Mechanismen der Nervenregeneration im ZNS - Fortschritte in der experimentellen Paraplegiologie

Zusammenfassung

Traumatisch bedingte Rückenmarkverletzungen führen sehr häufig zu einem lebenslangen Querschnittsyndrom, wobei die Ursache im Ausbleiben einer funktionell ausreichenden Regeneration verletzter Nervenfasern im ZNS liegt. In den letzten 10 - 15 Jahren wurden wesentliche Erkenntnisse zum Verständnis der zugrunde liegenden zellulären und molekularen Mechanismen gewonnen. In diesem Zusammenhang wurden zahlreiche Moleküle mit wachstumsfördernden und wachstumshemmenden Eigenschaften identifiziert. Diese neuen Erkenntnisse führten zu der Entwicklung zahlreicher experimenteller Therapiestrategien, die mit erheblich verbesserten motorischen Funktionen einhergingen. Auf dieser Grundlage werden bereits einige klinische Studien geplant. Trotzdem existieren weiterhin große Wissenslücken, unter welchen Bedingungen diese Therapiestrategien auf die individuellen Situationen akut oder chronisch querschnittgelähmter Patienten angepasst werden können.

Mechanism of Nerve Regeneration in the CNS - Progress in Experimental Paraplegiology

Traumatic spinal cord injury (SCI) usually leads to permanent motor and sensory deficits. This is due to a lack of any functionally significant regeneration of severed nerve fibres within the adult central nervous system (CNS). The last 10 - 15 years have witnessed remarkable progress in understanding the cellular and molecular mechanisms which contribute to the failure of CNS axon regeneration. In this context, several substances with growth promoting or growth inhibiting properties have been identified. This has led to the development of a number of experimental intervention strategies, many of which have promoted a substantial degree of improved motor function. This knowledge has already resulted in the planning of clinical trials. Nonetheless, there are still substantial gaps in the detailed understanding of how such intervention strategies should be applied to meet the individual circumstances of patients with acute or chronic SCI.

Literatur

• 1 Ramón y Cajal S. Degeneration and regeneration of the nervous system. New York; Hafner 1928 (Neuauflage: Oxford: University Press 1991)
• 2 Schwab M E, Thoenen H. Dissociated neurons regenerate into sciatic but not in optic nerve explants in culture irrespective of neurotrophic factors.  J Neuroscience. 1985;  5 2415-2423
• 3 Caroni P, Schwab M E. Two membrane protein fractions from rat central myelin with inhibitory properties for neurite growth and fibroblast spreading.  J Cell Biol. 1988;  106 1281-1288
• 4 Schnell L, Schwab M E. Axonal regeneration in the rat spinal cord produced by an antibody against myelin-associated neurite growth inhibitors.  Nature. 1990;  343 269-272
• 5 Schnell L, Schwab M E. Sprouting and regeneration of lesioned corticospinal tract fibres in the adult rat spinal cord.  Eur J Neuroscience. 1993;  5 1156-1171
• 6 Schnell L, Schneider R, Kolbeck R. et al . Neurotrophin-3 enhances sprouting of corticospinal tract during development and after adult spinal cord lesion.  Nature. 1994;  367 170-173
• 7 Schwab M E, Bartholdy D. Degeneration and regeneration of axons in the lesioned spinal cord.  Physiol Rev. 1996;  76 319-370
• 8 Fawcett J W, Asher R A. The glial scar and central nervous system barrier.  Brain Res Bull. 1999;  49 377-391
• 9 Beattie M S, Bresnahan J C, Komon J. et al . Endogenous repair after spinal cord contusion injuries in the rat.  Exp Neurol. 1997;  148 453-463
• 10 Brook G A, Plate D, Franzen R. et al . Spontaneous longitudinally orientated axonal regeneration is associated with the Schwann cell framework within the lesion site following spinal cord compression injury of the rat.  J Neuroscience Res. 1998;  53 51-65
• 11 Brook G A, Houweling D A, Gieling R G. et al . Attempted tissue repair following experimental spinal cord lesion: involvement of cell adhesion molecules L1 and NCAM?.  Eur J Neurosci. 2000;  12 3224-3238
• 12 Chen M S, Huber A B, Van der Haar M E. et al . Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1.  Nature. 2000;  403 434-439
• 13 Schwab M E, Kapfhammer J P, Bandtlow C E. Inhibitors of neurite growth.  Ann Rev Neurosci. 1993;  16 565-595
• 14 Bandtlow C E, Schmidt M F, Hassinger T D. et al . Role of intracellular calcium in NI-35-evoked collapse of neuronal growth cones.  Science. 1993;  259 80-83
• 15 McKerracher L, David S, Jackson D L. et al . Identification of myelin-associated glycoprotein as a major inhibitor of neurite growth.  Neuron. 1994;  13 805-811
• 16 Tang S, Woodall R W, Shen Y J. et al . Soluble myelin-associated glycoprotein (MAG) found in vivo inhibits axonal regeneration.  Mol Cell Neurosci. 1997;  9 333-346
• 17 Levine J M. Increased expression of the ng2 chondroitin sulphate proteoglycan after brain injury.  J Neurosci. 1994;  14 4716-4730
• 18 Krüger S, Sievers J, Hansen C. et al . Three morphologically distinct types of interface develop between adult host and fetal brain transplants: implications for scar formation in the adult central nervous system.  J Comp Neurol. 1986;  249 103-116
• 19 Reier P I, Stensaas L I, Guth L. The astrocytic scar as an impediment to regeneration in the central nervous system. In: Bunge RP, Reier PI (eds) Spinal Cord Reconstruction. New York; Raven 1983
• 20 Stichel C C, Müller H W. The CNS lesion scar: new vistas on an old regeneration barrier.  Cell Tissue Res. 1998;  294 1-9
• 21 Brook G A, Plate D, Franzen R. et al . Spontaneous longitudinally orientated axonal regeneration is associated with the Schwann cell framework within the lesion site following spinal cord compression injury of the rat.  J Neuroscience Res. 1998;  53 51-65
• 22 Stichel C C, Kappler J, Junghans U. et al . Differential expression of the small chondroitin/dermatan sulfate proteoglycans decorin and biglycan after injury of the adult rat brain.  Brain Res. 1995;  704 263-274
• 23 Canning D R, Hoke A, Malemud C J, Silver J. A potent inhibitor of neurite outgrowth that predominates in the extracellular matrix of reactive astrocytes.  Int J Devl Neurosci. 1996;  14 153-175
• 24 Pasterkamp R J, Giger R J, Ruitenberg M J. et al . Transplants of fibroblasts genetically modified to express BDNF promote regeneration of adult rat rubrospinal axons and recovery of forlimb function.  Mol Cell Neurosci. 1999;  13 143-166
• 25 Hatten M E, Liem R KH, Shelanski M L, Mason C A. Astroglia in CNS injury.  Glia. 1991;  4 233-243
• 26 Schnell L, Fearn S, Klassen H. et al . Acute inflammatory responses to mechanical lesions in the CNS: differences between brain and spinal cord.  Eur J Neurosci. 1999;  11 3648-3658
• 27 Wang Z H, Walter G F, Gerhard L. The expression of nerve growth factor receptor on Schwann cells and the effect of these cells on the regeneration of axons in traumatically injured human spinal cord.  Acta Neuropathol. 1996;  91 180-184
• 28 Seilheimer B, Schachner M. Studies of adhesion molecules mediating interactions between cells of peripheral nervous system indicate a major role for L1 in mediating sensory neuron growth on Schwann cells.  J Cell Biol. 1988;  107 341-351
• 29 Mohajeri M H, Bartsch U, Van der Putten H. et al . Neurite outgrowth on non-permissive substrates in vitro is enhanced by ectopic expression of the neural adhesion molecule L1 by mouse astrocytes.  Eur J Neurosci. 1996;  8 1085-1097
• 30 Woolhead C L, Zhang Y, Lieberman A R. et al . Differential effects of autologous peripheral nerve grafts to the corpus striatum of adult rats on the regeneration of axons of striatal and nigral neurons and on the expression of GAP-43 and the cell adhesion molecules N-CAM and L1.  J Comp Neurol. 1998;  391 259-273
• 31 Lazarov-Spiegler O, Solomon A S, Zeev-Brann A B. et al . Transplantation of activated macrophages overcomes central nervous system regrowth failure.  FASEB J. 1996;  10 665-672
• 32 Rapalino O, Lazarow-Spiegler O, Agranow E. et al . Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats.  Nature Medicine. 1998;  4 814-821
• 33 Blight A R. Macrophages and inflammatory damage in spinal cord injury.  J Neurotrauma. 1992;  9 83-91
• 34 Tetzlaff W, Kobayashi N R, Giehl K MG. et al . Response of rubrospinal and corticospinal neurons to injury and neurotrophins.  Prog Brain Res. 1994;  103 271-286
• 35 Raivich G, Bluethmann H, Kreutzberg G W. Signaling molecules and neuroglial activation in the injured central nervous system.  Keio J Med. 1996;  45 239-247
• 36 Schwaiger F W, Hager G, Schmitt A B. et al . Peripheral but not central axotomy induces changes in Janus kinases (JAK) and signal transducers and activators of transcription (STAT).  Eur J Neurosci. 2000;  12 1165-1176
• 37 Herdegen T, Skene P, Bähr M. The c-Jun transcription factor - bipotential mediator of neuronal death, survival and regeneration.  Trends in Neurosci. 1997;  20 227-231
• 38 Skene J HP. Axonal growth-associated proteins.  Ann Rev Neuroscience. 1989;  12 127-156
• 39 Leah J D, Herdegen T, Bravo R. Selective expression of Jun proteins following axotomy and axonal transport block in peripheral nerves in the rat: evidence for a role in the regeneration process.  Brain Res. 1991;  566 198-207
• 40 Herdegen T, Fiallos-Estrada C E, Schmid W. et al . The transcription factors c-JUN, JUN D and CREB, but not FOS and KROX-24, are differentially regulated in axotomized neurons following trasection of rat sciatic nerve.  Mol Brain Res. 1992;  14 155-156
• 41 Haas C A, Donath C, Kreutzberg G W. Differential expression of immediate early genes after transection of the facial nerve.  Neuroscience. 1993;  53 91-99
• 42 Leah J D, Herdegen T, Murashov A. et al . Expression of immediate early gene proteins following axotomy and inhibition of axonal transport in the rat central nervous system.  Neuroscience. 1993;  57 53-66
• 43 Jenkins R, Tetzlaff W, Hunt S P. Differential expression of immediate early genes in rubrospinal neurons following axotomy in rat.  Eur J Neuroscience. 1993;  5 203-209
• 44 Schmitt A B, Breuer S, Voell M. et al . GAP-43 (B-50) and C-Jun are up-regulated in axotomized neurons of Clarke's nucleus after spinal cord injury in the adult rat.  Neurobiol Disease. 1999;  6 122-130
• 45 Kobayashi N R, Fan D-P, Giehl K M. et al . BDNF and NT-4/5 prevent atrophy of rat rubrospinal neurons after cervical axotomy, stimulate GAP-43 and T-alpha-1-Tubulin mRNA expression, and promote axonal regeneration.  J Neuroscience. 1997;  17 9583-9595
• 46 Shibayama M, Hattori S, Himes B T. et al . Neurotrophin-3 prevents death of axotomized Clarke's nucleus neurons in adult rat.  J Comp Neurol. 1998;  390 102-111
• 47 Sendtner M, Kreutzberg G W, Thoenen H. Ciliary neurotrophic factor prevents the degeneration of motor neurons after axotomy.  Nature. 1990;  345 440-441
• 48 Klein M A, Möller J C, Jones L L. et al . Impaired neuroglial activation in interleukin-6 deficient mice.  Glia. 1997;  19 227-233
• 49 Hol E M, Schwaiger F-W, Werner A. et al . Regulation of the LIM-type homeobox gene Islet-1 in the facial nucleus after peripheral nerve axotomy.  Neuroscience. 1999;  88 (3) 122-130
• 50 Werner A, Willem M, Jones L L. et al . Impaired axonal regeneration in alpha7 integrin-deficient mice.  J Neurosci. 2000;  20 1822-1830
• 51 Hunter T. Protein kinases and phosphatases: The Ying and Yang of protein phosphorylation and signaling.  Cell. 1995;  80 225-236
• 52 Whitmarsh A J, Davis R J. Transcription factor AP-1 regulation by mitogen-activated protein kinase signal transduction pathways.  J Mol Med. 1996;  74 589-607
• 53 Heinrich P C, Behrmann I, Muller-Newen G. et al . Interleukin-6-type cytokine signalling through the gp130/STAT pathway.  J Biochem. 1998;  334 297-314
• 54 Mocchetti I, Wrathall J R. Neurotrophic factors in central nervous system trauma.  J Neurotrauma. 1995;  12 853-870
• 55 Xu X M, Guenard V, Kleitman N. et al . A combination of BDNF and NT-3 promotes supraspinal axonal regeneration into Schwann cell grafts in adult rat thoracic spinal cord.  Exp Neurol. 1995;  134 261-272
• 56 McTigue D M, Horner P J, Stokes B T. et al . Neurotrophin-3 and brain-derived neurotrophic factor induce oligodendrocyte proliferation and myelination of regenerating axons in the contused adult rat spinal cord.  J Neurosci. 1998;  18 5354-5365
• 57 Ramer M S, Priestley J V, McMahon S B. Functional regeneration of sensory axons into the adult spinal cord.  Nature. 2000;  403 312-316
• 58 Grill R, Murai K, Blesch A. et al . Cellular delivery of neurotrophin-3 promotes corticospinal axonal growth and partial functional recovery after spinal cord injury.  J Neurosci. 1997;  17 5560-5572
• 59 Blits B, Dijkhuizen P A, Carlstedt T P. et al . Adenoviral vector-mediated expression of a foreign gene in peripheral nerve tissue bridges implanted in the injured peripheral and central nervous system.  Exp Neurol. 1999;  160 256-267
• 60 Weidner N, Blesch A, Grill R J, Tuszynski M. Nerve growth factor-hypersecreting Schwann cell grafts augment and guide spinal cord axonal growth and remyelinate central nervous system axons in a phenotypically appropriate manner that correlates with expression of L1.  J Comp Neurol. 1999;  413 495-506
• 61 Blits B, Dijkhuizen P A, Boer G J, Verhaagen J. Intercostal nerve implants transduced with an adenoviral vector encoding neurotrophin-3 promote regrowth of injured rat corticospinal tract fibres and improve hindlimb function.  Exp Neurol. 2000;  164 25-37
• 62 Miyoshi M H, Blomer U, Takahashi M. et al . Development of a self-inactivating lentivirus vector.  J Virol. 1998;  72 8150-8157
• 63 Carter P J, Samulski R J. Adeno-associated viral vectors as gene delivery vehicles.  Int J Mol Med. 2000;  6 17-27
• 64 Brosamle C, Huber A B, Fiedler M. et al . Regeneration of lesioned corticospinal tract fibers in the adult rat induced by a recombinant, humanized IN-1 antibody fragment.  J Neurosci. 2000;  20 8061-8068
• 65 Bregman B S, Kunkel-Bagden E, Schnell L. et al . Recovery from spinal cord injury mediated by antibodies to neurite growth inhibitors.  Nature. 1995;  378 498-501
• 66 Thallmair M, Metz G A, Z'Graggen W J. et al . Neurite growth inhibitors restrict plasticity and functional recovery following corticospinal tract lesions.  Nature Neurosci. 1998;  1 124-131
• 67 Gage F H, Rosenberg M B, Tuszynski M H. et al . Gene therapy in the CNS: intracerbral grafting of genetically modified cells.  Prog Brain Res. 1990;  86 205-217
• 68 Iwashita Y, Kawaguchi S, Murata M. Restoration of function by replacement of spinal cord segments in the rat.  Nature. 1994;  367 167-170
• 69 Cheng H, Cao Y, Olson L. Spinal cord repair in adult paraplegic rats: partial restoration of hind limb function.  Science. 1996;  273 510-513
• 70 Martin D, Robe P, Franzen R. et al . Effects of Schwann cell transplantation in a contusion model of rat spinal cord injury.  J Neurosci Res. 1996;  45 588-597
• 71 Oudega M, Hagg T. Nerve growth factor promotes regeneration of sensory axons into rat spinal cord.  Exp Neurol. 1996;  140 218-229
• 72 Liu Y, Kim D, Himes T. et al . Transplants of fibroblasts genetically modified to express BDNF promote regeneration of adult rat rubrospinal axons and recovery of forlimb function.  J Neurosci. 1999;  19 4370-4387
• 73 Ramon-Cueto A, Cordero M I, Santos-Benito F F, Avila J. Functional recovery of paraplegic rats and motor axon regeneration in their spinal cords by olfactory ensheathing glia.  Neuron. 2000;  25 425-435
• 74 Fehlings M G, Tator C H. The relationships among the severity of spinal cord injury, residual neurological function, axon counts, and counts of retrogradely labeled neurons after experimental spinal cord injury.  Exp Neurol. 1995;  132 220-228
• 75 Li Y, Field P M, Raisman G. Regeneration of adult rat corticospinal axons induced by transplanted olfactory ensheathing cells.  J Neurosci. 1998;  18 10514-10524
• 76 Bray G M, Villegas-Perez M P. et al . Neuronal and nonneuronal influences on retinal ganglion cell survival, axonal regrowth, and connectivity after axotomy.  Ann NY Acad Sci. 1991;  633 214-228
• 77 Aviles-Trigueros M, Sauve Y, Lund R D, Vidal-Sanz M. Selective innervation of retinorecipient brainstem nuclei by retinal ganglion cell axons regenerating through peripheral nerve grafts in adult rats.  J Neurosci. 2000;  20 361-374
• 78 Bregman B S, Kunkel-Bagden E, Reier P J. et al . Recovery of function after spinal cord injury: mechanisms underlying transplant-mediated recovery of function differ after spinal cord injury in newborn and adult rats.  Exp Neurology. 1993;  123 3-16
• 79 Wirth E D, Reier P J, Fessler R G, Anderson D K. Intraspinal transplantation-update of ongoing clinical study.  Restor Neurol Neurosci. 2000;  16 191-192
• 80 Franklin R JM, Barnett S C. Do olfactory glia have advantages over Schwann cells for CNS repair.  J Neurosci Res. 1997;  50 665-672
• 81 Ramon-Cueto A, Nieto-Sampedro M. Regeneration into the spinal cord of transected dorsal root axons is promoted by ensheathing glia transplants.  Exp Neurol. 1994;  127 232-244
• 82 Li Y, Field P M, Raisman G. Repair of adult rat corticospinal tract by transplants of olfactory ensheathing cells.  Science. 1997;  277 2000-2002
• 83 McDonald J W, Liu X Z, Qu Y. et al . Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord.  Nature Med. 1999;  5 1410-1412
• 84 David S C, Bouchard C, Tsats O, Giftochristos N. Macrophages can modify the nonpermissive nature of adult mammalian central nervous system.  Neuron. 1990;  5 463-469
• 85 Brunelli G A, Brunelli G R. Restoration of walking in paraplegia by transferring the ulnar nerve to the hip: A report on the first patient.  Microsurgery. 1999;  19 223-226