Inhibition of Polyamine Oxidase Reduces Excitotoxicity‐mediated Retinal Neuro‐inflammation

Abstract

Cellular damage resulting from polyamine catabolism has been demonstrated to be a major player in many neurodegenerative conditions of the central nervous system. We have previously shown that inhibition of polyamine oxidase (PAO) using MDL 72527 significantly reduced neurodegeneration and cell death signaling pathways in hyperoxia‐mediated retinal neurodegeneration (Narayanan et al 2014). In the present study we investigated the impact of PAO inhibition in NMDA (N‐Methyl‐D‐aspartate)induced excitotoxic retinal neurodegeneration. A marked increase in retinal ganglion cell (RGC) death was observed in NMDA treated retinas compared to their sham and NMLA (N‐Methyl‐L‐aspartate) treated controls, as studied by quantitation of NeuN‐positive RGCs. Treatment using MDL 72527 reduced this RGC loss in NMDA treated retinas. This was confirmed by TUNEL labeling studies and morphometry analysis on retinal sections. Further studies demonstrated increased activation of microglia (studied by Iba1 immunostaining) and elevated ROS (reactive oxygen species) formation in NMDA treated retina, suggesting the involvement of inflammatory signaling in NMDA mediated neuronal injury. These changes were abrogated in response to PAO inhibition. Analysis of signaling pathways activated in response to excitotoxicity, showed increased level in BID expression, which was reduced by MDL 72527 treatment. Taken together, our data demonstrate that PAO inhibition offers a new therapeutic target for limiting central nervous system neuroinflammatory diseases.