Exogenous Tissue Plasminogen Activator Enhances Peripheral Nerve Regeneration and Functional Recovery After Injury In Mice

Tissue plasminogen activator (tPA) is an essential component of the proteolytic cascade that lyses blood clots. Various studies also suggest that tPA plays important roles in the nervous system. We show that exogenous tPA or tPA/plasminogen (plg) promotes axonal regeneration, remyelination, and func...

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Bibliographic Details
Published in:Journal of neuropathology and experimental neurology 2006-01, Vol.65 (1), p.78-86
Main Authors: Zou, Tie, Ling, Changchun, Xiao, Yao, Tao, Xianmei, Ma, Duan, Chen, Zu-Lin, Strickland, Sidney, Song, Houyan
Format: Article
Language:English
Subjects:
Animals
Antigens, Differentiation - metabolism
Azo Compounds
Biological and medical sciences
Blotting, Western - methods
Cell Count - methods
Cranial nerves. Spinal roots. Peripheral nerves. Autonomic nervous system. Gustation. Olfaction
Disease Models, Animal
Drug Interactions
Immunoglobulin G - metabolism
Immunohistochemistry - methods
Investigative techniques, diagnostic techniques (general aspects)
Male
Matrix Metalloproteinase 9 - metabolism
Medical sciences
Mice
Mice, Inbred C57BL
Muscular Atrophy - drug therapy
Muscular Atrophy - etiology
Muscular Atrophy - pathology
Myelin Sheath - metabolism
Nerve Fibers, Myelinated - drug effects
Nerve Fibers, Myelinated - metabolism
Nerve Fibers, Myelinated - pathology
Nerve Regeneration - drug effects
Nervous system
Nervous system (semeiology, syndromes)
Neurology
Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques
Plasminogen - administration & dosage
Recovery of Function - drug effects
Sciatic Neuropathy - complications
Sciatic Neuropathy - drug therapy
Sciatic Neuropathy - metabolism
Tissue Plasminogen Activator - therapeutic use
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Summary:Tissue plasminogen activator (tPA) is an essential component of the proteolytic cascade that lyses blood clots. Various studies also suggest that tPA plays important roles in the nervous system. We show that exogenous tPA or tPA/plasminogen (plg) promotes axonal regeneration, remyelination, and functional recovery after sciatic nerve injury in the mouse. Local application of tPA or tPA/plg 7 days after sciatic nerve crush significantly increased the total number of axons and myelinated axons, which is accompanied by enhanced expression of neurofilament. Treatment with tPA or tPA/plg reduced the deposition of fibrin(ogen) after nerve injury. Moreover, tPA or tPA/plg increased the number of macrophages and induced MMP-9 expression at the injury site, coincident with reduced collagen scar formation and accelerated clearance of myelin and lipid debris after treatment. Consequently, tPA or tPA/plg treatment protected muscles from atrophy after nerve injury, indicating better functional recovery. These results suggest that administration of exogenous tPA or tPA/plg promotes axonal regeneration and remyelination through removal of fibrin deposition and activation of MMP-9-positive macrophages, which may be responsible for myelin debris clearance and preventing collagen scar formation. Therefore, tPA may be useful for treatment of peripheral nerve injury.
ISSN:0022-3069
1554-6578
DOI:10.1097/01.jnen.0000195942.25163.f5