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Journal of Neuroscience, Vol 15, 8143-8155, Copyright © 1995 by Society for Neuroscience
At least two mechanisms are involved in the death of retinal ganglion cells following target ablation in neonatal rats
Q Cui and AR Harvey
Department of Anatomy and Human Biology, University of Western Australia, Nedlands, Perth, Australia.
Removal of the superior colliculus (SC) in neonatal Wistar rats results in
a rapid loss of retinal ganglion cells (RGCs). There is an early twofold
increase in RGC death 4-8 hr postlesion (PL) followed by a later 10-11-fold
increase in pyknosis about 24 hr PL. We have now used neurotrophic factors
(BDNF, NT-4/5, NT-3, NGF, LIF), glutamate receptor antagonists (MK-801,
DNQX, CNQX), an antioxidant (N-ace-tyl-L- cysteine), and an NOS inhibitor
(L-NAME) to determine whether the early and late phases of lesion-induced
RGC death involved similar or different mechanisms. Normal and pyknotic
nuclei of tectally projecting RGCs were visualized by injecting the left
s.c. of 2 d old rats with diamidino yellow (DY). Two days later the
injection site was removed. In most rats, right eyes were injected with
factors immediately after the s.c. ablation. Rats were perfused either 6 or
24 hr PL. In the latter group a second intravitreal injection of the
appropriate factor was sometimes made 12 hr PL. NT- 4/5 and BDNF
significantly decreased RGC pyknosis 6 and 24 hr PL, whereas NT-3 was only
protective 6 hr PL. LIF slightly reduced RGC death 24 hr PL, but NGF had no
influence on RGC survival at either time point. NT-4/5 also reduced the
rate of naturally occurring RGC death. MK-801, DNQX, CNQX,
N-acetylcysteine, and L-NAME all prevented the early lesion-induced
increase in RGC death but had no significant effect on RGC death measured
24 hr PL; none of these factors significantly reduced the rate of naturally
occuring RGC death. Cycloheximide, shown previously to reduce RGC pyknosis
24 hr PL, did not prevent RGC death 6 hr PL. The data indicate that there
are at least two mechanisms involved in RGC death after neonatal target
ablation. The early increase is related to excitotoxic effects mediated by
glutamate receptors and involves NOS and the production of free radicals.
We found no evidence that RGC death measured 24 hr PL is dependent on these
processes, but the later death does require protein synthesis and, most
likely, the activation of an endogenous suicide program. NT-4/5 and BDNF
protected RGCs from both types of lesion- induced death.
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