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 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.
Zou
Tie
T
Department of Molecular Genetics & the Key Laboratory of Molecular Medicine Ministry of Education, Fudan University, Shanghai, P.R. China.
Ling
Changchun
C
Xiao
Yao
Y
Tao
Xianmei
X
Ma
Duan
D
Chen
Zu-Lin
ZL
Strickland
Sidney
S
Song
Houyan
H
D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D001391:Azo Compounds; D015153:Blotting, Western / Q000379:methods; D002452:Cell Count / Q000379:methods; D004195:Disease Models, Animal; D004347:Drug Interactions; D007074:Immunoglobulin G / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009133:Muscular Atrophy / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D009186:Myelin Sheath / Q000378:metabolism; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009416:Nerve Regeneration / Q000187:drug effects*; D010958:Plasminogen / Q000008:administration & dosage; D020127:Recovery of Function / Q000187:drug effects*; D020426:Sciatic Neuropathy / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*
D000943:Antigens, Differentiation; D001391:Azo Compounds; D007074:Immunoglobulin G; C036763:monocyte-macrophage differentiation antigen; D010958:Plasminogen; D010959:Tissue Plasminogen Activator; D020780:Matrix Metalloproteinase 9; C011049:oil red O