Nature Medicine
- 12, 1380 - 1389 (2006)
Published online: 12 November 2006; | doi:10.1038/nm1505
A selective Sema3A inhibitor enhances regenerative responses and functional recovery of the injured spinal cordShinjiro Kaneko1, 2, 3, 9, Akio Iwanami1, 2, 4, 9, Masaya Nakamura1, Akiyoshi Kishino5, Kaoru Kikuchi5, Shinsuke Shibata2, Hirotaka J Okano2, Takeshi Ikegami1, Ayako Moriya2, Osamu Konishi5, Chikao Nakayama5, Kazuo Kumagai5, Toru Kimura5, Yasufumi Sato6, Yoshio Goshima6, Masahiko Taniguchi7, Mamoru Ito8, Zhigang He3, Yoshiaki Toyama1 & Hideyuki Okano21
Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjyuku-ku, Tokyo 160-8582, Japan. 2
Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjyuku-ku, Tokyo 160-8582, Japan. 3
Division of Neuroscience, Children's Hospital Boston, Harvard Medical School, 320 Longwood Avenue, Boston, Massachusetts 02115, USA. 4
Clinical Research Center, National Hospital Organization, Murayama Medical Center 2-37-1 Gakuen, Musashimurayama, Tokyo 208-0011, Japan. 5
Dainippon Sumitomo Pharma Co. Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan. 6
Department of Molecular Pharmacology and Neurobiology, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan. 7
Department of Biochemistry, Tokyo University School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. 8
Central Institute for Experimental Animals, 1430 Nogawa, Kawasaki, Kanagawa 216-0001, Japan. 9
These authors contributed equally to this work.
Correspondence should be addressed to Hideyuki Okano hidokano@sc.itc.keio.ac.jp 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.
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