Neurodegenerative influence of oxidative stress in the retina of a murine model of diabetes.
OBJECTIVE
Diabetic retinopathy is a progressive neurodegenerative disease, but the underlying mechanism is still obscure. Here, we focused on oxidative stress in the retina, and analysed its influence on retinal neurodegeneration, using an antioxidant, lutein.


METHODS
C57BL/6 mice with streptozotocin-induced diabetes were constantly fed either a lutein-supplemented diet or a control diet from the onset of diabetes, and their metabolic data were recorded. In 1-month-diabetic mice, reactive oxygen species (ROS) in the retina were measured using dihydroethidium and visual function was evaluated by electroretinograms. Levels of activated extracellular signal-regulated kinase (ERK), synaptophysin and brain-derived neurotrophic factor (BDNF) were also measured by immunoblotting in the retina of 1-month-diabetic mice. In the retinal sections of 4-month-diabetic mice, histological changes, cleaved caspase-3 and TUNEL staining were analysed.


RESULTS
Lutein did not affect the metabolic status of the diabetic mice, but it prevented ROS generation in the retina and the visual impairment induced by diabetes. ERK activation, the subsequent synaptophysin reduction, and the BDNF depletion in the diabetic retina were all prevented by lutein. Later, in 4-month-diabetic mice, a decrease in the thickness of the inner plexiform and nuclear layers, and ganglion cell number, together with increase in cleaved caspase-3- and TUNEL-positive cells, were avoided in the retina of lutein-fed mice.


CONCLUSIONS
The results indicated that local oxidative stress that has a neurodegenerative influence in the diabetic retina is prevented by constant intake of a lutein-supplemented diet. The antioxidant, lutein may be a potential therapeutic approach to protect visual function in diabetes.
Sasaki
M
M
Laboratory of Retinal Cell Biology, Keio University School of Medicine, Tokyo, Japan.
Ozawa
Y
Y
Kurihara
T
T
Kubota
S
S
Yuki
K
K
Noda
K
K
Kobayashi
S
S
Ishida
S
S
Tsubota
K
K
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D003930:Diabetic Retinopathy / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D019587:Dietary Supplements; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D014975:Lutein / Q000008:administration & dosage* / Q000378:metabolism; D051379:Mice; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D012160:Retina / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016708:Synaptophysin / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D017382:Reactive Oxygen Species; D016708:Synaptophysin; D048049:Extracellular Signal-Regulated MAP Kinases; D014975:Lutein