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J. Biol. Chem., Vol. 277, Issue 51, 49799-49807, December 20, 2002
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From the 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.
Anti-semaphorin 3A Antibodies Rescue Retinal Ganglion
Cells from Cell Death following Optic Nerve Axotomy*
§,
,,,,, and Department of Neurology and the Felsenstein
Medical Research Center, Rabin Medical Center, Beilinson Campus, and
the Sackler School of Medicine, Petach Tiqva 49100 and the
¶ Department of Neurobiochemistry, George S. Wise Faculty of Life
Sciences, the Department of Cell Research and Immunology, and
the ** Sam Rothberg Glaucoma Center, Goldschleger Eye
Research Institute, Tel Aviv University, Ramat Aviv,
Tel Aviv 69978, Israel
*
This work was supported in part by the National Parkinson
Foundation, by the Claire and Amedee Martier Institute for the Study of
Visual Disorders and Blindness, Tel Aviv University, and by the Israeli
Ministry of Health (to A. B.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence may be addressed. Tel.: 972-3-640-9782;
Fax: 972-3-640-7643; E-mail: barzilai@post.tau.ac.il.
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