Effects of Intravitreal Endothelin-1 on Anterograde Axonal Transport in Rat Optic Nerve: Evaluating a Possible Mechanism for Glaucomatous Optic Neuropathy

Stokely, Martha Elise Lambert, Effects of Intravitreal Endothelin-1 on Anterograde Axonal Transport in Rat Optic Nerve: Evaluating a possible mechanism for glaucomatous optic neuropathy. Doctor of Philosophy (Biomedical Sciences and Neuroscience), May 2002; 114 pages; 1 table; 12 figures; bibliography, 274 titles. Glaucoma presents a distinctive dysfunction in anterograde axonal transport that disproportionately affects the delivery of specific types of cargo(s) into the optic nerve. Previous models for pathogenesis of glaucoma have failed to provide an adequate mechanism to explain the characteristic cargo-selectivity. A new theoretical model, the “endothelin receptor-mediated model of neuropathogenesis,” was developed to explain the cargo-selective axonal transport dysfunction seen in glaucomtous optic neuropathy. In addition, a new experimental animal model, the “intravitreal endothlin/axonal transport” model was developed to test hypotheses generated by the new theoretical model. Intravitreal endothelin-1 significantly affected all of the known rate components and subcomponents of anterograde axonal transport in the rat optic nerve. Changes were seen in anterograde axonal transport in the rat optic nerve. Changes were seen in anterograde fast axonal transport for both the fastest moving small tubulovesicles, and slightly slower membrane bound organelles (MBOs), as well as in the slow transport of cytoplasmic matrix and cytoskeletal materials. Endothelin-1’s predominant effect was a severe depression in the mitochondrial subcomponent of fast anterograde axonal transport, which was most pronounced at 28 hours post-treatment. At that time, the effects of endothelin-1 were mimicked by endothelin-3, characteristic of the non-ischemic endothelin-B type of receptor. In addition, analysis of a cohort of 11 distinctive protein bands moving with the mitochondrial subcomponent demonstrated a cargo-selective effect of endothelin-1 and the delayed movement into the optic nerve for a chemically distinct subset of proteins, but not the majority of protein, in transport during this timeframe. These results appear to be consistent with what is known about the pathology of glaucomatous optic neuropathy and the neurochemistry of anterograde axonal transport and suggest that intravitreal may be an excellent model to study the mechanisms of neurodegeneration that occurs in glaucoma.