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Jeremy M Sivak, Darren Chan, Xiaoxin Guo, Izzy Livne-Bar; Pharmacologic Inhibition of Intermediate Filament Accumulation in Astrocytes and Müller Glia Mediates Retinal Neuroprotection. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4187.
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© ARVO (1962-2015); The Authors (2016-present)
Astrocyte reactivity in the retina is primarily characterized by accumulations of the type III intermediate filaments (IFs) vimentin and glial fibrillary acidic protein (GFAP). However it has proven challenging to modulate this accumulation under pathological conditions to explore the roles of this process experimentally. We conducted experiments with the small molecule antagonist, withaferin A (WFA), to block type III IF dynamics in vivo in conjunction with metabolic retinal injury, and in combination with a model of induced astrocyte reactivity.
Apoptosis of inner retinal neurons was induced in C57bl/6 mice by excitotoxic injury in combination with vehicle or WFA treatment. This injury model has been established to be dependent on astrocyte and müller glial derived secretion of TNF-α. In addition, this model was combined with induced retinal glial reactivity through transient corneal injury. Glial reactivity and retinal ganglion cell (RGC) apoptosis were imaged and quantified through immunofluorescence microscopy. TNF-α levels were also measured by immunofluorescent and ELISA based methods.
WFA treatment significantly blocked glial reactivity and RGC apoptosis by 80% and 60%, respectively. Induced glial reactivity exacerbated the gliosis by 16 fold, and RGC damage by 7 fold. This increased vulnerability in both parameters was completely rescued by WFA treatment. WFA inhibited p38 mediated TNF-α secretion in cultured retinal astrocytes, and significantly reduced injury induced TNF-α immunoreactivity in the inner retina in vivo.
Inhibition of IF dynamics effectively protected the inner retina from excitoxic damage. Our results suggest this mechanism is regulated through release of TNF-α by retinal astrocytes and müller glia.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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