title: Regulation of autophagy and ubiquitinated protein accumulation by bFGF promotes functional recovery and neural protection in a rat model of spinal cord injury.
abstract: The role of autophagy in the recovery of spinal cord injury remains controversial; in particular, the mechanism of autophagy regulated degradation of ubiquitinated proteins has not been discussed to date. In this study, we investigated the protective role of basic fibroblast growth factor (bFGF) both in vivo and in vitro and demonstrated that excessive autophagy and ubiquitinated protein accumulation is involved in the rat model of trauma. bFGF administration improved recovery and increased the survival of neurons in spinal cord lesions in the rat model. The protective effect of bFGF is related to the inhibition of autophagic protein LC3II levels; bFGF treatment also enhances clearance of ubiquitinated proteins by p62, which also increases the survival of neuronal PC-12 cells. The activation of the downstream signals of the PI3K/Akt/mTOR pathway by bFGF treatment was detected both in vivo and in vitro. Combination therapy including the autophagy activator rapamycin partially abolished the protective effect of bFGF. The present study illustrates that the role of bFGF in SCI recovery is related to the inhibition of excessive autophagy and enhancement of ubiquitinated protein clearance via the activation of PI3K/Akt/mTOR signaling. Overall, our study suggests a new trend for bFGF drug development for central nervous system injuries and sheds light on protein signaling involved in bFGF action.
authors.affiliation: School of Pharmacy, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical College, Wenzhou, 325035, China.
authors.forename: Hong-Yu
authors.initials: HY
authors.lastname: Zhang
authors.forename: Zhou-Guang
authors.initials: ZG
authors.lastname: Wang
authors.forename: Fen-Zan
authors.initials: FZ
authors.lastname: Wu
authors.forename: Xiao-Xia
authors.initials: XX
authors.lastname: Kong
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.forename: Bei-Bei
authors.initials: BB
authors.lastname: Lin
authors.forename: Shi-Ping
authors.initials: SP
authors.lastname: Zhu
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.forename: Chao-Shi
authors.initials: CS
authors.lastname: Gan
authors.forename: Xiao-Bing
authors.initials: XB
authors.lastname: Fu
authors.forename: Xiao-Kun
authors.initials: XK
authors.lastname: Li
authors.forename: Hua-Zi
authors.initials: HZ
authors.lastname: Xu
authors.forename: Jian
authors.initials: J
authors.lastname: Xiao
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects*; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D057149:Ubiquitinated Proteins / Q000378:metabolism*
chemical_list: D016222:Fibroblast Growth Factor 2; D006360:Heat-Shock Proteins; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000071456:Sequestosome-1 Protein; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D057149:Ubiquitinated Proteins; C491079:Sqstm1 protein, rat