Enteral Arg-Gln Dipeptide Administration Increases Retinal Docosahexaenoic Acid and Neuroprotectin D1 in a Murine Model of Retinopathy of Prematurity

Abstract

PurposeLow levels of the long chain polyunsaturated fatty acid (LCPUFA) docosahexaenoic acid (DHA) have been implicated in retinopathy of prematurity (ROP). However, oral DHA suffers from poor palatability and is associated with increased bleeding in premature infants. We asked whether oral administration of the neutraceutical arginine-glutamine (Arg-Glu) could increase retinal DHA and improve outcomes in a mouse model of oxygen-induced retinopathy (OIR).MethodsPostnatal day 7 (P7) pups were maintained at 75% oxygen for 5 days and then returned to room air on P12. Pups were gavaged twice daily with Arg-Gln or vehicle from P12 to P17 and eyes were harvested for analysis on P17. Vaso-obliteration and vascular density were assessed on retinal flat mounts and preretinal neovascularization was assessed on retinal cross sections. Retinas were used for measurement of DHA and 10,17S-docosatriene (neuroprotectin D1, NPD1), a key DHA-derived lipid, and for analysis by reverse-phase protein array (RPPA).ResultsWith Arg-Gln treatment, retinal DHA and NPD1 levels were increased in OIR pups. Arg-Gln reduced preretinal neovascularization by 39 ± 6% (P < 0.05) relative to vehicle control. This was accompanied by a restoration of vascular density of the retina in the pups treated with Arg-Gln (73.0 ± 3.0%) compared to vehicle (53.1 ± 3.4%; P < 0.05). Arg-Gln dipeptide restored OIR-induced signaling changes toward normoxia and was associated with normalization of insulin-like growth factor receptor 1 signaling and reduction of apoptosis and an increase in anti-apoptosis proteins.ConclusionsArg-Gln may serve as a safer and easily tolerated nutraceutical agent for prevention or treatment of ROP.

Amino acid transporter SLC38A5 regulates developmental and pathological retinal angiogenesis

“…Providing much needed AAs early on might promote normalization of delayed vessel growth, and thereby preventing the neovascular phase of retinopathy. Previously, supplement of an arginine-glutamine (Arg-Glu) dipeptide was found to dampen pathological neovascularization in OIR by promoting normal vascular restoration (85,86). Here our data suggest lack of SLC38A5, and likely subsequent impaired glutamine uptake, dampens developmental angiogenesis, in line with the pro-angiogenic role of AAs in the first phase of retinopathy.…”

Metabolomic shifts associated with heat stress in coral holobionts

“…Dipeptides also serve a diversity of other functions such as small-molecule regulators [e.g., H + buffers (27), antioxidants (28), and glucose regulators (29)]. RQ has been shown to ameliorate the impacts of oxygen imbalance in retinopathy of prematurity in murine models (30) and may have beneficial effects on the reversal of oxygen-induced lung damage (31). Some known primary metabolites have incrementally increased intensities during prolonged thermal stress in M. capitata.…”

Evaluation of Plasma Amino Acid Levels in Preterm Infants and Their Potential Correlation with Retinopathy of Prematurity

“…However, in contrast to these findings, Neu et al [ 19 ] previously demonstrated that the administration of dipeptide arginine and glutamine (Arg-Gln) dramatically inhibited retinal neovascularization by decreasing vascular endothelial growth factor (VEGF) mRNA levels in retinal tissue in an oxygen-induced retinopathy (OIR) model. Similarly, Shaw et al [ 20 ] showed a significant reduction in pre-retinal neovascularization and vaso-obliteration in pups that received dipeptide Arg-Gln supplementation in an OIR model through the restoration of retinal docosahexaenoic acid (DHA) and neuroprotectin D1 levels.…”