

Rev. Neurosci. - 1981. - V. 4. – P. 17-42.

13. Brown, R.H. SOD1 aggregates in ALS: cause, correlate or consequence? /R.H. Brown, Jr. // Nat Med. - 1998. - V. 4. - P. 1362-1364

14. Bruijn, L.I. Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1 /L.I. Bruijn // Science. - 1998. - V. 281.

- P. 1851-1854

15. Bruijn, L.I. Elevated free nitrotyrosine levels, but not protein-bound nitrotyrosine or hydroxyl radicals, throughout amyotrophic lateral sclerosis (ALS)-like disease implicate tyrosine nitration as an aberrant in vivo property of one familial ALS- linked superoxide dismutase 1 mutant /L.I. Bruijn // Proc Natl Acad Sci U S A. - 1997. - V. 94. - P. 7606-7611

16. Buffelli, M. Paralysis of rat skeletal muscle equally affects contractile properties as does permanent denervation /M. Buffelli, E. Pasino and A. Cangiano // J Muscle Res Cell Motil. - 1997. - V. 18. - P. 683-695

17. Chio, A. Risk factors in the early diagnosis of ALS: European epidemiological studies / A. Chio // Amyotrop Lateral Scler. and Other Motor Neuron Disord.- 2000.- V. 1.- suppl. 1.- P. 13-18

18. Cifra, A. Respiratory motoneurons and pathological conditions: lessons from hypoglossal motoneurons challenged by excitotoxic or oxidative stress /A. Cifra, F. Nani and A. Nistri // Respir Physiol Neurobiol. - 2011. - V. 179. - P. 89-96

19. Coffman, C. Estimating the occurrence of amyotrophic lateral sclerosis among Gulf War (1990-1991) veterans using capture-recapture methods / C. Coffman, R. Horner, S. Grambow et al. // Neuroepidemiology.- 2005.- V. 24.- P. 141-150

20. Crouch, P.J. Mechanisms of Aβ-mediated neurodegeneration in Alzheimer’s disease /P.J. Crouch, S.M. Harding, A.R. White et al. // Int. J. Biochem. Cell Biol.

- 2008. - V. 40. – P. 181-198.

21. Czerwinski, S.M. Modulation of IGF mRNA abundance during muscle denervation atrophy /S.M. Czerwinski, J. Novakofski and P.J. Bechtel // Med Sci Sports Exerc. - 1993. - V. 25. - P. 1005-1008

22. Dadon-Nachum, M. The "dying-back" phenomenon of motor neurons in ALS /M. Dadon-Nachum, E. Melamed and D. Offen // J Mol Neurosci. - 2011. - V. 43. - P. 470-477

23. Dupuis, L. Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: benefit of a high-energy diet in a transgenic mouse model /L. Dupuis // Proc Natl Acad Sci U S A. - 2004. - V. 101. - P. 11159-11164

24. Dupuis, L. Neuromuscular junction destruction during amyotrophic lateral sclerosis: insights from transgenic models /L. Dupuis and J.P. Loeffler // Curr Opin Pharmacol. - 2009. - V. 9. - P. 341-346

25. Dupuis, L. Nogo provides a molecular marker for diagnosis of amyotrophic lateral sclerosis /L. Dupuis // Neurobiol Dis. - 2002. - V. 10. - P. 358-365

26. Elliott, J.L. Cytokine upregulation in a murine model of familial amyotrophic lateral sclerosis /J.L. Elliott // Brain Res Mol Brain Res. - 2001. - V. 95. - P. 172- 178

27. Fischer, L.R. Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man /L.R. Fischer // Exp Neurol. - 2004. - V. 185. - P. 232-240

28. Fowler, K.J. Combined hepatocellular and cholangiocarcinoma (biphenotypic) tumors: imaging features and diagnostic accuracy of contrast-enhanced CT and MRI /K.J. Fowler // AJR Am J Roentgenol. - 2013. - V. 201. - P. 332-339

29. Frey, D. Early and selective loss of neuromuscular synapse subtypes with low sprouting competence in motoneuron diseases /D. Frey // J Neurosci. - 2000. - V. 20. - P. 2534-2542

30. Gordon, T. Adaptive and maladaptive motor axonal sprouting in aging and motoneuron disease /T. Gordon, J. Hegedus and S.L. Tam // Neurol Res. - 2004. - V. 26. - P. 174-185

31. Govoni, V. Incidence of amyotrophic lateral sclerosis in the local health district of Ferrara, Italy, 1964-1998 / V. Govoni, E. Granieri, J. Capone et al. // Neuroepidemiology.- 2003.- V. 22.- P. 229-234

32. Guillot, S. Local GDNF expression mediated by lentiviral vector protects facial nerve motoneurons but not spinal motoneurons in SOD1(G93A) transgenic mice

/S. Guillot // Neurobiol Dis. - 2004. - V. 16. - P. 139-149

33. Haley, R. Excess incidence of ALS in young Gulf War veterans / R. Haley // Neurology.- 2003.- V. 61.- P. 750-756

34. Hanley, K. Fetal epidermal differentiation and barrier development In vivo is accelerated by nuclear hormone receptor activators /K. Hanley // J Invest Dermatol. - 1999. - V. 113. - P. 788-795

35. Hashimoto, T. Forme fruste or incipient form of widespread-type amyotrophic lateral sclerosis, or motor neuron disease with pallido-nigro-luysian atrophy? An autopsy case report /T. Hashimoto // Neuropathology. - 2008. - V. 28. - P. 309-316 36.Jokic, N. Nogo expression in muscle correlates with amyotrophic lateral sclerosis

severity /N. Jokic // Ann Neurol. - 2005. - V. 57. - P. 553-556

37. Jokic, N. The neurite outgrowth inhibitor Nogo-A promotes denervation in an amyotrophic lateral sclerosis model /N. Jokic // EMBO Rep. - 2006. - V. 7. - P. 1162-1167

38. Kiernan, M.C. Amyotrophic lateral sclerosis /M.C. Kiernan // Lancet. - 2011. - V.

377. - P. 942-955

39. Kobayashi, Z. FALS with Gly72Ser mutation in SOD1 gene: report of a family including the first autopsy case /Z. Kobayashi // J Neurol Sci. - 2011. - V. 300. - P. 9-13

40. Koliatsos, V.E. Evidence that brain-derived neurotrophic factor is a trophic factor for motor neurons in vivo /V.E. Koliatsos // Neuron. - 1993. - V. 10. - P. 359-367 41.Kondo, K. Case-control studies of motor neuron disease: Association with

mechanical injuries / K. Kondo, T. Tsubaki // Arch. Neurol.- 1981.- V. 38.- P. 220- 226

42. Kraft, A.D. Activation of the Nrf2-ARE pathway in muscle and spinal cord during ALS-like pathology in mice expressing mutant SOD1 /A.D. Kraft // Exp Neurol. - 2007. - V. 207. - P. 107-117

43. Krakora, D. Neuromuscular junction protection for the potential treatment of amyotrophic lateral sclerosis /D. Krakora, C. Macrander and M. Suzuki // Neurol Res Int. - 2012. - V. 2012. - P. 379657

44. Kunst, C.B. Complex genetics of amyotrophic lateral sclerosis /C.B. Kunst // Am J Hum Genet. - 2004. - V. 75. - P. 933-947

45. Lechtzin, N. Respiratory effects of amyotrophic lateral sclerosis: problems and solutions /N. Lechtzin // Respir Care. - 2006. - V. 51. - P. 871-881; discussion 881- 874

46. Li, J. Electromyography of sternocleidomastoid muscle in ALS: a prospective study /J. Li // Muscle Nerve. - 2002. - V. 25. - P. 725-728

47. Lie, D.C. GDNF expression is increased in denervated human skeletal muscle

/D.C. Lie and J. Weis // Neurosci Lett. - 1998. - V. 250. - P. 87-90

48. Llado, J. Degeneration of respiratory motor neurons in the SOD1 G93A transgenic rat model of ALS /J. Llado // Neurobiol Dis. - 2006. - V. 21. - P. 110-118

49. Lyall, R.A. Respiratory muscle strength and ventilatory failure in amyotrophic lateral sclerosis /R.A. Lyall // Brain. - 2001. - V. 124. - P. 2000-2013

50. Marti-Fabregas, J. Respiratory function deterioration is not time-linked with upper- limb onset in amyotrophic lateral sclerosis /J. Marti-Fabregas // Acta Neurol Scand. - 1995. - V. 92. - P. 261-264

51. Mattson, M.P. Energy intake and amyotrophic lateral sclerosis /M.P. Mattson, R.G. Cutler and S. Camandola // Neuromolecular Med. - 2007. - V. 9. - P. 17-20

52. Miscio, G. The cortico-diaphragmatic pathway involvement in amyotrophic lateral sclerosis: neurophysiological, respiratory and clinical considerations /G. Miscio // J Neurol Sci. - 2006. - V. 251. - P. 10-16

53. Mitsumoto, H. Amyotrophic lateral sclerosis / H. Mitsumoto, D. Chad, E. Pioro // Davis Philadelphia Company.- 1998.- V. 480

54. Motoi, Y. A 49-year-old man with progressive bulbar palsy and respiratory failure

/Y. Motoi // No To Shinkei. - 1998. - V. 50. - P. 93-100

55. Mukhamedyarov, M.A. Analysis of the efficiency of gene-cell therapy in transgenic mice with amyotrophic lateral sclerosis phenotype /M.A. Mukhamedyarov // Bull Exp Biol Med. - 2013. - V. 154. - P. 558-561

56. Naumenko, N. Gender-Specific Mechanism of Synaptic Impairment and Its Prevention by GCSF in a Mouse Model of ALS /N. Naumenko // Front Cell Neurosci. - 2011. - V. 5. - P. 26

57. Nichols, N.L. Intermittent hypoxia and stem cell implants preserve breathing capacity in a rodent model of amyotrophic lateral sclerosis /N.L. Nichols // Am J Respir Crit Care Med. - 2013. - V. 187. - P. 535-542

58. Nichols, N.L. Ventilatory control in ALS /N.L. Nichols // Respir Physiol Neurobiol. - 2013. - V. 189. - P. 429-437

59. Norris, F. Onset, natural history and outcome in idiopathic, adult motor neuron disease / F. Norris, R. Shepherd, E. Denys et al. // J. Neurol. Sci.- 1993.- V. 118.- P. 48-55

60. Pellegrino, C. An Electron Microscope Study of Denervation Atrophy in Red and White Skeletal Muscle Fibers /C. Pellegrino and C. Franzini // J Cell Biol. - 1963. - V. 17. - P. 327-349

61. Pinto, S. Changes of the phrenic nerve motor response in amyotrophic lateral sclerosis: longitudinal study /S. Pinto // Clin Neurophysiol. - 2009. - V. 120. - P. 2082-2085

62. Pollari, E. The role of oxidative stress in degeneration of the neuromuscular junction in amyotrophic lateral sclerosis /E. Pollari // Front Cell Neurosci. - 2014. - V. 8. - P. 131

63. Pradat, P.F. Muscle Nogo-A expression is a prognostic marker in lower motor neuron syndromes /P.F. Pradat // Ann Neurol. - 2007. - V. 62. - P. 15-20

64. Pun, S. Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF /S. Pun // Nat Neurosci. - 2006. - V. 9. - P. 408-419

65. Rocha, J.A. Diagnostic investigation and multidisciplinary management in motor neuron disease /J.A. Rocha // J Neurol. - 2005. - V. 252. - P. 1435-1447

66. Rocha, M.C. Early changes of neuromuscular transmission in the SOD1(G93A) mice model of ALS start long before motor symptoms onset /M.C. Rocha // PLoS One. - 2013. - V. 8. - P. e73846

67. Rosen, D. R. Mutation in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis / D. R. Rosen, T. Siddique, D. Patterson, et al. // Nature.- 1993.- V. 362.- P. 59-62

68. Sakuma, K. The recent understanding of the neurotrophin's role in skeletal muscle adaptation /K. Sakuma and A. Yamaguchi // J Biomed Biotechnol. - 2011. - V. 2011. - P. 201-696

69. Schaefer, A.M. A compensatory subpopulation of motor neurons in a mouse model of amyotrophic lateral sclerosis /A.M. Schaefer, J.R. Sanes and J.W. Lichtman // J Comp Neurol. - 2005. - V. 490. - P. 209-219

70. Schmalbruch, H. Dynamics of nuclei of muscle fibers and connective tissue cells in normal and denervated rat muscles /H. Schmalbruch and D.M. Lewis // Muscle Nerve. - 2000. - V. 23. - P. 617-626

71. Shimizu, T. Electrophysiological assessment of corticorespiratory pathway function in amyotrophic lateral sclerosis /T. Shimizu // Amyotroph Lateral Scler. - 2010. - V. 11. - P. 57-62

72. Sieck, G.C. Physiological effects of diaphragm muscle denervation and disuse

/G.C. Sieck // Clin Chest Med. - 1994. - V. 15. - P. 641-659

73. Siklos, L. Calcium-containing endosomes at oculomotor terminals in animal models of ALS /L. Siklos // Neuroreport. - 1999. - V. 10. - P. 2539-2545

74. Sirdofsky, M. Progressive motor neuron disease associated with electrical injury /

M. Sirdofsky, R. Hawley, H. Manz // Muscle Nerve.- 1991.- V. 14.- P. 977-980 75.Smith, P.E. Practical problems in the respiratory care of patients with muscular

dystrophy /P.E. Smith // N Engl J Med. - 1987. - V. 316. - P. 1197-1205 76.Smittkamp,  S.E.  Measures  of  bulbar  and  spinal  motor  function,  muscle

innervation, and mitochondrial function in ALS rats /S.E. Smittkamp // Behav Brain Res. - 2010. - V. 211. - P. 48-57

77. Sobue, G. Degenerating compartment and functioning compartment of motor neurons in ALS: possible process of motor neuron loss /G. Sobue // Neurology. - 1983. - V. 33. - P. 654-657

78. Stonnington, H.H. Normal and denervated muscle. A morphometric study of fine structure /H.H. Stonnington and A.G. Engel // Neurology. - 1973. - V. 23. - P. 714- 724

79. Stya, M. Mobility of extrajunctional acetylcholine receptors on denervated adult muscle fibers /M. Stya and D. Axelrod // J Neurosci. - 1984. - V. 4. - P. 70-74

80. Su, M. An autopsy case of amyotrophic lateral sclerosis with concomitant Alzheimer's and incidental Lewy body diseases /M. Su // No To Shinkei. - 1996. - V. 48. - P. 931-936

81. Sunderland, S. Denervation changes in mammalian striated muscle /S. Sunderland and L.J. Ray // J Neurol Neurosurg Psychiatry. - 1950. - V. 13. - P. 159-177

82. Sutedja, N.A. Exposure to chemicals and metals and risk of amyotrophic lateral sclerosis: a systematic review /N.A. Sutedja // Amyotroph Lateral Scler. - 2009. - V. 10. - P. 302-309

83. Suzuki, M. Direct muscle delivery of GDNF with human mesenchymal stem cells improves motor neuron survival and function in a rat model of familial ALS /M. Suzuki // Mol Ther. - 2008. - V. 16. - P. 2002-2010

84. Tankersley, C.G. Respiratory impairment in a mouse model of amyotrophic lateral sclerosis /C.G. Tankersley, C. Haenggeli and J.D. Rothstein // J Appl Physiol (1985). - 2007. - V. 102. - P. 926-932

85. Testa, D. Survival of 793 patients with amyotrophic lateral sclerosis diagnosed over a 28-year period / D. Testa, R. Lovati, M. Ferrarini et al. // Amyotrop Lateral Scler. and Other Motor Neuron Disord.- 2004.- V. 5.- P. 208-212

86. Tsuchiya, K. Sporadic amyotrophic lateral sclerosis with circumscribed temporal atrophy: a report of an autopsy case without dementia and with ubiquitinated intraneuronal inclusions /K. Tsuchiya // Neuropathology. - 2002. - V. 22. - P. 308- 316

87. Valdez, G. Shared resistance to aging and ALS in neuromuscular junctions of specific muscles /G. Valdez // PLoS One. - 2012. - V. 7. - P. e34640

88. Williamson, T.L. Absence of neurofilaments reduces the selective vulnerability of motor neurons and slows disease caused by a familial amyotrophic lateral sclerosis-linked superoxide dismutase 1 mutant /T.L. Williamson // Proc Natl Acad Sci U S A. - 1998. - V. 95. - P. 9631-9636

89. Wong, M. Skeletal muscle-restricted expression of human SOD1 causes motor neuron degeneration in transgenic mice /M. Wong and L.J. Martin // Hum Mol Genet. - 2010. - V. 19. - P. 2284-2302

90. Wong, P.C. An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria /P.C. Wong // Neuron. - 1995. - V. 14. - P. 1105-1116

91. Worms, P. The epidemiology of motor neuron diseases: a review of recent studies / P. Worms // J. Neurol. Sci.- 2001.- V. 191.- P. 3-9

92. Xu, Y.S. Upper trapezius electromyography aids in the early diagnosis of bulbar involvement in amyotrophic lateral sclerosis /Y.S. Xu // Amyotroph Lateral Scler.

- 2011. - V. 12. - P. 345-348

93. Young, R. Spasticity: a review / R. Young // Neurology.- 1994.- V. 44(suppl. 9).- P. 12-20