Isolated axonal strokes comprise more than 3/4ths of the 166,000 strokes that occur in the US every year, but until now there has been no in-vivo model to analyze this stroke form. We have developed a new rodent anterior ischemic optic neuropathy (rAION) model of CNS axonal stroke that directly correlates with human AION. We have characterized the response of the neurons and optic nerve following axonal stroke. We have determined that rAlON results in optic nerve demyelination and loss of function. We have also found that estrogen significantly reduces the loss of neurons following rAION. We hypothesize that: 1) axon ischemia-associated demyelination blocks optic nerve repair. 2) Estrogen enhances post-stroke optic nerve recovery. Our proposal is designed to answer three related questions: 1) What RGC axonal transport and glial changes occur in-vivo following rAION, contributing to permanent optic nerve damage? To answer this question, we will use the rAION model to define early retina and optic nerve stress-related cellular events, and identify the time course of optic nerve demyelination and remodeling resulting from optic nerve stroke. This work will be performed using histological, electrophysiological, and molecular methods. 2) Can reducing post-stroke demyelination increase post-stroke function? With the rAION model, we will use anti-demyelinating drugs, to determine whether reducing post-stroke demyelination decreases permanent optic nerve damage and increases function. This work will be performed using electrophysiological, stereotactic retrograde tracing, molecular, and histological methods. 3) Does estrogen also exert neuroprotective effects when administered after optic nerve insult? With the rAION model, estrogen and estrogen inhibitors, electrophysiological, histological, stereotactic, and molecular methods, we will determine the effect of differences in dose, timing, sex, and blockade of endogenous estrogen. Our experimental results obtained with this model will enable rational design of clinically effective, neuroprotective strategies that can minimize ischemic axonal stroke damage.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Special Emphasis Panel (ZRG1-VISC (01))
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Liberman, Ellen S
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University of Maryland Baltimore
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Mehrabian, Zara; Guo, Yan; Weinreich, Daniel et al. (2017) Oligodendrocyte death, neuroinflammation, and the effects of minocycline in a rodent model of nonarteritic anterior ischemic optic neuropathy (rNAION). Mol Vis 23:963-976
Guo, Yan; Mehrabian, Zara; Bernstein, Steven L (2016) The Rodent Model of Nonarteritic Anterior Ischemic Optic Neuropathy (rNAION). J Vis Exp :
Nicholson, James D; Guo, Yan; Bernstein, Steven L (2016) SUR1-Associated Mechanisms Are Not Involved in Ischemic Optic Neuropathy 1 Day Post-Injury. PLoS One 11:e0148855
Guo, Yan; Johnson, Mary A; Mehrabian, Zara et al. (2016) Dendrimers Target the Ischemic Lesion in Rodent and Primate Models of Nonarteritic Anterior Ischemic Optic Neuropathy. PLoS One 11:e0154437
Bernstein, Steven L; Miller, Neil R (2015) Ischemic optic neuropathies and their models: disease comparisons, model strengths and weaknesses. Jpn J Ophthalmol 59:135-47
Mathews, Michaela K; Guo, Yan; Langenberg, Patricia et al. (2015) Ciliary neurotrophic factor (CNTF)-mediated ganglion cell survival in a rodent model of non-arteritic anterior ischaemic optic neuropathy (NAION). Br J Ophthalmol 99:133-7
Ziesel, Alison; Bernstein, Steven; Wong, Paul W (2014) Generation of a foveomacular transcriptome. Mol Vis 20:947-54
Slater, Bernard J; Vilson, Fernandino L; Guo, Yan et al. (2013) Optic nerve inflammation and demyelination in a rodent model of nonarteritic anterior ischemic optic neuropathy. Invest Ophthalmol Vis Sci 54:7952-61
Touitou, Valerie; Johnson, Mary A; Guo, Yan et al. (2013) Sustained neuroprotection from a single intravitreal injection of PGJ2 in a rodent model of anterior ischemic optic neuropathy. Invest Ophthalmol Vis Sci 54:7402-9
Nicholson, James D; Puche, Adam C; Guo, Yan et al. (2012) PGJ(2) provides prolonged CNS stroke protection by reducing white matter edema. PLoS One 7:e50021

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