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Journal of Neuroscience, Vol 13, 455-466, Copyright © 1993 by Society for Neuroscience
Treatment of the adult retina with microglia-suppressing factors retards axotomy-induced neuronal degradation and enhances axonal regeneration in vivo and in vitro
S Thanos, J Mey and M Wild
Department of Ophthalmology, University of Tubingen, School of Medicine, Germany.
To monitor the cascade of events initiated by injury of adult neurons, and
to explore whether and how neighboring microglial cells contribute to the
degradation of lesioned neurons, axotomy-induced ganglion cell degeneration
was investigated in adult rats. Suppression of macrophage and microglia
activity during the weeks following transection of the optic nerve was
performed with the immunoglobulin-derived tripeptide Thr-Lys-Pro, which is
a macrophage inhibitory factor (MIF) and retards the activity of cells of
monocytic origin. Single or repeated injection of MIF into the vitreous
body during and after transection of the optic nerve resulted in
significant retardation of axotomy-induced ganglion cell degradation in the
retina as detected by specific labeling with the retrogradely transported
fluorescent dye 4Di-10ASP. MIF specifically altered the morphology of
labeled microglial cells from a ramified to an oval, less ramified shape,
indicating that these cells were targets of its activity. Injection of the
tetrapeptide macrophage stimulating factor, also known as tuftsin
(Thr-Lys-Pro-Arg), revealed effects opposite to those described for the
MIF: it increased the number of labeled microglial cells and enhanced the
devastating effects of axotomy on ganglion cells. The viability of rescued
ganglion cells in retinas treated with the various drugs was assessed both
in vivo and in vitro. (1) Intravitreal injection of MIF to prevent
degradation of neurons combined with transplantation of autologous
peripheral nerve grafts, which facilitate regrowth of the transected
neurites, revealed that significantly more ganglion cells contributed to
axonal regeneration (17.1%) than in untreated controls (9.5%). (2)
Explantation of retinas that were pretreated with MIF in situ revealed
higher incidence of axonal outgrowth in organ cultures than untreated
control explants or retinas treated with either the basic fibroblast growth
factor or brain-derived neurotrophic factor. The present results
demonstrate that axotomy initializes a cascade of microglia-mediated
autodestructive retinal responses, which culminate in degradation of
"sick," but obviously viable neurons. We postulate that the retinal
microglial system has a key role in recognizing and eliminating severed
neurons.
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