Cytoplasmic p21(Cip1/WAF1) enhances axonal regeneration and functional recovery after spinal cord injury in rats.
p21(Cip1/WAF1), known as a cell-cycle inhibitory protein, facilitates neurite outgrowth from neurons when present in the cytoplasm. The molecular mechanism of this action is that p21(Cip1/WAF1) forms a complex with Rho-kinase and inhibits its activity. As myelin-derived inhibitors of axonal outgrowth act on neurons by activating Rho, that is responsible for the lack of spontaneous regeneration of the injured central nervous system (CNS), Rho-kinase may be a good molecular target against injuries in the CNS. In this study, we delivered TAT-fusion protein of cytoplasmic p21(Cip1/WAF1) locally after dorsal hemisection of the thoracic spinal cord in rats. The treatment significantly stimulated axonal regeneration and recovery of hindlimb function, and inhibited the cavity formation in the spinal cord after the injury. Cytoplasmic p21(Cip1/WAF1) may provide a potential therapeutic agent that produces functional regeneration following CNS injuries.
Tanaka
H
H
Department of Orthopaedic Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Yamashita
T
T
Yachi
K
K
Fujiwara
T
T
Yoshikawa
H
H
Tohyama
M
M
D000818:Animals; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004576:Electromyography; D005333:Fetus; D015696:Gene Products, tat / Q000235:genetics; D006614:Hindlimb / Q000294:innervation / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009185:Myelin Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009410:Nerve Degeneration / Q000188:drug therapy / Q000201:enzymology / Q000517:prevention & control; D009416:Nerve Regeneration / Q000187:drug effects* / Q000235:genetics; D010264:Paraplegia / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D020127:Recovery of Function / Q000187:drug effects* / Q000235:genetics; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D054460:rho-Associated Kinases
C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D015696:Gene Products, tat; D047908:Intracellular Signaling Peptides and Proteins; D009185:Myelin Proteins; D011993:Recombinant Fusion Proteins; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases