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Physiological Effects of Superoxide Dismutase on Altered Visual Function of Retinal Ganglion Cells in db/db Mice  [PDF]
Chunxia Xiao,Meihua He,Yan Nan,Dongjuan Zhang,Baiyu Chen,Youfei Guan,Mingliang Pu
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0030343
Abstract: The C57BLKS/J db/db (db/db) mouse is a widely used type 2 diabetic animal model, and this model develops early inner retinal neuronal dysfunction beginning at 24 weeks. The neural mechanisms that mediate early stage retinal dysfunction in this model are unknown. We evaluated visual response properties of retinal ganglion cells (RGCs) during the early stage of diabetic insult (8, 12, and 20 wk) in db/db mice and determined if increased oxidative stress plays a role in impaired visual functions of RGCs in 20 wk old db/db mice.
Astaxanthin Attenuates the Apoptosis of Retinal Ganglion Cells in db/db Mice by Inhibition of Oxidative Stress  [PDF]
Ling-Yan Dong,Jie Jin,Gao Lu,Xiao-Li Kang
Marine Drugs , 2013, DOI: 10.3390/md11030960
Abstract: Diabetic retinopathy is a common diabetic eye disease caused by changes in retinal ganglion cells (RGCs). It is an ocular manifestation of systemic disease, which affects up to 80% of all patients who have had diabetes for 10 years or more. The genetically diabetic db / db mouse, as a model of type-2 diabetes, shows diabetic retinopathy induced by apoptosis of RGCs. Astaxanthin is a carotenoid with powerful antioxidant properties that exists naturally in various plants, algae and seafood. Here, astaxanthin was shown to reduce the apoptosis of RGCs and improve the levels of oxidative stress markers, including superoxide anion, malondialdehyde (MDA, a marker of lipid peroxidation), 8-hydroxy-2-deoxyguanosine (8-OHdG, indicator of oxidative DNA damage) and MnSOD (manganese superoxide dismutase) activity in the retinal tissue of db / db mouse. In addition, astaxanthin attenuated hydrogen peroxide(H 2O 2)-induced apoptosis in the transformed rat retinal ganglion cell line RGC-5. Therefore, astaxanthin may be developed as an antioxidant drug to treat diabetic retinopathy.
Neurodegeneration: An early event of diabetic retinopathy  [cached]
Marta Villarroel,Andreea Ciudin,Cristina Hernández,Rafael Simó
World Journal of Diabetes , 2010,
Abstract: Diabetic retinopathy (DR) has been classically considered to be a microcirculatory disease of the retina caused by the deleterious metabolic effects of hyperglycemia per se and the metabolic pathways triggered by hyperglycemia. However, retinal neurodegeneration is already present before any microcirculatory abnormalities can be detected in ophthalmoscopic examination. In other words, retinal neurodegeneration is an early event in the pathogenesis of DR which predates and participates in the microcirculatory abnormalities that occur in DR. Therefore, the study of the mechanisms that lead to neurodegeneration will be essential to identify new therapeutic targets in the early stages of DR. Elevated levels of glutamate and the overexpression of the renin- angiotensin-system play an essential role in the neurodegenerative process that occurs in diabetic retina. Among neuroprotective factors, pigment epithelial derived factor, somatostatin and erythropoietin seem to be the most relevant and these will be considered in this review. Nevertheless, it should be noted that the balance between neurotoxic and neuroprotective factors rather than levels of neurotoxic factors alone will determine the presence or absence of retinal neurodegeneration in the diabetic eye. New strategies, based on either the delivery of neuroprotective agents or the blockade of neurotoxic factors, are currently being tested in experimental models and in clinical pilot studies. Whether these novel therapies will eventually supplement or prevent the need for laser photocoagulation or vitrectomy awaits the results of additional clinical research.
Neurodegeneration and Neuroprotection in Diabetic Retinopathy  [PDF]
Mohammad Shamsul Ola,Mohd Imtiaz Nawaz,Haseeb A. Khan,Abdullah S. Alhomida
International Journal of Molecular Sciences , 2013, DOI: 10.3390/ijms14022559
Abstract: Diabetic retinopathy is widely considered to be a neurovascular disease. This is in contrast to its previous identity as solely a vascular disease. Early in the disease progression of diabetes, the major cells in the neuronal component of the retina consist of retinal ganglion cells and glial cells, both of which have been found to be compromised. A number of retinal function tests also indicated a functional deficit in diabetic retina, which further supports dysfunction of neuronal cells. As an endocrinological disorder, diabetes alters metabolism both systemically and locally in several body organs, including the retina. A growing body of evidences indicates increased levels of excitotoxic metabolites, including glutamate, branched chain amino acids and homocysteine in cases of diabetic retinopathy. Also present, early in the disease, are decreased levels of folic acid and vitamin-B12, which are potential metabolites capable of damaging neurons. These altered levels of metabolites are found to activate several metabolic pathways, leading to increases in oxidative stress and decreases in the level of neurotrophic factors. As a consequence, they may damage retinal neurons in diabetic patients. In this review, we have discussed those potential excitotoxic metabolites and their implications in neuronal damage. Possible therapeutic targets to protect neurons are also discussed. However, further research is needed to understand the exact molecular mechanism of neurodegeneration so that effective neuroprotection strategies can be developed. By protecting retinal neurons early in diabetic retinopathy cases, damage of retinal vessels can be protected, thereby helping to ameliorate the progression of diabetic retinopathy, a leading cause of blindness worldwide.
Loss of Synaptic Connectivity, Particularly in Second Order Neurons Is a Key Feature of Diabetic Retinal Neuropathy in the Ins2Akita Mouse  [PDF]
Jose R. Hombrebueno, Mei Chen, Rosana G. Penalva, Heping Xu
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0097970
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.
Diabetes and Overexpression of proNGF Cause Retinal Neurodegeneration via Activation of RhoA Pathway  [PDF]
Mohammed M. H. Al-Gayyar, Barbara A. Mysona, Suraporn Matragoon, Mohammed A. Abdelsaid, Mona F. El-Azab, Ahmed Y. Shanab, Yonju Ha, Sylvia B. Smith, Kathryn E. Bollinger, Azza B. El-Remessy
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0054692
Abstract: Our previous studies showed positive correlation between accumulation of proNGF, activation of RhoA and neuronal death in diabetic models. Here, we examined the neuroprotective effects of selective inhibition of RhoA kinase in the diabetic rat retina and in a model that stably overexpressed the cleavage-resistance proNGF plasmid in the retina. Male Sprague-Dawley rats were rendered diabetic using streptozotosin or stably express cleavage-resistant proNGF plasmid. The neuroprotective effects of the intravitreal injection of RhoA kinase inhibitor Y27632 were examined in vivo. Effects of proNGF were examined in freshly isolated primary retinal ganglion cell (RGC) cultures and RGC-5 cell line. Retinal neurodegeneration was assessed by counting TUNEL-positive and Brn-3a positive retinal ganglion cells. Expression of proNGF, p75NTR, cleaved-PARP, caspase-3 and p38MAPK/JNK were examined by Western-blot. Activation of RhoA was assessed by pull-down assay and G-LISA. Diabetes and overexpression of proNGF resulted in retinal neurodegeneration as indicated by 9- and 6-fold increase in TUNEL-positive cells, respectively. In vitro, proNGF induced 5-fold cell death in RGC-5 cell line, and it induced >10-fold cell death in primary RGC cultures. These effects were associated with significant upregulation of p75NTR and activation of RhoA. While proNGF induced TNF-α expression in vivo, it selectively activated RhoA in primary RGC cultures and RGC-5 cell line. Inhibiting RhoA kinase with Y27632 significantly reduced diabetes- and proNGF-induced activation of proapoptotic p38MAPK/JNK, expression of cleaved-PARP and caspase-3 and prevented retinal neurodegeneration in vivo and in vitro. Taken together, these results provide compelling evidence for a causal role of proNGF in diabetes-induced retinal neurodegeneration through enhancing p75NTR expression and direct activation of RhoA and p38MAPK/JNK apoptotic pathways.
Mesenteric Resistance Arteries in Type 2 Diabetic db/db Mice Undergo Outward Remodeling  [PDF]
Flavia M. Souza-Smith,Paige S. Katz,Aaron J. Trask,James A. Stewart Jr,Kevin C. Lord,Kurt J. Varner,Dalton V. Vassallo,Pamela A. Lucchesi
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0023337
Abstract: Resistance vessel remodeling is controlled by myriad of hemodynamic and neurohormonal factors. This study characterized structural and molecular remodeling in mesenteric resistance arteries (MRAs) in diabetic (db/db) and control (Db/db) mice.
The antidiabetic effects of a dry powder of dietary vegetable and fruit mixtures in diabetic db/db mice
Chung-Man Yeung,Yi Tan,Sidney Tam,Liwei Lu
Biologics: Targets and Therapy , 2008,
Abstract: Chung-Man Yeung1, Yi Tan1, Sidney Tam2, Liwei Lu3, King-Hung Ko3, Pai-Hao Yang1,4, Hsiang-Fu Kung4, Marie C Lin11Department of Chemistry, Open Laboratory of Chemical Biology of the Institute of Molecular Technology, 2Clinical Biochemistry Unit, 3Department of Pathology, The University of Hong Kong, Hong Kong, China; 4Centre of Emerging Infectious Diseases, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, ChinaAbstract: We evaluated the antidiabetic effects of a mixed vegetable powder-formula I (MVP-FI), which is a dry powder mixture of over 65 kinds of vegetables and fruits, using the db/db type 2 diabetes mouse model. The db/db mice at 8–10 weeks of age were randomly divided into three groups: vehicle treatment, 1.575 g/kg MVP-FI treatment, and 3.15 g/kg MVP-FI treatment. During 12 days of treatment, we measured food intake and body weight changes, fasting blood glucose levels, and plasma lipid levels. Our results showed that the food intake and the body weight of MVP-FI-treated group were decreased gradually. Moreover, the fasting blood glucose level of the treated group was significantly dropped to a normal level comparable to that of the lean mice. Furthermore, we also found that the plasma triglyceride level in the treated group was dropped, whereas the high-density lipoprotein (HDL) level was increased and total cholesterol/HDL-cholesterol ratio was decreased. Taken together, these results suggest that the diabetic conditions of the db/db mice have been improved after 12 days treatment with MVP-FI. The antihyperglycemic and antiobese activities of the MVP-FI, as demonstrated in the present study, may have important clinical implications for improving the management of type 2 diabetic patients.Keywords: traditional Chinese medicine (TCM), db/db mice, diabetes
Retinal Layers Changes in Human Preclinical and Early Clinical Diabetic Retinopathy Support Early Retinal Neuronal and Müller Cells Alterations  [PDF]
Stela Vujosevic,Edoardo Midena
Journal of Diabetes Research , 2013, DOI: 10.1155/2013/905058
Abstract: Purpose. To evaluate the changes in thickness of individual inner and outer macular and peripapillary retinal layers in diabetes. Methods. 124 subjects (124 eyes) were enrolled: 74 diabetics and 50 controls. Macular edema, proliferative diabetic retinopathy (DR), any intraocular treatment and refractive error diopters were the main exclusion criteria. Full ophthalmic examination, stereoscopic fundus photography, and spectral domain-OCT were performed. After automatic retinal segmentation (layering) in 5 layers, the thickness of each layer was calculated, and values compared among groups. Results. Thirty patients had no DR, 44 patients had non proliferative DR. A significant increase of inner plexiform and nuclear layers was found in DR eyes versus controls ( ). A significant decrease ( ) of retinal nerve fiber layer (RNFL) and at specific sites of retinal ganglion cell layer ( ) was documented in the macula. In the peripapillary area there were no differences between diabetics and controls. Conclusions. Decreased RNFL thickness and increased INL/OPL thickness in diabetics without DR or with initial DR suggest early alterations in the inner retina. On the contrary, the outer retina seems not to be affected at early stages of DM. Automatic intraretinal layering by SD-OCT may be a useful tool to diagnose and monitor early intraretinal changes in DR. 1. Introduction Diabetic retinopathy (DR) is the first cause of visual impairment and blindness in the adult working-age population [1]. For a long period of time, DR has been considered primarily a retinal microvascular disorder caused by the direct effects of hyperglycemia and by the metabolic pathways it activates [2]. Nevertheless, some recent studies have demonstrated that retinal neurodegeneration (the result of a negative balance between neurotoxic and neuroprotective factors) is present even before the development of clinically detectable microvascular damage. Retinal neurodegeneration may therefore represent an early event in the pathophysiology of DR and may anticipate the onset of microvascular changes [2–4]. The term neurodegeneration used in this paper encompasses pathologic phenomena affecting both the pure neuronal component and the glial one. The hypothesis according to which neurodegeneration precedes the vascular one is confirmed by some electrophysiological and psychophysical studies, which show that the alterations are present even before the microvascular damage becomes ophthalmoscopically or angiographically visible. Such retinal function alterations mainly consist in contrast sensitivity
Edaravone Protect against Retinal Damage in Streptozotocin-Induced Diabetic Mice  [PDF]
Dongqing Yuan, Yidan Xu, Hui Hang, Xiaoyi Liu, Xi Chen, Ping Xie, Songtao Yuan, Weiwei Zhang, Xiaojun Lin, Qinghuai Liu
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0099219
Abstract: Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a free radical scavenger, is used for the clinical treatment of retinal injury. In this study, we investigated the protective effects of edaravone against diabetic retinal damage in the mouse. Diabetic retinopathy in the mouse was induced by injection of streptozotocin. Edaravone was given once-daily and was intraperitoneally (i.p.) treated at a dose of 3 mg/kg from streptozotocin injection to 4 weeks after onset of diabetes. Retinal ganglion cells (RGCs) damage was evaluated by recording the pattern electroretinogram (ERG). RGCs damage was also detected by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and the levels of reactive oxygen species (ROS) were determined fluorometrically. The expressions of phosporylated-ERK1/2, BDNF, and caspase-3 were determined by Western blot analysis. Retinal levels of ROS, phosphorylated ERK1/2, and cleaved caspase-3 were significantly increased, whereas the expression of BDNF was significantly decreased in the retinas of diabetic mice, compared to nondiabetic mice. Administration of edaravone significantly attenuated diabetes induced RGCs death, upregulation of ROS, ERK1/2 phosphorylation, and cleaved caspase-3 and downregulation of BDNF. These findings suggest that oxidative stress plays a pivotal role in diabetic retinal damage and that systemic administration of edaravone may slow the progression of retinal neuropathy induced by diabetes.
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