Long-term lutein administration attenuates retinal inflammation and functional deficits in early diabetic retinopathy using the Ins2^Akita/+mice

Abstract

IntroductionLutein is a carotenoid whose protective effects in the retina have been reported in various studies. The effect of lutein has not been reported in the retina of the Ins2Akita/+ mouse, a well-characterized genetic model for diabetic retinopathy (DR) in which the etiology of diabetes is better defined than the chemically induced diabetes. The objective of the present study is to investigate the effect of long-term administration of lutein in early stages of DR using the Ins2Akita/+ mouse.Research design and methodsHeterozygous male Ins2Akita/+ and age-matched wild-type mice were used. Lutein was administered to the mice in drinking water starting 6 weeks old daily until analysis at 4.5, 6.5 or 9 months of age. Plain water served as non-treatment control. Microglia were immunostained with ionized calcium-binding adapter molecule 1 (Iba-1) and cluster of differentiation 68 (CD68) in retinal flat-mounts. Vascular endothelial growth factor (VEGF) level in the retina was assessed by enzyme-linked immunosorbent assay (ELISA). Vascular permeability was analyzed in retinal flat-mounts after fluorescein isothiocyanate (FITC)-dextran perfusion. Retinal occludin expression was assessed via Western blots. Retinal function was examined by electroretinography (ERG).ResultsIncreased microglial reactivity was detected in the Ins2Akita/+ mouse retina and was suppressed by lutein. Lutein administration also reduced the upregulation of VEGF in the Ins2Akita/+ mouse retina. Increased vascular leakage and decreased occludin expression were observed in the Ins2Akita/+ mouse retina, and these alterations were attenuated by lutein treatment. ERG recordings showed reduced a-wave and b-wave amplitudes in the Ins2Akita/+ mice. With lutein treatment, the ERG deficits were significantly alleviated.ConclusionsWe showed beneficial effects of long-term lutein administration in the Ins2Akita/+ mouse retina, including suppression of retinal inflammation, protection of retinal vasculature and preservation of retinal function. These results point to lutein’s potential as a long-term therapeutic intervention for prevention of inflammation and retinal degeneration in patients with early DR.

Neurovascular unit in diabetic retinopathy: pathophysiological roles and potential therapeutical targets

“…• Anti-oxidative stress • Anti-inflammation • Anti-angiogenesis • Decrease of retinal neurons apoptosis [153][154][155][156][157][158] Carotenoids (Lutein, Zeaxanthin) [160][161][162][163][164] Anti-inflammation agents TNFα antagonist (Etanercept, Adalimumab, Infliximab)…”

“…In type 2 diabetics, an increased thickness in the central fovea and improved retinal response density were observed after a two-year supplementation of combined lutein (10mg/day), zeaxanthin (2mg/day) and meso-zeaxanthin (10mg/day) [ 162 ]. The studies using diabetic animal models to investigate lutein and zeaxanthin effects have also demonstrated protection from diabetes-induced retinal apoptosis, abnormal capillaries formation, and visual dysfunction through decreased ROS, and inflammatory factors such as VEGF, IL-1β, and NF-ΚB in the retina [ 159 , 163 , 164 ].…”

“…Lutein and zeaxanthin, the carotenoids highly concentrated in the retina, play a major role in filtering blue light, preventing oxidative damage and protecting neural retina [159][160][161][162][163][164]. In non-proliferative DR patients, the serum concentration of lutein and zeaxanthin was significantly lower than individuals without diabetes [160].…”

Lutein attenuates angiotensin II- induced cardiac remodeling by inhibiting AP-1/IL-11 signaling

“…Lutein, a natural dihydroxycarotenoid, can be obtained from a wide variety of fruits and vegetables [ 16 ]. Dramatically, lutein has been reported to inhibit inflammation in diabetic retinopathy (DR) [ 17 ] and coronary artery disease [ 18 ] and exert antioxidative effects on cerebrovascular endothelial cells [ 19 ] and retinal pigment epithelial (ARPE-19) cells [ 20 ]. Moreover, many randomized clinical trials have reported that a lutein-rich diet decreases the incidence of nonalcoholic fatty liver disease [ 21 ], age-related macular degeneration (AMD) [ 22 ], breast cancer [ 23 ] and cognitive dysfunction [ 24 ] and reduces the risk of cardiovascular events, including atrial fibrillation [ 25 ], atherosclerosis [ 26 ] and hypertension [ 27 ].…”

Anti-Apoptotic Effects of Carotenoids in Neurodegeneration

“…Along with zeaxanthin, it is the only carotenoid that is found in the macula of the eye after crossing the blood-retina barrier [155]. Treatment with lutein attenuates retinopathy associated with photo stress, inflammation, and oxidative stress [156][157][158], and dietary lutein prevents aging-and diabetes-related eye diseases [159,160]. Lutein also crosses the blood-brain barrier to allow for delivery to various regions of the brain.…”