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Pavlina Tsoka, Keiko Kataoka, Joan W Miller, Demetrios G. Vavvas; NMDA-induced Retinal Excitotoxicity Triggers Inflammation and Inflammasome Activation in Mice.. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2248.
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© 2017 Association for Research in Vision and Ophthalmology.
Overactivation of the N-methyl-D-aspartate (NMDA) receptor results in excitotoxic cell death and has been implicated in various eye disorders. However, the death modality and the inflammatory response following NMDA-induced retinal injury have not been fully characterized. Our purpose was to investigate the time course of cell death, the inflammatory response and the role of the NLRP3 inflammasome in experimental NMDA-induced retinal excitotoxicity.
NMDA-induced retinal excitotoxicity was induced in C57BL/6 mice by an intravitreal injection of 2 ul of NMDA (100nmoles), while the control group received an intravitreal injection of 2 ul of vehicle only (PBS). A time course of retinal cell death was assessed by TUNEL assay. The inflammatory process following NMDA-induced retinal injury was evaluated by macrophage/microglia infiltration and inflammatory cytokines secretion by immunohistochemistry and RT-PCR respectively. Induction of NLRP3 inflammasome by NMDA excitotoxicity in the retina was assessed by RT-PCR and ELISA. Finally, the neuroprotective role of inflammasome inhibition in NMDA-induced retinal excitotoxicity was investigated in NLRP3 and caspase-1/11 KO mice.
NMDA intravitreal administration resulted in rapid cell death of several types of retinal neurons, starting 4 hours post injury with cells in the inner nuclear layer (INL) and followed 12 hours post injury with retinal ganglion cell layer and photoreceptors. Cell death peaked 24 hours post injection for all retina layers. Monocyte chemoattractant protein 1, macrophage/microglia infiltration and Interleukin-1β secretion peaked 24 hours post injury, while NLRP3 and caspase-1 levels peaked 7 days post injury. Furthermore, cell death in the INL was significantly reduced in caspase 1/11 KO and NLRP3 KO mice.
Conclusions: This study contributes to the understanding of the NMDA-induced excitotoxicity in the retina and highlights the role of inflammatory response following this type of injury. In addition it suggests potential therapeutic targets for diseases where excitotoxicity by the NMDA receptor is involved.
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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