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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

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

Nozomu Yoshioka, Junko Kimura-Kuroda, Taro Saito, Koki Kawamura, Shin-ichi Hisanaga, Hitoshi Kawano

J Neurosci Res. 2011 Mar;89(3):381-93.

PMID: 21259325

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP396129536	LY-364947		396129-53-6	Price

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