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Steven L Bernstein, Yan Guo, Valerie Touitou, Zara Mehrabyan; NAION: Analysis of the cellular immune response and treatment targeting. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5858.
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© ARVO (1962-2015); The Authors (2016-present)
We recently demonstrated that optic nerve lesion in clinical specimens and in both the primate (pNAION) and rodent (rAION) NAION models generates a strong, stereotypical cellular immune response that extends over days and weeks (Salgado and Vilson, 2012; Zhang et al 2008). Cellular macrophage responses can be either M1 (classical neurodegenerative) or M2 (alternative-neuroprotective). We wanted to use the rAION model to: 1) Evaluate the specific M-type response in the primary and secondary optic nerve damage regions; 2) Determine whether we could switch the M-type response by pharmacological means.
We utilized Sprague-Dawley male rats and induced rAION in one eye; the second eye was left as a control. Animals were treated post-induction with either vehicle, minocycline (30mg/kg/IP/day, or administered an intraventricular dose of IL4+TGFβ. Tissues were collected from the lamina and distal ON at a variety of times post-induction, and evaluated for M1 markers CD16/32 and iNOS, M2 markers Arginase-1 (Arg1) and Ym1, and microglia and universal immune cell markers CD11b and Iba1.
The primary ON lesion at the lamina in vehicle treated animals exhibited a strong M1 response by 3 days and continued to at least 7 days post-induction, with upregulation of M1 markers. . Early and late analysis of the primary lesion in treated animals revealed a only a modest M2 response, in the minocycline treatment group, with continuing M1 expression. Interestingly, Arg-1 expression was also seen. Although axons degenerate along the entire ON with oligodendrocyte death, there was minimal M1 response in the distal ON at either 7- or 30 days post-induction, in either vehicle or minocycline-treated animals.
NAION likely induces a strong early (3-7d) M1 cellular response at the primary lesion, with minimal alteration of the M1/M2 macrophage response in regions with only secondary axonal degeneration. The lack of M2 response in animals given minocycline after induction, compared with the reported neuroprotective response in animals given minocycline prior to treatment (Fel et al, 2014), as well as the reported post-induction neuroprotection in rodents and primates using prostaglandin J2 suggests that minocycline may be ineffective when given after ON damage has commenced.
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