In vitro and in vivo characterization of a novel semaphorin 3A inhibitor, SM-216289 or xanthofulvin.
SM-216289 (xanthofulvin) isolated from the fermentation broth of a fungal strain, Penicillium sp. SPF-3059, was identified as a strong semaphorin 3A (Sema3A) inhibitor. Sema3A-induced growth cone collapse of dorsal root ganglion neurons in vitro was completely abolished in the presence of SM-216289 at levels less than 2 mum (IC50 = 0.16 mum). When dorsal root ganglion explants were co-cultured with Sema3A-producing COS7 cells in a collagen gel matrix, SM-216289 enabled neurites to grow toward the COS7 cells. SM-216289 diminished the binding of Sema3A to its receptor neuropilin-1 in vitro, suggesting a direct interference of receptor-ligand association. Moreover, our data suggest that SM-216289 interacted with Sema3A directly and blocked the binding of Sema3A to its receptor. We examined the efficacy of SM-216289 in vivo using a rat olfactory nerve axotomy model, in which strong Sema3A induction has been reported around regenerating axons. The regeneration of olfactory nerves was significantly accelerated by a local administration of SM-216289 in the lesion site, suggesting the involvement of Sema3A in neural regeneration as an inhibitory factor. SM-216289 is an excellent molecular probe to investigate the function of Sema3A, in vitro and in vivo, and may be useful for the treatment of traumatic neural injuries.
Kikuchi
Kaoru
K
Research Division, Sumitomo Pharmaceuticals Co., Ltd., 3-1-98, Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.
Kishino
Akiyoshi
A
Konishi
Osamu
O
Kumagai
Kazuo
K
Hosotani
Nobuo
N
Saji
Ikutaro
I
Nakayama
Chikao
C
Kimura
Toru
T
D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002642:Chick Embryo; D002867:Chromones / Q000494:pharmacology*; D018920:Coculture Techniques; D003094:Collagen / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D020128:Inhibitory Concentration 50; D008024:Ligands; D051379:Mice; D008954:Models, Biological; D008956:Models, Chemical; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009832:Olfactory Nerve / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D040121:Semaphorin-3A / Q000037:antagonists & inhibitors*; D013997:Time Factors; D044004:Xanthones / Q000494:pharmacology*
D002867:Chromones; D008024:Ligands; D040121:Semaphorin-3A; D044004:Xanthones; C477901:xanthofulvin; D003094:Collagen