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K. G. Csaky, G. Malek, R. Herrmann, F. Wu, P. Saloupis, S. Cousins; Intravitreal Injection of TNF Causes Decreased Neurosensory Retinal Function in the Mouse: A Potential Mechanism of Vision Loss in Neovascular AMD in vivo. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5158.
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Choroidal neovascularization (CNV) in age-related macular degeneration (AMD) is associated with infiltration of macrophages into CNV and overlying retina, where they presumably secrete inflammatory molecules (i.e, TNFα) and angiogenic factors (i.e.,VEGF). Current treatments for CNV using intravitreal injection of anti-VEGF produces improvement of fluid leakage in most eyes, but vision improvement in only a fraction of eyes with anatomic resolution of leakage. This suggests that mechanisms other than fluid leakage may contribute to retinal dysfunction. We compared functional and anatomical consequences of intravitreal injections of TNFα and VEGF in the mouse.
Twenty four C57BL/6 female mice aged 14-18 wks, were divided into 7 groups: control (no injection), PBS injection, mVEGF-164 injection (0.5µg, 5µg, 50µg), and mTNFα injection (0.5µg, 1.0µg and 10µg) (n=2-5 per group). Fluorescein angiography (FA) was performed post injection. Retinal function was assessed by electroretinography (ERG) following 24hr dark adaptation. Scotopic responses were elicited using a series of stimuli ranging 0.0005-1000 cd-s/m2. Flicker responses to sinusoidal light stimuli ranging 3-50 Hz were recorded under photopic conditions. Eyes were collected and processed for electron microscopy and immunohistochemistical staining (F4/80, Iba-1, vimentin, caveolin-1, GFAP, PKCα, pERK, SV2 and synaptophysin).
FA showed no evidence of NV or leakage in any group. Histologically, no significant morphologic abnormalities in the architecture of the retina were observed in any group. None of the VEGF injected mice demonstrated major changes in scotopic or photopic a- or b-wave amplitudes or implicit times on ERG. However, TNFα injected eyes demonstrated ERG abnormalities. The ERG b-wave amplitudes were reduced in eyes injected with 1.0µg and 10µg of TNFα at both 24 and 48hrs. The amplitudes of the oscillatory potentials and first and second harmonics of the flicker response were reduced in these mice compared to no injection and PBS injected mice.
Retinal dysfunction, in the absence of overt anatomic changes, appears to occur following exposure to TNFα but not VEGF. It is possible that local release of TNFα by infiltrating monocytes could contribute to vision loss in neovascular AMD, and TNFα may be a potential therapeutic target for vision recovery in some eyes. Electrophysiological studies would be required to identify this subset of eyes.
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