Minocycline alleviates death of oligodendrocytes by inhibiting pro-nerve growth factor production in microglia after spinal cord injury.
Spinal cord injury (SCI) causes a permanent neurological disability, and no satisfactory treatment is currently available. After SCI, pro-nerve growth factor (proNGF) is known to play a pivotal role in apoptosis of oligodendrocytes, but the cell types producing proNGF and the signaling pathways involved in proNGF production are primarily unknown. Here, we show that minocycline improves functional recovery after SCI in part by reducing apoptosis of oligodendrocytes via inhibition of proNGF production in microglia. After SCI, the stress-responsive p38 mitogen-activated protein kinase (p38MAPK) was activated only in microglia, and proNGF was produced by microglia via the p38MAPK-mediated pathway. Minocycline treatment significantly reduced proNGF production in microglia in vitro and in vivo by inhibition of the phosphorylation of p38MAPK. Furthermore, minocycline treatment inhibited p75 neurotrophin receptor expression and RhoA activation after injury. Finally, minocycline treatment inhibited oligodendrocyte death and improved functional recovery after SCI. These results suggest that minocycline may represent a potential therapeutic agent for acute SCI in humans.
Yune
Tae Y
TY
Age-Related and Brain Diseases Research Center, Kyung Hee University, Seoul 130-701, Korea.
Lee
Jee Y
JY
Jung
Gil Y
GY
Kim
Sun J
SJ
Jiang
Mei H
MH
Kim
Young C
YC
Oh
Young J
YJ
Markelonis
George J
GJ
Oh
Tae H
TH
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001369:Axons / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D020287:In Situ Nick-End Labeling / Q000379:methods; D008297:Male; D008911:Minocycline / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology; D009414:Nerve Growth Factors / Q000378:metabolism*; D009836:Oligodendroglia / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012234:Rho Factor / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000473:pathology*
D000900:Anti-Bacterial Agents; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D012234:Rho Factor; D008911:Minocycline