A selective Sema3A inhibitor enhances regenerative responses and functional recovery of the injured spinal cord.
Axons in the adult mammalian central nervous system (CNS) exhibit little regeneration after injury. It has been suggested that several axonal growth inhibitors prevent CNS axonal regeneration. Recent research has demonstrated that semaphorin3A (Sema3A) is one of the major inhibitors of axonal regeneration. We identified a strong and selective inhibitor of Sema3A, SM-216289, from the fermentation broth of a fungal strain. To examine the effect of SM-216289 in vivo, we transected the spinal cord of adult rats and administered SM-216289 into the lesion site for 4 weeks. Rats treated with SM-216289 showed substantially enhanced regeneration and/or preservation of injured axons, robust Schwann cell-mediated myelination and axonal regeneration in the lesion site, appreciable decreases in apoptotic cell number and marked enhancement of angiogenesis, resulting in considerably better functional recovery. Thus, Sema3A is essential for the inhibition of axonal regeneration and other regenerative responses after spinal cord injury (SCI). These results support the possibility of using Sema3A inhibitors in the treatment of human SCI.
Kaneko
Shinjiro
S
Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjyuku-ku, Tokyo 160-8582, Japan.
Iwanami
Akio
A
Nakamura
Masaya
M
Kishino
Akiyoshi
A
Kikuchi
Kaoru
K
Shibata
Shinsuke
S
Okano
Hirotaka J
HJ
Ikegami
Takeshi
T
Moriya
Ayako
A
Konishi
Osamu
O
Nakayama
Chikao
C
Kumagai
Kazuo
K
Kimura
Toru
T
Sato
Yasufumi
Y
Goshima
Yoshio
Y
Taniguchi
Masahiko
M
Ito
Mamoru
M
He
Zhigang
Z
Toyama
Yoshiaki
Y
Okano
Hideyuki
H
D000818:Animals; D019556:COS Cells; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D002522:Chlorocebus aethiops; D002867:Chromones / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009046:Motor Neurons / Q000187:drug effects; D009416:Nerve Regeneration / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012583:Schwann Cells / Q000187:drug effects; D040121:Semaphorin-3A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects* / Q000502:physiology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000534:rehabilitation; D044004:Xanthones / Q000627:therapeutic use*; D023084:alpha-Defensins / Q000378:metabolism
D002867:Chromones; C488217:Sema3a protein, mouse; D040121:Semaphorin-3A; D044004:Xanthones; D023084:alpha-Defensins; C406564:defensin NP-1; C477901:xanthofulvin