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G. Chidlow, A. Ebneter, M. C. Holman, J. P. Wood, R. Casson; Axonal Transport Disruption at the Optic Nerve Head: Comparison Between Rat Models of Retinal Ganglion Cell Degeneration and Utility of the Novel Marker Interleukin-6. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2103.
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© ARVO (1962-2015); The Authors (2016-present)
The primary site of injury in glaucoma is yet to be unequivocally identified, but a body of evidence points towards the optic nerve head (ONH), the site at which retinal ganglion cell (RGC) axons pass through the connective tissue of the lamina cribrosa. In the current study, we investigated the accumulation of endogenous markers of axonal transport disruption within the optic pathway in three distinct animal models of retinal ganglion cell death, namely experimental glaucoma, excitotoxicity and chronic ischemia.
Experimental glaucoma was induced in one eye by lasering the trabecular meshwork to chronically elevate the intraocular pressure. Excitotoxicity was induced in one eye by intravitreal injection of 30nmol NMDA. Chronic ischemia was achieved by permanent, bilateral occlusion of the common carotid arteries (2VO). Sham animals received the same operation without occlusion of the vessels. Rats were killed at various time points. Eyes with optic nerve attached were carefully dissected, fixed in buffered formalin, embedded in paraffin and 5µm thick sections taken. Sections were then processed for immunohistochemistry and RT-PCR using standard methodologies.
Experimental glaucoma, 2VO and NMDA-induced excitotoxicity all caused the death of a proportion of the RGC population. Following experimental glaucoma and 2VO, but not NMDA, accumulation of the stereotypical marker of fast axonal transport, amyloid precursor protein (APP), was evident within axons in the prelaminar and laminar regions of the ONH. APP immunoreactivity was strongest 1 day after induction of 2VO and 4-7 days after induction of glaucoma. Similar results to APP were obtained with brain-derived neurotrophic factor (BDNF), another molecule synthesised by RGCs and transported along the optic nerve. While investigating the localisation of cytokines after injury, the serendipitous finding was made that interleukin-6 (IL-6) also accumulated at the ONH after experimental glaucoma and 2VO, but not NMDA, with the same time course as APP and BDNF. Immunoreactivity for IL-6 co-localised perfectly with both APP and BDNF within RGC axons. Comparison of the efficacy of the three markers revealed the following order of magnitude: IL-6>APP>BDNF.
Axonal transport failure at the ONH is a feature of chronic ischemia and experimental glaucoma, but not NMDA-induced excitotoxicity, in rats. IL-6 represents a novel, specific, highly efficacious marker of axonal transport disruption.
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