Small molecule inhibitor of type I transforming growth factor-β receptor kinase ameliorates the inhibitory milieu in injured brain and promotes regeneration of nigrostriatal dopaminergic axons.
Transforming growth factor-β (TGF-β), a multifunctional cytokine, plays a crucial role in wound healing in the damaged central nervous system. To examine effects of the TGF-β signaling inhibition on formation of scar tissue and axonal regeneration, the small molecule inhibitor of type I TGF-β receptor kinase LY-364947 was continuously infused in the lesion site of mouse brain after a unilateral transection of the nigrostriatal dopaminergic pathway. At 2 weeks after injury, the fibrotic scar comprising extracellular matrix molecules including fibronectin, type IV collagen, and chondroitin sulfate proteoglycans was formed in the lesion center, and reactive astrocytes were increased around the fibrotic scar. In the brain injured and infused with LY-364947, fibrotic scar formation was suppressed and decreased numbers of reactive astrocytes occupied the lesion site. Although leukocytes and serum IgG were observed within the fibrotic scar in the injured brain, they were almost absent in the injured and LY-364947-treated brain. At 2 weeks after injury, tyrosine hydroxylase (TH)-immunoreactive fibers barely extended beyond the fibrotic scar in the injured brain, but numerous TH-immunoreactive fibers regenerated over the lesion site in the LY-364947-treated brain. These results indicate that inhibition of TGF-β signaling suppresses formation of the fibrotic scar and creates a permissive environment for axonal regeneration.
Department of Developmental Morphology, Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan.
Nozomu
N
Yoshioka
Junko
J
Kimura-Kuroda
Taro
T
Saito
Koki
K
Kawamura
Shin-ichi
S
Hisanaga
Hitoshi
H
Kawano
D000818:Animals; D000941:Antigens / Q000378:metabolism; D001369:Axons / Q000187:drug effects; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002921:Cicatrix / Q000517:prevention & control; D003342:Corpus Striatum / Q000293:injuries; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009416:Nerve Regeneration / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011509:Proteoglycans / Q000378:metabolism; D011720:Pyrazoles / Q000627:therapeutic use*; D011758:Pyrroles / Q000627:therapeutic use*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism; D013378:Substantia Nigra / Q000293:injuries; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*; D000099216:Chondroitin Sulfate Proteoglycan 4; D011804:Quinolines
D000941:Antigens; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D017493:Leukocyte Common Antigens; D017346:Protein Serine-Threonine Kinases; D011509:Proteoglycans; D011720:Pyrazoles; D011758:Pyrroles; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D014446:Tyrosine 3-Monooxygenase; D000099216:Chondroitin Sulfate Proteoglycan 4; C506615:HTS 466284; D011804:Quinolines; C497783:Smad2 protein, mouse; C516770:Ptprc protein, mouse