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R. J. Casson, S. Saggu, G. Chidlow, J. Wood, Z. Cai, P. Blumbergs; Dying Back-Like Axonopathy and Early Neurofilament Degeneration in the Optic Nerve After Perikaryal Excitotoxic Injury to Retinal Ganglion Cells. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5386.
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Excitotoxicity may be involved in glaucoma. Although excitotoxicity is usually considered as a somatodendritic insult, axonopathy is an early feature in several disorders which may involve excitotoxicity, including glaucoma. However, to our knowledge, the pathological features of axonal pathology after perikaryal excitotoxic injury have never been reported. The retina and optic nerve provide a unique anatomical substrate to investigate this pathology. Here, we describe spatiotemporal aspects of the somal and axonal pathologic changes after perikaryal excitotoxic injury to retinal ganglion cells (RGCs).
40 Sprague Dawley rats were killed at 0hrs, 24hrs, 72hrs and 7days after injecting 20 nmoles N-methyl-D-aspartate (NMDA) into the vitreous of the left eye. The saline-injected right eye served as a control. Eyes and optic nerves were carefully dissected. Tissues from half of the animals in each group were embedded in paraffin for light microscopy and immunohistochemistry for neurofilament-light (NF-L) and amyloid precursor protein (APP; a marker of dysfunctional fast axonal transport); the other half were resin-embedded for electron microscopy (EM). Proximal (intraorbital) and distal (intracranial) optic nerves were compared using the following parameters: axon counts, axonal swellings and myelin changes.
Retinae showed RGC loss and reduction in the inner retinal thickness 72hrs after NMDA injection (p <0.05), increasing after 7 days (p < 0.001). The RGC somata counts correlated strongly with the axonal counts. (r = 0.929. p<0.001) Axon loss, axon swellings and myelin damage were seen throughout the optic nerve after 72hrs (p <0.05), with changes increasing at 7 days (p<0.001). There was early degradation of NF-L (on immuno and EM), but APP was not evident. At all time points, pathological changes were more prominent in the distal segments. (p < 0.05).
Excitotoxic perikaryal injury causes an axonopathy which is synchronous with the somal degeneration, NF-L degradation is an early feature, with possible vesicular transport failure at the somal level. The pathology is most prominent in the distal portions of the axon, consistent with dying back-like neuropathy.
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