Abstract
Hyperoxia treatment has been known to induce neuronal and glial death in the developing central nervous system. Retinopathy of prematurity (ROP) is a devastating disease in premature infants and a major cause of childhood vision impairment. Studies indicate that, in addition to vascular injury, retinal neurons are also affected in ROP. Using an oxygen-induced retinopathy (OIR) mouse model for ROP, we have previously shown that deletion of the arginase 2 (A2) significantly reduced neuro-glial injury and improved retinal function. In the current study, we investigated the mechanism of A2 deficiency-mediated neuroprotection in the OIR retina. Hyperoxia treatment has been known to induce neuronal death in neonates. During the hyperoxia phase of OIR, a significant increase in the number of apoptotic cells was observed in the wild-type (WT) OIR retina compared with A2-deficient OIR. Mass spectrometric analysis showed alterations in polyamine metabolism in WT OIR retina. Further, increased expression level of spermine oxidase was observed in WT OIR retina, suggesting increased oxidation of polyamines in OIR retina. These changes were minimal in A2-deficient OIR retina. Treatment using the polyamine oxidase inhibitor, N, N′-bis (2, 3-butadienyl)-1, 4-butanediamine dihydrochloride, significantly improved neuronal survival during OIR treatment. Our data suggest that retinal arginase is involved in the hyperoxia-induced neuronal degeneration in the OIR model, through the regulation of polyamine metabolism.
Highlights
From the clinical perspective, Retinopathy of prematurity (ROP) is considered as a vascular disease and current treatments such as laser photocoagulation and cryotherapy target abnormal retinal angiogenesis
Using the oxygeninduced retinopathy (OIR) mouse model of ROP, we have previously shown a significant increase in retinal cell death immediately following hyperoxia treatment.[18]
After 24 h of hyperoxia there was a significant increase in the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells in the wild-type (WT) OIR retina compared with room air (RA) controls (Po0.01)
Summary
ROP is considered as a vascular disease and current treatments such as laser photocoagulation and cryotherapy target abnormal retinal angiogenesis. Various studies including ours confirmed neuronal apoptosis and/or retinal degeneration in the ROP retina.[14,15,16,17,18] the cellular mechanisms causing this neurodegeneration are still unknown. Oxygen treatment has been identified as a trigger of neuronal and glial apoptosis in the developing brain[3,19,20] and adult retinal neurons.[21,22,23]. Based on this evidence it is suggested that hyperoxiamediated neuronal death could be a major cause for visual dysfunction in ROP. We investigated whether arginase/polyamine signaling mechanisms are associated with the neurodegeneration in ROP retina
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