Publikationsserver der Universitätsbibliothek Marburg

Titel:Hat intrathekal appliziertes Baclofen (Lioresal) einen neuroprotektiven Effekt im 4-Gefäßverschlussmodell der Ratte?
Autor:Stubenvoll, Florian Michael
Weitere Beteiligte: Becker, Ralf (Prof. Dr.)
URN: urn:nbn:de:hebis:04-z2015-05837
DDC: Medizin
Titel (trans.):Does intrathecally administered Baclofen (Lioresal) have a neuroprotective effect in the 4-vessel occlusion model in the rat?


Lioresal, vessel occlusion model, Neurochirurgie, Ischämie, intrathekal, Stereotaxie, Zerebrale Ischämie, neuroprotection, Neuroprotektion, Hippocampus, Baclofen, intrathecal, Ratte, Hirnchirurgie, Lioresal, Gefäßverschlussmodell, excitotoxicity, Exzitotoxizität

Einleitung: Im 4-Gefäßverschlussmodell der Ratte wird überprüft, ob intrathekal appliziertes Baclofen einen neuroprotektiven Effekt hat. Material und Methoden: Hierzu werden zunächst 1µg/5µl Baclofen über 5 Minuten beginnend 30 Minuten vor einer 10-minütigen zerebralen Ischämie bei männlichen Wistar-Ratten intrazerebroventrikulär appliziert und gegen eine Kontrollgruppe verglichen, dann werden 2µg/5µl Baclofen über 5 Minuten beginnend 30 Minuten nach einer 10-minütigen zerebralen Ischämie bei männlichen Wistar-Ratten intrazerebroventrikulär appliziert und gegen eine Kontrollgruppe verglichen. Lichtmikroskpisch durch Auszählen quantifiziert werden die geschädigten Pyramidenzellen und ins Verhältnis gesetzt zu den gesamten Pyramidenzellen in einem histologisch aufgearbeiteten Hirnschnitt durch das CA1- bis CA3-Band des Hippocampus. Resultat: Baclofen hat in der o.g. Dosierung und Applikationsform präischämisch einen signifikant schädigenden Effekt, während es postischämisch appliziert keinen signifikant neuroprotektiven Effekt hat.

Bibliographie / References

  1. Price, G. W., Kelly, J. S. and Bowery, N. G., The location of GABA B receptor binding sites in mammalian spinal cord. Synapse, 1987. 1(6): p. 530-8.
  2. Miyazawa, T. et al., Heating of the brain to maintain normothermia during ischemia aggravates brain injury in the rat. Acta Neuropathol (Berl), 1993. 85(5): p. 488-94.
  3. Pluta, R., et al., Reassessment of a new model of complete cerebral ischemia in rats.
  4. Smith, M. L., Auer, R. N., Siesjo, B. K., The density and distribution of ischemic brain injury in the rat following 2-10 min of forebrain ischemia. Acta Neuropathol (Berl), 1984. 64 (4): p. 319-32.
  5. Van Reempts, J., The hypoxic brain: histological and ultrastructural aspects. Behav Brain Res, 1984. 14(2): p. 99-108.
  6. Li, P. A., et al., The influence of plasma glucose concentrations on ischemic brain damage is a threshold function. Neurosci Lett, 1994. 177(12-): p. 63-5.
  7. Xu, Z. C. and Pulsinelli, W. A., Responses of CA1 pyramidal neurons in rat hippocampus to transient forebrain ischemia: an in vivo intracellular recording study.
  8. Mitani, A. and Kataoka, K., Critical levels of extracellular glutamate mediating gerbil hippocampal delayed neuronal death during hyperthermia: brain microdialysis study.
  9. Mennel, H. D., et al., Morphology of tissue damage due to experimental cerebral ischemia in rats. Exp Pathol, 1988. 35(4) p. 219-30.
  10. Nakamura, T., et al., Increased intracellular Ca 2+ concentration in the hippocampal CA1 area during global ischemia and reperfusion in the rat: a possible cause of delayed neuronal death. Neuroscience, 1999. 88(1): 57-67.
  11. Gudermann, T., et al., Specificity and complexity of receptor-G-protein interaction.
  12. Dietrich, W. D., et al., The importance of brain temperature in alterations of the blood-brain barrier following cerebral ischemia. J Neuropathol Exp Neurol, 1990. 49(5): p. 486-97.
  13. Li, D. P. and Pan, H. L., Role of gamma-aminobutyric acid (GABA) A and GABA B receptors in paraventricular nucleus in control of sympathetic vasomotor tone in hypertension. J Pharmacol Exp Ther, 2007. 320(2): p. 615-26.
  14. Cotran, S., Kumar, V. and Collins, T., Robbins pathologic basis of disease. 7th ed Vol.
  15. Trippodo, N. C., Yamamoto, J. and Frolich, E. D., Whole body venous capacity and effective total tissue compliance in SHR. Hypertension, 1981. 3(1): p. 104-12.
  16. Pulsinelli, W. A. and Buchan, A. M., The four-vessel occlusion rat model: method for complete occlusion of vertebral arteries and control of collateral circulation. Stroke, 1988. 19(7): p. 913-4.
  17. Koch, H. J., Szecsey, A. and Haen, E., NMDA-antagonism (memantine): an alternative pharmacological therapeutic principle in Alzheimer's and vascular dementia. Curr Pharm Des, 2004. 10(3): p. 253-9.
  18. Verhaegen, M., Iaizzo, P. A. and Todd, M. M., A comparison of the effects of hypothermia, pentobarbital, and isoflurane on cerebral energy stores at the time of ischemic depolarization. Anesthesiology, 1995. 82(5): p. 1209-15.
  19. Sallerin, B. and Lazorthes, Y., Intrathecal baclofen. Experimental and pharmacokinetic studies. Neurochirurgie, 2003. 49(2-3 Pt 2): p. 271-5.
  20. Wahlestedt, C., et al., Antisense oligodeoynucleotides to NMDA-R1 receptor channel protect cortical neurons from excitotoxicity and reduce focal ischemic infarctions. Nature, 1993. 363(6426): p. 260-3.
  21. Petito, C. K., et al., DNA fragmentation follows delayed neuronal death in CA1 neurons exposed to transient global ischemia in the rat. J Cereb Blood Flow Metab, 1997. 17(9): p. 967-76.
  22. Walton, M., et al., Annexin V labels apoptotic neurons following hypoxia-ischemia. Neuroreport, 1997. 8(18): p. 3871-5.
  23. Kirino, T. and Sano, K., Fine structural nature of delayed neuronal death following ischemia in the gerbil hippocampus. Acta Neuropathol (Berl), 1984. 62(3): p. 209-18.
  24. Lehmann, A., et al., Effects of repeated administration of baclofen to rats on GABA B receptor binding sites and subunit expression in the brain. Neurochem Res, 2003. 28(2): p. 387-93.
  25. Hill, D. R. and Bowery, N. G., 3H-baclofen and 3H-GABA bind to bicuculline- insensitive GABA B sites in rat brain. Nature, 1981. 290(5802): p. 149-52.
  26. Ludolph, A., 4-VOM of the rat for global cerebral ischemia. Unpublished poster, 2002.
  27. Angenommen vom Fachbereich Medizin der Philipps-Universität Marburg am: 20. Oktober 2015
  28. Ochs, G. A. and Reimann, I. W., Baclofen Intrathekal – Leitfaden für die praktische Anwendung. 2., vollständig überarbeitete Auflage ed. 2004, Stuttgart; New York: Georg Thieme Verlag. 120 S., 24 Abb.
  29. Obrenovitch, T. P., Richards, D. A., Extracellular neurotransmitter changes in cerebral ischemia. Cerebrovasc Brain Metab Rev, 1995. 7(1): p. 1-54.
  30. Marshall, F. H., et al., GABA B receptors – the first 7TM heterodimers. Trends Pharmacol Sci, 1999. 20(10): p. 396-9.
  31. Zornow, M. H., Inhibition of glutamate release: a possible mechanism of hyperthermic neuroprotection. J Neurosurg Anesthesiol, 1995. 7(2): p. 148-51.
  32. Method of induction of clinical death, pathophysiology and cerebrovascular pathology.
  33. Minamisawa, H., et al., Preservation of brain temperature during ischemia in rats. Stroke, 1990. 21(5): p. 758-64.
  34. Gudermann, T., Nurnberg, B. and Schultz, G., Receptors and G proteins as primary components of transmembrane signal transduction. Part 2. G proteins: structure and function. J Mol Med, 1995. 73(2): p. 51-63.
  35. Kroin, J. S., et al., Reduced spinal reflexes following intrathecal baclofen in the rabbit. Exp Brain Res, 1984. 54(1): p. 191-4.
  36. Heron, A., et al., Regional variability in DNA fragmentation after global ischemia evidenced by combined histological and gel electrophoresis observations in the rat brain. J Neurochem, 1993. 61(5): p. 1973-6.
  37. Ginsberg, M. D. and Busto, R., Rodent models of cerebral ischemia. Stroke, 1989. 20(12): p. 1627-42.
  38. Busto, R., et al., Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury. J Cereb Blood Flow Metab, 1987. 7(6): p. 729-38.
  39. Somjen, G. G., et al., Spreading depression-like depolarization and selective vulnerability of neurons. A brief review. Stroke, 1990. 21(11 suppl): p. III 179-83.
  40. Olpe, H. R., et al., The biological activity of d-and l-baclofen (Lioresal). Eur J Pharmacol, 1978. 52(1): p. 133-6.
  41. Minamisawa, H., Smith, M. L., Siesjo, B. K., The effect of mild hyperthermia and hypothermia on brain damage following 5, 10, and 15 minutes of forebrain ischemia. Ann Neuro., 1990. 28(1): p. 26-33.
  42. Minamisawa, H., et al., The influence of mild body and brain hypothermia on ischemic brain damages. J Cereb Blood Flow Metab, 1990. 10(3): p. 365-75.
  43. Nixon, R. A. and Cataldo, A. M., The lysosomal system in neuronal cell death: a review. Ann N Y Acad Sci, 1993. 679: p. 87-109.
  44. Paxinos, G. and Watson, C., The rat brain in stereotaxic coordinates. 1986, New York, Sydney: Academic Press, Inc.
  45. Ritter, A. M., et al., Evaluation of carbohydrate-free diet for patients with severe head injury. J Neurotrauma, 1996. 13(8): p. 473-85.
  46. Nicholls, D. G., Budd, S. L., Neuronal excitotoxicity: the role of mitochondria. Biofactors, 1998. 8(3-4): p. 287-99.
  47. Poncer, J. C., et al., Differential control of GABA release at synapses from distinct interneurons in rat hippocampus. J. Physiol, 2000. 528(1): p. 123-30.
  48. Bowery, N. G., et al., International Union of Pharmacology. XXIII. Mammalian gamma-aminobutyric acid (B) receptors: structure and function. Pharmacol Rev, 2002. 54(2): p. 247-64.
  49. Lipton, P., Ischemic cell death in brain neurons. Physiol Rev, 1999. 79(4): p. 1431- 568.
  50. Nicoll, R. A., Malenka, R. C. and Kauer, J. A., Functional comparison of neurotransmitter receptor subtypes in mammalian central nervous system. Physiol Rev, 1990. 70(2): p. 513-65.
  51. Olney, J., Brain-lesions obesity, and other disturbances in mice treated with monosodium glutamate. Science, 1969. 164: p. 719-21.
  52. Kameyama, M., et al., A new model of bilateral hemispheric ischemia in the rat-three vessel occlusion model. Stroke, 1985. 16(3): p. 267-72.
  53. Kirino, T., Tamura, A. and Sano, K., A reversible type of neuronal injury following ischemia in the gerbil hippocampus. Stroke, 1986. 17(3): p. 455-9.
  54. de Courten-Myers, G., Myers, R. E., Schoolfield, L., Hyperglycemia enlarges infarct size in cerebrovascular occlusion in cats. Stroke, 1988. 19(5): p. 623-30.
  55. Busto, R., et al., Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain. Stroke, 1989. 20(7): p. 904-10.
  56. Nagasawa, H. and Kogure, K., Correlation between cerebral blood flow and histologic changes in a new rat model of middle cerebral artery occlusion. Stroke, 1989. 20(8): p. 1037-43.
  57. Rosenbaum, D. M., et al., Baclofen does not protect against cerebral ischemia in rats.
  58. Zhang, R. L., et al., Postischemic (1 hour) hypothermia significantly reduces ischemic cell damage in rats subjected to 2 hours of middle cerebral artery occlusion. Stroke, 1993. 24(8): p. 1235-40.
  59. Li, Y., et al., Induction of DNA fragmentation after 10 to 120 minutes of focal cerebral ischemia in rats. Stroke, 1995. 26(7): p. 1252-8.
  60. Kim, Y., et al., Delayed postischemic hyperthermia in awake rats worsens the histopathological outcome of transient focal cerebral ischemia. Stroke, 1996. 27(12): p. 2274-80; discussion 2281.
  61. Corbett, D., Nurse, S. and Colbourne, F., Hypothermic neuroprotection. A global ischemia study using 18-to 20-month-old gerbils. Stroke, 1997. 28(11): p. 2238-42; discussion 2243.
  62. Payan, H. M. and Conrad, J. R., Carotid ligation in gerbils. Influence of age, sex and gonades. Stroke, 1977. 8(2): p. 194-6.
  63. Lobner, D. and Lipton, P., Intracellular calcium levels and calcium fluxes in the CA1 region of the rat hippocampal slice during in vitro ischemia: relationship to electrophysiological cell damage. J Neurosci, 1993. 13(11): p. 4861-71.
  64. Hartley, D., et al., Glutamate receptor induced 45CA 2+ accumulation in cortical cell culture correlates with subsequent neuronal degeneration. Journal Neurosci, 1993. 13(5): p. 1993-2000.
  65. Nitatori, T., et al., Delayed neuronal death in the CA1 pyramidal cell layer of the gerbil hippocampus following transient ischemia is apoptosis. J Neuosci, 1995. 15(2): p. 1001-11.
  66. Colbourne, F., Sutherland, G. R. and Auer, R. N., Electron microscopic evidence against apoptosis as the mechanism of neuronal death in global ischemia. J Neurosci, 1999. 19(11): p. 42100-10.
  67. Wahlgren, N. G. and Ahmed, N., Neuroprotection in cerebral ischemia. Facts and fancies – the need for new approaches. Cerebrovascular Disease, 2004. 17(Suppl 1): p. 153-66.
  68. Wagner, K. R., et al., Hyperglycemic versus normoglycemic stroke: topography of brain metabolites, intracellular pH, and infarct size. J Cereb Blood Flow Metab, 1992. 12(2): p. 213-22.
  69. Majno, G. and Joris, I., Apoptosis, oncosis, and necrosis. An overview of cell death.
  70. Pulsinelli, W. A., et al., Moderate hyperglycemia augments ischemic brain damage: a neuropathologic study in the rat. Neurology, 1982. 32(11): p. 1239-46.
  71. Sakhi, S., et al., p53 induction is associated with neuronal damage in the central nervous system. Proc Natl Acad Sci U S A, 1994. 91(16): p. 7525-9.
  72. Kirino, T., Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res, 1982. 239(1): p. 57-69.
  73. Freund, T. F., et al., Hippocampal cell death following ischemia: effects of brain temperature and anesthesia. Exp Neurol, 1990. 108(3): p. 251-60.
  74. Kristian, T. and Siesjo, B. K., Calcium-related damage in ischemia. Life Sci, 1996. 59(5-6): p. 357-67.
  75. MacManus, J. P., et al., Global ischemia can cause DNA fragmentation indicative of apoptosis in rat brain. Neurosci Lett, 1993. 164(1-2): p. 89-92.
  76. Bowery, N. G., Hudson, A. L. and Price, G. W., GABA A and GABA B receptor site distribution in the rat central nervous system. Neuroscience, 1987. 20(2): p. 365-83.
  77. Chu, D. C., et al., Distribution and kinetics of GABA B binding sites in rat central nervous system: a quantitative autoradiographic study. Neuroscience, 1990. 34(2): p. 341-57.
  78. Nicoll, R. A., My close encounter with GABA B receptors. Biochem Pharmacol, 2004. 68(8): p. 1667-74.
  79. Brambrink, A. L., et al., Control of brain temperature during experimental global ischemia in rats. J Neurosci Methods, 1999. 92(1-2): p. 111-22.
  80. Friedman, L. K., et al., Intraischemic but not postischemic hypothermia prevents non- selective hippocampal downregulation of AMPA and NMDA receptor gene expression after global ischemia. Brain Res Mol Brain Res, 2001. 86(1-2): p. 34-47.
  81. Martin, L. J., et al., Neurodegeneration in excitotoxicity, global cerebral ischemia, and target deprivation: A perspective on the contributions of apoptosis and necrosis. Brai Res Bull, 1998. 46(4): p. 281-309.

* Das Dokument ist im Internet frei zugänglich - Hinweise zu den Nutzungsrechten