title: Anti-semaphorin 3A antibodies rescue retinal ganglion cells from cell death following optic nerve axotomy.
abstract: Damage to the optic nerve in mammals induces retrograde degeneration and apoptosis of the retinal ganglion cell (RGC) bodies. The mechanisms that mediate the response of the neuronal cells to the axonal injury are still unknown. We have previously shown that semaphorins, axon guidance molecules with repulsive cues, are capable of mediating apoptosis in cultured neuronal cells (Shirvan, A., Ziv, I., Fleminger, G., Shina, R., He, Z., Brudo, I., Melamed, E., and Brazilai, A. (1999) J. Neurochem. 73, 961-971). In this study, we examined the involvement of semaphorins in an in vivo experimental animal model of complete axotomy of the rat optic nerve. We demonstrate that a marked induction of type III semaphorin proteins takes place in ipsilateral retinas at early stages following axotomy, well before any morphological signs of RGC apoptosis can be detected. Time course analysis revealed that a peak of expression occurred after 2-3 days and then declined. A small conserved peptide derived from semaphorin 3A that was previously shown to induce neuronal death in culture was capable of inducing RGC loss upon its intravitreous injection into the rat eye. Moreover, we demonstrate a marked inhibition of RGC loss when axotomized eyes were co-treated by intravitreous injection of function-blocking antibodies against the semaphorin 3A-derived peptide. Marked neuronal protection from degeneration was also observed when the antibodies were applied 24 h post-injury. We therefore suggest that semaphorins are key proteins that modulate the cell fate of axotomized RGC. Neutralization of the semaphorin repulsive function may serve as a promising new approach for treatment of traumatic injury in the adult mammalian central nervous system or of ophthalmologic diseases such as glaucoma and ischemic optic neuropathy that induce apoptotic RGC death.
authors.affiliation: Department of Neurology and the Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Campus, and the Sackler School of Medicine, Petach Tiqva 49100, Israel. anat@nst.co.il
authors.forename: Anat
authors.initials: A
authors.lastname: Shirvan
authors.forename: Michal
authors.initials: M
authors.lastname: Kimron
authors.forename: Vered
authors.initials: V
authors.lastname: Holdengreber
authors.forename: Ilan
authors.initials: I
authors.lastname: Ziv
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Ben-Shaul
authors.forename: Shlomo
authors.initials: S
authors.lastname: Melamed
authors.forename: Eldad
authors.initials: E
authors.lastname: Melamed
authors.forename: Ari
authors.initials: A
authors.lastname: Barzilai
authors.forename: Arieh S
authors.initials: AS
authors.lastname: Solomon
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D017209:Apoptosis; D019771:Axotomy; D015153:Blotting, Western; D016923:Cell Death; D002470:Cell Survival; D007150:Immunohistochemistry; D008297:Male; D009900:Optic Nerve / Q000166:cytology / Q000601:surgery*; D010455:Peptides / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000276:immunology*; D040121:Semaphorin-3A / Q000037:antagonists & inhibitors* / Q000276:immunology*; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D000906:Antibodies; D010455:Peptides; D040121:Semaphorin-3A