Article

Neural Degeneration in the Retina of the Streptozotocin-Induced Type 1 Diabetes Model

Laboratory of Retinal Cell Biology, Keio University School of Medicine, 35 Shinanomachi, Tokyo 160-8582, Japan.
Experimental Diabetes Research (Impact Factor: 3.54). 11/2011; 2011(11):108328. DOI: 10.1155/2011/108328
Source: PubMed

ABSTRACT Diabetic retinopathy, a vision-threatening disease, has been regarded as a vascular disorder. However, impaired oscillatory potentials (OPs) in the electroretinogram (ERG) and visual dysfunction are recorded before severe vascular lesions appear. Here, we review the molecular mechanisms underlying the retinal neural degeneration observed in the streptozotocin-(STZ-) induced type 1 diabetes model. The renin-angiotensin system (RAS) and reactive oxygen species (ROS) both cause OP impairment and reduced levels of synaptophysin, a synaptic vesicle protein for neurotransmitter release, most likely through excessive protein degradation by the ubiquitin-proteasome system. ROS also decrease brain-derived neurotrophic factor (BDNF) and inner retinal neuronal cells. The influence of both RAS and ROS on synaptophysin suggests that RAS-ROS crosstalk occurs in the diabetic retina. Therefore, suppressors of RAS or ROS, such as angiotensin II type 1 receptor blockers or the antioxidant lutein, respectively, are potential candidates for neuroprotective and preventive therapies to improve the visual prognosis.

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    • "Synaptophysin knockout mice exhibited a significant decrease in synaptic vesicles in retinal rod photoreceptors which disturbs neurotransmitter release and synaptic network activity [27]. Previous studies demonstrated that 1 month of diabetes decreases retinal expression of synaptophysin [3, 28–30]. TH is the rate-limiting biosynthetic enzyme for dopamine synthesis. "
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    ABSTRACT: To test the hypothesis that increased expression of proinflammatory cytokine high-mobility group box-1 (HMGB1) in epiretinal membranes and vitreous fluid from patients with proliferative diabetic retinopathy and in retinas of diabetic rats plays a pathogenetic role in mediating diabetes-induced retinal neuropathy. Retinas of 1-month diabetic rats and HMGB1 intravitreally injected normal rats were studied using Western blot analysis, RT-PCR and glutamate assay. In addition, we studied the effect of the HMGB1 inhibitor glycyrrhizin on diabetes-induced biochemical changes in the retina. Diabetes and intravitreal injection of HMGB1 in normal rats induced significant upregulation of HMGB1 protein and mRNA, activated extracellular signal-regulated kinase 1 and 2 (ERK1/2), cleaved caspase-3 and glutamate; and significant downregulation of synaptophysin, tyrosine hydroxylase, glutamine synthetase, and glyoxalase 1. Constant glycyrrhizin intake from the onset of diabetes did not affect the metabolic status of the diabetic rats, but it significantly attenuated diabetes-induced upregulation of HMGB1 protein and mRNA, activated ERK1/2, cleaved caspase-3, and glutamate. In the glycyrrhizin-fed diabetic rats, the decrease in synaptophysin, tyrosine hydroxylase, and glyoxalase 1 caused by diabetes was significantly attenuated. These findings suggest that early retinal neuropathy of diabetes involves upregulated expression of HMGB1 and can be ameliorated by inhibition of HMGB1.
    Mediators of Inflammation 09/2014; 2014(11):746415. DOI:10.1155/2014/746415 · 3.24 Impact Factor
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    • "Gao et al. [40] reported a reduction in OPL thickness and OCT-reflectance in patients with mild DR. It has been proposed that the collapse of synaptic structures may be related to the generation of reactive oxygen species [41], [15], a condition that is particularly aggravated in 9-month old Ins2Akita mice [33]. Furthermore, previous studies have shown that hyperglycemic stress can also impair synaptic function in the nervous system [42], [43]. "
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    ABSTRACT: Retinal neurodegeneration is a key component of diabetic retinopathy (DR), although the detailed neuronal damage remains ill-defined. Recent evidence suggests that in addition to amacrine and ganglion cell, diabetes may also impact on other retinal neurons. In this study, we examined retinal degenerative changes in Ins2Akita diabetic mice. In scotopic electroretinograms (ERG), b-wave and oscillatory potentials were severely impaired in 9-month old Ins2Akita mice. Despite no obvious pathology in fundoscopic examination, optical coherence tomography (OCT) revealed a progressive thinning of the retina from 3 months onwards. Cone but not rod photoreceptor loss was observed in 3-month-old diabetic mice. Severe impairment of synaptic connectivity at the outer plexiform layer (OPL) was detected in 9-month old Ins2Akita mice. Specifically, photoreceptor presynaptic ribbons were reduced by 25% and postsynaptic boutons by 70%, although the density of horizontal, rod- and cone-bipolar cells remained similar to non-diabetic controls. Significant reductions in GABAergic and glycinergic amacrine cells and Brn3a+ retinal ganglion cells were also observed in 9-month old Ins2Akita mice. In conclusion, the Ins2Akita mouse develops cone photoreceptor degeneration and the impairment of synaptic connectivity at the OPL, predominately resulting from the loss of postsynaptic terminal boutons. Our findings suggest that the Ins2Akita mouse is a good model to study diabetic retinal neuropathy.
    PLoS ONE 05/2014; 9(5):e97970. DOI:10.1371/journal.pone.0097970 · 3.23 Impact Factor
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    • "Since neurodegeneration in diabetic animal models can potentially be detected by ERG [59], preliminary ERG studies were conducted to determine whether neurodegeneration occurs in the AK-SMAA-GFP-hAR mice. Compared to nondiabetic SMAA-GFP-hAR mice, AK-SMAA-GFP-hAR mice demonstrated a decrease in the b-wave maximum response (Fig. 5). "
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    PLoS ONE 12/2012; 7(12):e49422. DOI:10.1371/journal.pone.0049422 · 3.23 Impact Factor
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