Enteral arg-gln dipeptide administration increases retinal docosahexaenoic acid and neuroprotectin D1 in a murine model of retinopathy of prematurity

Lynn Calvin Shaw, Sergio Li Calzi, Nan Li, Leni Moldovan, Nilanjana Sengupta-Caballero, Judith Lindsey Quigley, Mircea Ivan, Bokkyoo Jun, Nicolas G. Bazan, Michael Edwin Boulton, Julia Busik, Josef Neu, Maria B. Grant

Research output: Contribution to journalArticle

Abstract

PURPOSE. Low 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). METHODS. Postnatal 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). RESULTS. With 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. CONCLUSIONS. Arg-Gln may serve as a safer and easily tolerated nutraceutical agent for prevention or treatment of ROP.

Original languageEnglish (US)
Pages (from-to)858-869
Number of pages12
JournalInvestigative Ophthalmology and Visual Science
Volume59
Issue number2
DOIs
StatePublished - Feb 1 2018

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arginyl-glutamine
Retinopathy of Prematurity
Docosahexaenoic Acids
Dipeptides
Small Intestine
Oxygen
Dietary Supplements
Blood Vessels
Retina
Apoptosis
Somatomedin Receptors
Protein Array Analysis
Glutamine
Unsaturated Fatty Acids
Premature Infants
Oral Administration
Arginine
protectin D1
Air
Hemorrhage

Keywords

  • Arg-gln dipeptide
  • Docosahexaenoic acid
  • Neutraceuticals
  • Oxygen-induced retinopathy
  • Retinal proteomic analysis

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Enteral arg-gln dipeptide administration increases retinal docosahexaenoic acid and neuroprotectin D1 in a murine model of retinopathy of prematurity. / Shaw, Lynn Calvin; Calzi, Sergio Li; Li, Nan; Moldovan, Leni; Sengupta-Caballero, Nilanjana; Quigley, Judith Lindsey; Ivan, Mircea; Jun, Bokkyoo; Bazan, Nicolas G.; Boulton, Michael Edwin; Busik, Julia; Neu, Josef; Grant, Maria B.

In: Investigative Ophthalmology and Visual Science, Vol. 59, No. 2, 01.02.2018, p. 858-869.

Research output: Contribution to journalArticle

Shaw, LC, Calzi, SL, Li, N, Moldovan, L, Sengupta-Caballero, N, Quigley, JL, Ivan, M, Jun, B, Bazan, NG, Boulton, ME, Busik, J, Neu, J & Grant, MB 2018, 'Enteral arg-gln dipeptide administration increases retinal docosahexaenoic acid and neuroprotectin D1 in a murine model of retinopathy of prematurity', Investigative Ophthalmology and Visual Science, vol. 59, no. 2, pp. 858-869. https://doi.org/10.1167/iovs.17-23034
Shaw, Lynn Calvin ; Calzi, Sergio Li ; Li, Nan ; Moldovan, Leni ; Sengupta-Caballero, Nilanjana ; Quigley, Judith Lindsey ; Ivan, Mircea ; Jun, Bokkyoo ; Bazan, Nicolas G. ; Boulton, Michael Edwin ; Busik, Julia ; Neu, Josef ; Grant, Maria B. / Enteral arg-gln dipeptide administration increases retinal docosahexaenoic acid and neuroprotectin D1 in a murine model of retinopathy of prematurity. In: Investigative Ophthalmology and Visual Science. 2018 ; Vol. 59, No. 2. pp. 858-869.
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abstract = "PURPOSE. Low 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). METHODS. Postnatal 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). RESULTS. With 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. CONCLUSIONS. Arg-Gln may serve as a safer and easily tolerated nutraceutical agent for prevention or treatment of ROP.",
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T1 - Enteral arg-gln dipeptide administration increases retinal docosahexaenoic acid and neuroprotectin D1 in a murine model of retinopathy of prematurity

AU - Shaw, Lynn Calvin

AU - Calzi, Sergio Li

AU - Li, Nan

AU - Moldovan, Leni

AU - Sengupta-Caballero, Nilanjana

AU - Quigley, Judith Lindsey

AU - Ivan, Mircea

AU - Jun, Bokkyoo

AU - Bazan, Nicolas G.

AU - Boulton, Michael Edwin

AU - Busik, Julia

AU - Neu, Josef

AU - Grant, Maria B.

PY - 2018/2/1

Y1 - 2018/2/1

N2 - PURPOSE. Low 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). METHODS. Postnatal 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). RESULTS. With 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. CONCLUSIONS. Arg-Gln may serve as a safer and easily tolerated nutraceutical agent for prevention or treatment of ROP.

AB - PURPOSE. Low 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). METHODS. Postnatal 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). RESULTS. With 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. CONCLUSIONS. Arg-Gln may serve as a safer and easily tolerated nutraceutical agent for prevention or treatment of ROP.

KW - Arg-gln dipeptide

KW - Docosahexaenoic acid

KW - Neutraceuticals

KW - Oxygen-induced retinopathy

KW - Retinal proteomic analysis

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