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Mu J, Zhang Z, Jiang C, Geng H, Duan J. Role of Tau Protein Hyperphosphorylation in Diabetic Retinal Neurodegeneration. J Ophthalmol 2025; 2025:3278794. [PMID: 40109357 PMCID: PMC11922625 DOI: 10.1155/joph/3278794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 12/25/2024] [Accepted: 02/22/2025] [Indexed: 03/22/2025] Open
Abstract
Diabetic retinal neurodegeneration (DRN) is an early manifestation of diabetic retinopathy (DR) characterized by neurodegeneration that precedes microvascular abnormalities in the retina. DRN is characterized by apoptosis of retinal ganglion cells (involves alterations in retinal ganglion cells [RGCs], photoreceptors, amacrine cells and bipolar cells and so on), reactive gliosis, and reduced retinal neuronal function. Tau, a microtubule-associated protein, is a key mediator of neurotoxicity in neurodegenerative diseases, with functions in phosphorylation-dependent microtubule assembly and stabilization, axonal transport, and neurite outgrowth. The hyperphosphorylated tau (p-tau) loses its ability to bind to microtubules and aggregates to form paired helical filaments (PHFs), which further form neurofibrillary tangles (NFTs), leading to abnormal cell scaffolding and cell death. Studies have shown that p-tau can cause degeneration of RGCs in DR, making tau pathology a new pathophysiological model for DR. Here, we review the mechanisms by which p-tau contribute to DRN, including insulin resistance or lack of insulin, mitochondrial damage such as mitophagy impairment, mitochondrial axonal transport defects, mitochondrial bioenergetics dysfunction, and impaired mitochondrial dynamics, Abeta toxicity, and inflammation. Therefore, this article proposes that tau protein hyperphosphorylation plays a crucial role in the pathogenesis of DRN and may serve as a novel therapeutic target for combating DRN.
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Affiliation(s)
- Jingyu Mu
- Eye School of Chengdu University of TCM, Chengdu, Sichuan, China
- Key Laboratory of Sichuan Province Ophthalmopathy Prevention & Cure and Visual Function Protection with TCM Laboratory, Chengdu, Sichuan, China
- Retinal Image Technology and Chronic Vascular Disease Prevention & Control and Collaborative Innovation Center, Chengdu, Sichuan, China
| | - Zengrui Zhang
- Eye School of Chengdu University of TCM, Chengdu, Sichuan, China
- Key Laboratory of Sichuan Province Ophthalmopathy Prevention & Cure and Visual Function Protection with TCM Laboratory, Chengdu, Sichuan, China
- Retinal Image Technology and Chronic Vascular Disease Prevention & Control and Collaborative Innovation Center, Chengdu, Sichuan, China
| | - Chao Jiang
- College of Life and Health Sciences, Institute of Neuroscience, Northeastern University, Shenyang, China
| | - Haoming Geng
- Eye School of Chengdu University of TCM, Chengdu, Sichuan, China
- Key Laboratory of Sichuan Province Ophthalmopathy Prevention & Cure and Visual Function Protection with TCM Laboratory, Chengdu, Sichuan, China
- Retinal Image Technology and Chronic Vascular Disease Prevention & Control and Collaborative Innovation Center, Chengdu, Sichuan, China
| | - Junguo Duan
- Eye School of Chengdu University of TCM, Chengdu, Sichuan, China
- Key Laboratory of Sichuan Province Ophthalmopathy Prevention & Cure and Visual Function Protection with TCM Laboratory, Chengdu, Sichuan, China
- Retinal Image Technology and Chronic Vascular Disease Prevention & Control and Collaborative Innovation Center, Chengdu, Sichuan, China
- Ineye Hospital of Chengdu University of TCM, Chengdu, Sichuan, China
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Vrabec R, Bulum T, Ljubić S, Tomić M. Association Between Macular Ganglion Cell-Inner Plexiform Layer and Non-Proliferative Retinopathy Without Macular Edema in Type 2 Diabetes via Diabetes Duration and HbA 1c Link. Biomedicines 2025; 13:398. [PMID: 40002811 PMCID: PMC11853396 DOI: 10.3390/biomedicines13020398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Revised: 01/26/2025] [Accepted: 02/04/2025] [Indexed: 02/27/2025] Open
Abstract
Background/Objectives: This study aimed to evaluate the association between the thickness of the macular ganglion cell-inner plexiform layer (GC-IPL), a marker of retinal neurodegeneration, and diabetic retinopathy (DR), a microvasculopathy, in type 2 diabetic patients (T2DM), and to determine the related risk factors. Methods: This cross-sectional study included 50 eyes of 25 T2DM with a median age of 64 and a median diabetes duration of 13 years. Complete diabetological, nephrological, and ophthalmological examination was performed, including color fundus photography according to the EURODIAB methodology and optical coherence tomography (OCT) of the macula. Patients with proliferative DR and diabetic macular edema were not included in the study. Data were analyzed using the software package Statistica™ 14.0.1.25 (TIBCO Inc., USA). Results: Fifty eyes were divided into two groups: no DR (n = 34) and non-proliferative DR (NPDR) (n = 16). The NPDR group had longer diabetes duration (p = 0.042), higher HbA1c (p = 0.002), lower HDL cholesterol (p = 0.036), and also lower macular GC-IPL thickness (p = 0.027) than those without DR. The correlation between DR and GC-IPL was significantly negative (R = -0.319, p = 0.024). DR was positively related to diabetes duration (p = 0.047) and HbA1c (p = 0.003), while the relation between GC-IPL and diabetes duration (p = 0.042) and HbA1c (p = 0.043) was negative. Binary logistic regression analysis showed that HbA1c (OR = 2.77, p = 0.007) and HDL cholesterol (OR = 0.08, p = 0.031) were the main predictors for DR, whereas the best model for predicting the GC-IPL thickness (R2 = 0.223) obtained from stepwise regression analysis included HDL cholesterol, triglycerides, estimated glomerular filtration rate, and albumin/creatinine ratio. Conclusions: The negative correlation between macular GC-IPL and DR in T2DM indicates the coexistence of two parts, neurodegenerative and microvascular, in one diabetic eye complication, linked by the same well-known risk factors: diabetes duration and HbA1c.
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Affiliation(s)
- Romano Vrabec
- Department of Ophthalmology, Vuk Vrhovac University Clinic for Diabetes, Endocrinology and Metabolic Diseases, Merkur University Hospital, 10000 Zagreb, Croatia
| | - Tomislav Bulum
- Department of Diabetes and Endocrinology, Vuk Vrhovac University Clinic for Diabetes, Endocrinology and Metabolic Diseases, Merkur University Hospital, 10000 Zagreb, Croatia
- School of Medicine, University of Zagreb, Šalata 3, 10000 Zagreb, Croatia
| | - Spomenka Ljubić
- Department of Diabetes and Endocrinology, Vuk Vrhovac University Clinic for Diabetes, Endocrinology and Metabolic Diseases, Merkur University Hospital, 10000 Zagreb, Croatia
- School of Medicine, University of Zagreb, Šalata 3, 10000 Zagreb, Croatia
| | - Martina Tomić
- Department of Ophthalmology, Vuk Vrhovac University Clinic for Diabetes, Endocrinology and Metabolic Diseases, Merkur University Hospital, 10000 Zagreb, Croatia
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Morya AK, Ramesh PV, Nishant P, Kaur K, Gurnani B, Heda A, Salodia S. Diabetic retinopathy: A review on its pathophysiology and novel treatment modalities. World J Methodol 2024; 14:95881. [PMID: 39712561 PMCID: PMC11287547 DOI: 10.5662/wjm.v14.i4.95881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Revised: 05/28/2024] [Accepted: 07/10/2024] [Indexed: 07/26/2024] Open
Abstract
Diabetes mellitus (DM) is a chronic metabolic non-communicable disease with the ability to cause serious microvascular and macrovascular complications throughout the body, including in the eye. Diabetic retinopathy (DR), present in one-third of patients with diabetes, is a vision-threatening complication caused by uncontrolled diabetes, which greatly affects the retinal blood vessels and the light-sensitive inner retina, eventually leading to blindness. Several epidemiological studies elucidate that DR can vary by age of onset, duration, types of diabetes, and ethnicity. Recent studies show that the pathogenesis of diabetic retinopathy has spread its roots beyond merely being the result of hyperglycemia. The complexity of its etiopathology and diagnosis makes therapeutic intervention challenging. This review throws light on the pathological processes behind DR, the cascade of events that follow it, as well as the available and emerging treatment options.
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Affiliation(s)
- Arvind Kumar Morya
- Head of the Department, Department of Ophthalmology, All India Institute of Medical Sciences, Hyderabad 508126, Telangana, India
| | - Prasanna Venkatesh Ramesh
- Glaucoma Medical Officer, Department of Glaucoma and Research, Mahathma Eye Hospital Private Limited, Trichy 620017, Tamil Nadu, India
| | - Prateek Nishant
- Department of Ophthalmology, ESIC Medical College, Patna 801103, Bihar, India
| | - Kirandeep Kaur
- Department of Pediatric Ophthalmology and Strabismus, Gomabai Netralaya and Research Centre, Neemuch 458441, Madhya Pradesh, India
| | - Bharat Gurnani
- Cornea and Refractive Services, Gomabai Netralaya and Research Centre, Neemuch 458441, Madhya Pradesh, India
| | - Aarti Heda
- Department of Ophthalmology, National Institute of Ophthalmology, Pune 411000, Maharashtra, India
| | - Sarika Salodia
- Global Medical Safety, Lundbeck, Singapore 569933, Singapore, Singapore
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Pandey S, Mishra D, Singh TB, Tiwari P, Manisha, Ekagrata, Parihar S. Correlation of glycosylated hemoglobin (HbA1c) with retinal nerve fiber layer (RNFL) thickness and central macular thickness (CMT) in the diabetic population in North India. Indian J Ophthalmol 2024; 72:1186-1191. [PMID: 39078964 PMCID: PMC11451771 DOI: 10.4103/ijo.ijo_2981_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 03/13/2024] [Accepted: 04/01/2024] [Indexed: 09/17/2024] Open
Abstract
PURPOSE The current study was aimed to find correlation of glycosylated hemoglobin with retinal nerve fiber layer thickness (RNFLT) and central macular thickness (CMT) in the diabetic population in North India. METHODS This was a cross-sectional observational study of 300 diabetic patients divided equally in two groups with and without retinopathy, and 150 people were included as control. The study was conducted from October 2020 to August 2022. All patients underwent slitlamp fundoscopy with a +78 D lens, and spectral-domain (SD) optical coherence tomography was performed to measure the RNFLT and CMT, and the staging of retinopathy was done as per the ETDRS classification. Along with that, blood investigations were ordered, including fasting (FBS) and post-prandial (PPBS) blood sugar and glycosylated hemoglobin (HbA1c). Quantitative variables were compared using one-way analysis of variance, or Kruskal-Wallis test was applied for inter-group comparison, followed by a Student Newman Keuls Test. RESULTS The mean age of the patients in the diabetic group with retinopathy was 52.62 ± 9.38 years. The overall male: female ratio was 3:2. The mean FBS in the diabetic group with retinopathy was 146.54 ± 45.40mg/dl; the PPBS and HbA1c in the same were 210.39 ± 63.71mg/dl and 7.85 ± 1.33%, respectively. RNFL thinning was found in all four quadrants in diabetics irrespective of the status of retinopathy (P-value = 0.000) with a significant weak negative (r<0.4) correlation of glycosylated hemoglobin values with RNFLT in the inferior (r value = -0.300, P-value = 0.000) and superior (r value = -0.236, P-value = 0.004) quadrants of right eyes and in inferior (r value = -0.176, p- value = 0.031), superior (r value = -0.222, P value = 0.006), and nasal quadrants (r value = -0.166, p- value = 0.043) of left eyes in diabetics with retinopathy. However, in diabetics without retinopathy, no correlation was found. On correlating HbA1c with CMT, a weak positive (r<0.3) association existed in both eyes in the diabetic group without retinopathy (r = 0.020 and 0.048 for OD and OS, respectively) and diabetics with retinopathy (r = 0.152 and 0.127 for OD and OS, respectively). However, the association was not found to be significant in either of the groups (P-value > 0.05). CONCLUSION The study concluded that neurodegeneration occurs in diabetic retinopathy as evident with nerve fiber layer thinning, and it is negatively correlated with glycosylated hemoglobin (HbA1c).
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Affiliation(s)
- Swasti Pandey
- Department of Ophthalmology, Vivekananda Polyclinic and Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Deepak Mishra
- Department of Ophthalmology, Regional Institute of Ophthalmology, Institute of Medical Sciences, BHU, Varanasi, Uttar Pradesh, India
| | - Tej Bali Singh
- Department of Biostatistics, BHU, Varanasi, Uttar Pradesh, India
| | - Praveen Tiwari
- Forensic Sciences, Galgotias University, Noida, Uttar Pradesh, India
| | - Manisha
- Department of Ophthalmology, Ganga Devi Pandey Eye Hospital, Mahendragarh, Haryana, India
| | - Ekagrata
- Department of Ophthalmology, Regional Institute of Ophthalmology, Institute of Medical Sciences, BHU, Varanasi, Uttar Pradesh, India
| | - Samvida Parihar
- Department of Ophthalmology, Regional Institute of Ophthalmology, Institute of Medical Sciences, BHU, Varanasi, Uttar Pradesh, India
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Ye X, Fung NSK, Lam WC, Lo ACY. Nutraceuticals for Diabetic Retinopathy: Recent Advances and Novel Delivery Systems. Nutrients 2024; 16:1715. [PMID: 38892648 PMCID: PMC11174689 DOI: 10.3390/nu16111715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 05/22/2024] [Accepted: 05/27/2024] [Indexed: 06/21/2024] Open
Abstract
Diabetic retinopathy (DR) is a major vision-threatening disease among the working-age population worldwide. Present therapeutic strategies such as intravitreal injection of anti-VEGF and laser photocoagulation mainly target proliferative DR. However, there is a need for early effective management in patients with early stage of DR before its progression into the more severe sight-threatening proliferative stage. Nutraceuticals, natural functional foods with few side effects, have been proposed to be beneficial in patients with DR. Over the decades, many studies, either in vitro or in vivo, have demonstrated the advantages of a number of nutraceuticals in DR with their antioxidative, anti-inflammatory, neuroprotective, or vasoprotective effects. However, only a few clinical trials have been conducted, and their outcomes varied. The low bioavailability and instability of many nutraceuticals have indeed hindered their utilization in clinical use. In this context, nanoparticle carriers have been developed to deliver nutraceuticals and to improve their bioavailability. Despite its preclinical nature, research of interventive nutraceuticals for DR may yield promising information in their clinical applications.
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Affiliation(s)
- Xiaoyuan Ye
- Department of Ophthalmology, The University of Hong Kong, Hong Kong 999077, China; (X.Y.); (N.S.K.F.); (W.C.L.)
| | - Nicholas Siu Kay Fung
- Department of Ophthalmology, The University of Hong Kong, Hong Kong 999077, China; (X.Y.); (N.S.K.F.); (W.C.L.)
| | - Wai Ching Lam
- Department of Ophthalmology, The University of Hong Kong, Hong Kong 999077, China; (X.Y.); (N.S.K.F.); (W.C.L.)
- Department of Ophthalmology, University of British Columbia, 2550 Willow Street, Room 301, Vancouver, BC V5Z 3N9, Canada
| | - Amy Cheuk Yin Lo
- Department of Ophthalmology, The University of Hong Kong, Hong Kong 999077, China; (X.Y.); (N.S.K.F.); (W.C.L.)
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Abstract
Although diabetic retinopathy (DR) is clinically diagnosed as a vascular disease, many studies find retinal neuronal and visual dysfunction before the onset of vascular DR. This suggests that DR should be viewed as a neurovascular disease. Prior to the onset of DR, human patients have compromised electroretinograms that indicate a disruption of normal function, particularly in the inner retina. They also exhibit reduced contrast sensitivity. These early changes, especially those due to dysfunction in the inner retina, are also seen in rodent models of diabetes in the early stages of the disease. Rodent models of diabetes exhibit several neuronal mechanisms, such as reduced evoked GABA release, increased excitatory glutamate signaling, and reduced dopamine signaling, that suggest specific neuronal deficits. This suggests that understanding neuronal deficits may lead to early diabetes treatments to ameliorate neuronal dysfunction.
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Affiliation(s)
- Erika D Eggers
- Departments of Physiology and Biomedical Engineering, University of Arizona, Tucson, Arizona, USA;
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Sequential and Dynamic Variations of IL-6, CD18, ICAM, TNF-α, and Microstructure in the Early Stage of Diabetic Retinopathy. DISEASE MARKERS 2022; 2022:1946104. [PMID: 35126785 PMCID: PMC8813280 DOI: 10.1155/2022/1946104] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 12/28/2021] [Indexed: 12/19/2022]
Abstract
Objective The purpose of this project is to make sequential and indepth observation of the variations of retinal microvascular, microstructure, and inflammatory mediators at the early stage of diabetic retinopathy (DR) in streptozotocin-induced diabetes mellitus (DM) rats. Methods DM was induced by a single intraperitoneal injection of 60 mg/kg body weight streptozotocin (STZ). The fluorescein fundus angiography, hematoxylin and eosin staining, periodic acid-Schiff staining, fluorescence imaging techniques, quantitative real-time PCR, and vascular endothelial growth factor- (VEGF-) A ELISA were performed on the 8th day, at the 4th week, 6th week, 8th week, and 10th week after DM induction, respectively. Results In this study, we observed not only the decrease of retinal ganglion cells (RGCs) and the increase of endotheliocytes to pericytes (E/P) ratio, acellular capillaries, and type IV collagen-positive strands began to occur on the 8th day after induction but the vascular permeability and new vessel buds began to appear in the diabetes group at the 8th week, while the expression of VEGF-A, VEGF mRNA, IL-6 mRNA, ICAM mRNA, and TNF-α mRNA were significantly higher in the diabetes group compared with the normal group(P < 0.01) on the 8th day after induction and maintained a high expression level throughout the 10-week observation period. However, the expression of CD18 mRNA began to increase significantly at the 4th week after induction and reached a peak at the 6th week. Conclusion Our study indicated the abnormal alterations of microvessels, microstructure, and inflammatory mediators at the early stage of DR, which confirms and supplements the previous research, and also promotes an indepth understanding and exploration of the pathophysiology and underlying pathogenesis of DR.
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Patel VK, Padnick-Silver L, D'Souza S, Bhattacharya RK, Francis-Sedlak M, Holt RJ. Characteristics of Diabetic and Nondiabetic Patients With Thyroid Eye Disease in the United States: A Claims-Based Analysis. Endocr Pract 2021; 28:159-164. [PMID: 34781042 DOI: 10.1016/j.eprac.2021.11.080] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/15/2021] [Accepted: 11/08/2021] [Indexed: 12/29/2022]
Abstract
OBJECTIVE Thyroid eye disease (TED) is a debilitating autoimmune disease characterized by ocular and periorbital tissue inflammation, proptosis, and visual impairment. The known risk factors for TED include radioactive iodine therapy, female sex, and smoking. The risk factors for severe TED include hyperthyroidism, male sex, smoking, and diabetes; however, little is known about how diabetes mellitus (DM) influences TED. This claims-based analysis examined TED characteristics in patients with and without diabetes. METHODS Symphony database (2010-2015 U.S. claims) was mined for patients with ≥1 Graves' disease diagnosis code and ≥1 TED-associated eye code, including proptosis, strabismus, diplopia, lid retraction, exposure keratoconjunctivitis, and optic neuropathy (ON). DM status was determined based on type 1 or type 2 diabetes coding. Sight-threatening TED was defined as ≥1 ON or exposure keratoconjunctivitis code. RESULTS A total of 51 220 patients were identified. Of them, 2618 (5.1%) and 12 846 (25.1%) had type 1 and type 2 DM, respectively. Patients with and without DM had similar characteristics, but patients with DM were more often men (type 1: 30.3%, type 2: 28.7% vs no DM: 20.5%; both P < .001) and older at the first TED code. In patients with DM, strabismus (25.4%, 22.6% vs 19.9%) and diplopia (38.6%, 37.9% vs 29.9%) occurred more often but proptosis occurred less often (42.3%, 46.3% vs 58.5%; all P < .001). Sight-threatening TED occurred more often in patients with DM because of higher ON rates. CONCLUSION Patients with TED and DM may have more extraocular muscle involvement. Furthermore, the higher prevalence of severe TED stemmed from higher ON rates, possibly associated with diabetes-related vasculopathies. These hypothesis-generating data warrant further exploration.
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Affiliation(s)
- Vishal K Patel
- Rosalind Franklin University of Medicine and Science, College of Pharmacy, North Chicago, Illinois; Horizon Therapeutics plc, Deerfield, Illinois
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Bontzos G, Kabanarou SA, Gkizis I, Ragkousis A, Xirou T, Peto T. Retinal neurodegeneration, macular circulation and morphology of the foveal avascular zone in diabetic patients: quantitative cross-sectional study using OCT-A. Acta Ophthalmol 2021; 99:e1135-e1140. [PMID: 33423370 DOI: 10.1111/aos.14754] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Accepted: 12/07/2020] [Indexed: 12/15/2022]
Abstract
PURPOSE Using OCT-A to investigate the association between neurodegeneration and vascular morphology in diabetic retinopathy (DR). METHODS Cross-sectional study. One hundred and sixty-two patients were enrolled and following fundoscopy were assigned to two groups according to DR severity: 54 patients to the group of no clinical signs of DR (noDR) and 54 to the non-proliferative DR (NPDR) group. Fifty-four age-matched patients without known diabetes were recruited as the control group. Patients underwent full ophthalmic examination followed by OCT-A. Central retinal thickness (CRT), vessel density (VD) in the superficial and deep retinal layers and foveal avascular zone (FAZ) area were measured. Additionally, ganglion cell complex (GCC) layer thickness along with global loss volume (GLV) and focal loss volume (FLV) indices was measured. RESULTS In total, 85 men with mean age of 51.93 ± 9.03 and 77 women with age of 50.14 ± 10.35 were examined. Mean diabetes duration was 4.62 ± 2.16 years in the noDR group and 11.34 ± 2.73 years in the NPDR group (p < 0.001). Superficial VD (sVD) and deep VD (dVD) were significantly different only between noDR and NPDR groups (p < 0.001 for both comparisons), but no statistically significant difference was observed between the controls and the DR groups. Global loss volume was significantly higher in the NPDR (4.38 ± 2.22) compared to the noDR group (3.24 ± 1.76; p < 0.03). Focal loss volume was significantly higher in both noDR (1.22 ± 1.03) and NPDR (2.09 ± 1.72) groups compared to controls (0.95 ± 0.83; p < 0.001 between noDR and NPDR and p = 0.02 between control and noDR groups). Significant associations were found between GLV and deep VD (p < 0.01, r = -0.48), FLV and superficial VD (p < 0.01, r = -0.42) and FLV with deep VD (p < 0.01, r = -0.64). CONCLUSION In this study, we evaluated the impact of DR in both the vascular layers and neural components of the retina as expressed by FAZ, sVD, dVD and GCC thickness, FLV and GLV using OCT-A. We found that FLV was significantly higher in both noDR and NPDR groups indicating that in progressive DR stages FLV values might be increased, which might serve as an early index of neuronal damage in patients with diabetes even in the absence of overt DR signs.
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Affiliation(s)
- Georgios Bontzos
- Department of Ophthalmology Korgialenio‐Benakio Hellenic Red Cross Hospital Athens Greece
| | - Stamatina A. Kabanarou
- Department of Ophthalmology Korgialenio‐Benakio Hellenic Red Cross Hospital Athens Greece
| | - Ilias Gkizis
- Department of Ophthalmology Korgialenio‐Benakio Hellenic Red Cross Hospital Athens Greece
| | - Antonios Ragkousis
- Department of Ophthalmology Korgialenio‐Benakio Hellenic Red Cross Hospital Athens Greece
| | - Tina Xirou
- Department of Ophthalmology Korgialenio‐Benakio Hellenic Red Cross Hospital Athens Greece
| | - Tunde Peto
- Department of Ophthalmology Centre for Public Health Institute of Clinical Sciences School of Medicine Queen's University Belfast Belfast UK
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Yang P, Chen L, Shi Y, Zhou F, Tian H, Li J, Gao L. Progesterone alters the activation and typing of the microglia in the optic nerve crush model. Exp Eye Res 2021; 212:108805. [PMID: 34699875 DOI: 10.1016/j.exer.2021.108805] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 10/18/2021] [Accepted: 10/21/2021] [Indexed: 12/21/2022]
Abstract
Microglia have a protective effect on the central nervous system (CNS), but their over-proliferation can cause secondary injury to the retina following optic nerve crush (ONC). Progesterone as a steroid gonadal hormone has been used in some experimental animal models for its neuroprotective effect. However, there is limited attention on the interactions between progesterone and microglia in retinal diseases. This study investigated the proliferation, morphology changes, and cell types of microglia at 3 days and 7 days after ONC. We found that progesterone treatment in unilateral optic nerve injury mice significantly reduced densities and morphological change of microglia at 7 days in the ganglion cell layer (GCL), especially in the retinal central. Inhibition of the microglia proliferation and transformation of ramified microglia into ameboid macrophages also appeared in the inner plexiform layer (IPL). Moreover, progesterone also regulated the TNF signal pathway, which was similar to the specific elimination of the M1 phenotype. M1 marks such as tumor necrosis factor alpha (TNF-α), inducible NOS(iNOS), interleukin-6 (IL-6), and Fc receptor (CD16 and CD32) significantly downregulated by progesterone treatment whether at 3 days or 7 days after ONC. On the other hand, progesterone continuously increased the expression of the M2 marks, including interleukin-4 (IL-4), arginase 1 (Arg1), and mannose receptor (CD206) since the third day, while the expression levels of transforming growth factor (TGF-β) only increased at 7 days. In general, this study elucidated the mechanism that progesterone prevented further damage on the retina by inhibiting proliferation, activation, and changing the type of microglia.
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Affiliation(s)
- Pengfei Yang
- School of Life Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Linchi Chen
- School of Life Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Yongpeng Shi
- School of Life Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Fangfang Zhou
- College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou, 730020, China
| | - Huanbing Tian
- School of Life Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Jiande Li
- School of Life Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Lan Gao
- School of Life Sciences, Lanzhou University, Lanzhou, 730000, China.
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Tonade D, Kern TS. Photoreceptor cells and RPE contribute to the development of diabetic retinopathy. Prog Retin Eye Res 2021; 83:100919. [PMID: 33188897 PMCID: PMC8113320 DOI: 10.1016/j.preteyeres.2020.100919] [Citation(s) in RCA: 118] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 10/27/2020] [Accepted: 10/31/2020] [Indexed: 12/26/2022]
Abstract
Diabetic retinopathy (DR) is a leading cause of blindness. It has long been regarded as vascular disease, but work in the past years has shown abnormalities also in the neural retina. Unfortunately, research on the vascular and neural abnormalities have remained largely separate, instead of being integrated into a comprehensive view of DR that includes both the neural and vascular components. Recent evidence suggests that the most predominant neural cell in the retina (photoreceptors) and the adjacent retinal pigment epithelium (RPE) play an important role in the development of vascular lesions characteristic of DR. This review summarizes evidence that the outer retina is altered in diabetes, and that photoreceptors and RPE contribute to retinal vascular alterations in the early stages of the retinopathy. The possible molecular mechanisms by which cells of the outer retina might contribute to retinal vascular damage in diabetes also are discussed. Diabetes-induced alterations in the outer retina represent a novel therapeutic target to inhibit DR.
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Affiliation(s)
- Deoye Tonade
- Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA
| | - Timothy S Kern
- Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA; Veterans Administration Medical Center Research Service, Cleveland, OH, USA; Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA, USA; Veterans Administration Medical Center Research Service, Long Beach, CA, USA.
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12
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Srinivasan S, Pritchard N, Sampson GP, Edwards K, Vagenas D, Russell AW, Malik RA, Efron N. Focal loss volume of ganglion cell complex in diabetic neuropathy. Clin Exp Optom 2021; 99:526-534. [DOI: 10.1111/cxo.12379] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Revised: 11/18/2015] [Accepted: 11/28/2015] [Indexed: 11/28/2022] Open
Affiliation(s)
- Sangeetha Srinivasan
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Queensland, Australia,
| | - Nicola Pritchard
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Queensland, Australia,
| | - Geoff P Sampson
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Queensland, Australia,
- Deakin University, Geelong, Victoria, Australia,
| | - Katie Edwards
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Queensland, Australia,
| | - Dimitrios Vagenas
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Queensland, Australia,
| | - Anthony W Russell
- Princess Alexandra Hospital, Woolloongabba, Queensland, Australia,
- School of Medicine, University of Queensland, Woolloongabba, Queensland, Australia,
| | - Rayaz A Malik
- Centre for Endocrinology and Diabetes, Institute of Human Development, University of Manchester, UK,
- Weill Cornell Medical College in Qatar, Doha, Qatar,
| | - Nathan Efron
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Queensland, Australia,
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13
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Targeted pharmacotherapy against neurodegeneration and neuroinflammation in early diabetic retinopathy. Neuropharmacology 2021; 187:108498. [PMID: 33582150 DOI: 10.1016/j.neuropharm.2021.108498] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 01/18/2021] [Accepted: 02/06/2021] [Indexed: 02/07/2023]
Abstract
Diabetic retinopathy (DR), the most frequent complication of diabetes, is one of the leading causes of irreversible blindness in working-age adults and has traditionally been regarded as a microvascular disease. However, increasing evidence has revealed that synaptic neurodegeneration of retinal ganglion cells (RGCs) and activation of glial cells may represent some of the earliest events in the pathogenesis of DR. Upon diabetes-induced metabolic stress, abnormal glycogen synthase kinase-3β (GSK-3β) activation drives tau hyperphosphorylation and β-catenin downregulation, leading to mitochondrial impairment and synaptic neurodegeneration prior to RGC apoptosis. Moreover, glial cell activation triggers enhanced inflammation and oxidative stress, which may accelerate the deterioration of diabetic RGCs neurodegeneration. These findings have opened up opportunities for therapies, such as inhibition of GSK-3β, glial cell activation, glutamate excitotoxicity and the use of neuroprotective drugs targeting early neurodegenerative processes in the retina and halting the progression of DR before the manifestation of microvascular abnormalities. Such interventions could potentially remedy early neurodegeneration and help prevent vision loss in people suffering from DR.
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14
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Şahin İO. How curcumin affects hyperglycemia-induced optic nerve damage: A short review. J Chem Neuroanat 2021; 113:101932. [PMID: 33581265 DOI: 10.1016/j.jchemneu.2021.101932] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 01/30/2021] [Accepted: 02/03/2021] [Indexed: 11/19/2022]
Abstract
Considered to be one of the most important non-contagious systemic diseases worldwide, diabetes mellitus is still a topical issue on the health agenda with the problems it causes. Exposure to long-term hyperglycemia causes diabetic complications (diabetic neuropathy, nephropathy and retinopathy). The optic nerve can suffer damage by both diabetic retinopathy and neuropathy during diabetes, both because it is formed by axons of retinal ganglion cells and these axons belong to the central nervous system. The issue of hyperglycemia on the optic nerve have been described as diabetic papillopathy, posterior ischemic optic neuropathy, nonarteritic anterior ischemic optic neuropathy and optic atrophy in clinical studies. Experimental studies indicated axon-myelin degeneration in addition to microvascular and ultrastructural changes caused by the hyperglycemia-induced optic nerve damage. Although there are several proposed biochemical mechanisms to cause these damages, oxidative stress emerges as an important factor among them. Oxidative stress leads to pathological state on the nerve cells by affecting the DNA, protein and lipids at different levels. These are causing deterioration on nerve conduction velocity, myelin sheath and nerve structure, neurotrophic support system, glial cells and nerve function. Curcumin, as an important antioxidant, can be an ideal prophylactic agent to eliminate damages on optic nerve. Curcumin helps to regulate the balance of antioxidant and reactive oxygen species by targeting various molecules (NF-κB, STAT3, MAPK, Mfn2, Nrf2, pro-inflammatory cytokines). In addition, it shows healing or preventive effects on myelin sheath damage via regulating ferritin protein in oligodendrocytes. It is also effective in preventing neurovascular damage.
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Affiliation(s)
- İzem Olcay Şahin
- Department of Histology and Embryology, Medical School, Ondokuz Mayis University, 55139 Samsun, Turkey.
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15
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Flood MD, Wellington AJ, Cruz LA, Eggers ED. Early diabetes impairs ON sustained ganglion cell light responses and adaptation without cell death or dopamine insensitivity. Exp Eye Res 2020; 200:108223. [PMID: 32910942 DOI: 10.1016/j.exer.2020.108223] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 08/17/2020] [Accepted: 09/03/2020] [Indexed: 10/23/2022]
Abstract
Retinal signaling under dark-adapted conditions is perturbed during early diabetes. Additionally, dopamine, the main neuromodulator of retinal light adaptation, is diminished in diabetic retinas. However, it is not known if this dopamine deficiency changes how the retina responds to increased light or dopamine. Here we determine whether light adaptation is impaired in the diabetic retina, and investigate potential mechanism(s) of impairment. Diabetes was induced in C57BL/6J male mice via 3 intraperitoneal injections of streptozotocin (75 mg/kg) and confirmed by blood glucose levels more than 200 mg/dL. After 6 weeks, whole-cell recordings of light-evoked and spontaneous inhibitory postsynaptic currents (IPSCs) or excitatory postsynaptic currents (EPSCs) were made from rod bipolar cells and ON sustained ganglion cells, respectively. Light responses were recorded before and after D1 receptor (D1R) activation (SKF-38393, 20 μM) or light adaptation (background of 950 photons·μm-2 ·s-1). Retinal whole mounts were stained for either tyrosine hydroxylase and activated caspase-3 or GAD65/67, GlyT1 and RBPMS and imaged. D1R activation and light adaptation both decreased inhibition, but the disinhibition was not different between control and diabetic rod bipolar cells. However, diabetic ganglion cell light-evoked EPSCs were increased in the dark and showed reduced light adaptation. No differences were found in light adaptation of spontaneous EPSC parameters, suggesting upstream changes. No changes in cell density were found for dopaminergic, glycinergic or GABAergic amacrine cells, or ganglion cells. Thus, in early diabetes, ON sustained ganglion cells receive excessive excitation under dark- and light-adapted conditions. Our results show that this is not attributable to loss in number or dopamine sensitivity of inhibitory amacrine cells or loss of dopaminergic amacrine cells.
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Affiliation(s)
- Michael D Flood
- Departments of Physiology and Biomedical Engineering, P.O. Box 245051, University of Arizona, Tucson, AZ, 85724, USA.
| | - Andrea J Wellington
- Departments of Physiology and Biomedical Engineering, P.O. Box 245051, University of Arizona, Tucson, AZ, 85724, USA.
| | - Luis A Cruz
- Departments of Physiology and Biomedical Engineering, P.O. Box 245051, University of Arizona, Tucson, AZ, 85724, USA.
| | - Erika D Eggers
- Departments of Physiology and Biomedical Engineering, P.O. Box 245051, University of Arizona, Tucson, AZ, 85724, USA.
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16
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Cui RZ, Wang L, Qiao SN, Wang YC, Wang X, Yuan F, Weng SJ, Yang XL, Zhong YM. ON-Type Retinal Ganglion Cells are Preferentially Affected in STZ-Induced Diabetic Mice. Invest Ophthalmol Vis Sci 2019; 60:1644-1656. [PMID: 30995300 DOI: 10.1167/iovs.18-26359] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Purpose We investigate morphologic and physiologic alterations of ganglion cells (GCs) in a streptozocin (STZ)-induced diabetic mouse model. Methods Experiments were conducted in flat-mount retinas of mice 3 months after the induction of diabetes. Changes in morphology of four subtypes of GCs (ON-type RGA2 [ON-RGA2], OFF-type RGA2 [OFF-RGA2], ON-type RGC1 [ON-RGC1], and ON-OFF type RGD2 [ON-OFF RGD2]) were characterized in Thy1-YFP transgenic mice. Using whole-cell patch-clamp recording, passive membrane properties and action potential (AP) firing properties were further investigated in transient ON- and OFF-RGA2 cells. Results Morphologic parameters were significantly altered in the dendrites branching in the ON sublamina of the inner plexiform layer (IPL) for ON-RGA2 cells and ON-OFF RGD2 cells. Much less significant changes, if any, were seen in those arborizing in the OFF sublamina of the IPL for OFF-RGA2 and ON-OFF RGD2 cells. No detectable changes in morphology were seen in RGC1 cells. Electrophysiologically, increased resting membrane potentials and decreased membrane capacitance were found in transient ON-RGA2 cells, but not in transient OFF-RGA2 cells. Similar alterations in AP firing properties, such as an increase in AP width and reduction in maximum spiking rate, were shared by these two subtypes. Furthermore, in response to depolarizing current injections, both cells generated more APs suggesting an enhanced excitability of these cells in diabetic conditions. Conclusions These differential changes in morphology and electrophysiology in subtypes of GCs may be responsible for reduced contrast sensitivity known to occur during the early stage of diabetic retinopathy.
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Affiliation(s)
- Run-Ze Cui
- Department of Neurology, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.,Department of Ophthalmology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Lu Wang
- Department of Neurology, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.,Department of Ophthalmology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Sheng-Nan Qiao
- Department of Neurology, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.,Department of Ophthalmology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Yong-Chen Wang
- Department of Neurology, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.,Department of Ophthalmology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Xin Wang
- Department of Neurology, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.,Department of Ophthalmology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Fei Yuan
- Department of Ophthalmology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Shi-Jun Weng
- Department of Neurology, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.,Department of Ophthalmology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Xiong-Li Yang
- Department of Neurology, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.,Department of Ophthalmology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Yong-Mei Zhong
- Department of Neurology, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.,Department of Ophthalmology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
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17
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Sinclair SH, Schwartz SS. Diabetic Retinopathy-An Underdiagnosed and Undertreated Inflammatory, Neuro-Vascular Complication of Diabetes. Front Endocrinol (Lausanne) 2019; 10:843. [PMID: 31920963 PMCID: PMC6923675 DOI: 10.3389/fendo.2019.00843] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Accepted: 11/19/2019] [Indexed: 12/14/2022] Open
Abstract
Diabetes mellitus is a world-wide epidemic and diabetic retinopathy, a devastating, vision-threatening condition, is one of the most common diabetes-specific complications. Diabetic retinopathy is now recognized to be an inflammatory, neuro-vascular complication with neuronal injury/dysfunction preceding clinical microvascular damage. Importantly, the same pathophysiologic mechanisms that damage the pancreatic β-cell (e.g., inflammation, epigenetic changes, insulin resistance, fuel excess, and abnormal metabolic environment), also lead to cell and tissue damage causing organ dysfunction, elevating the risk of all complications, including diabetic retinopathy. Viewing diabetic retinopathy within the context whereby diabetes and all its complications arise from common pathophysiologic factors allows for the consideration of a wider array of potential ocular as well as systemic treatments for this common and devastating complication. Moreover, it also raises the importance of the need for methods that will provide more timely detection and prediction of the course in order to address early damage to the neurovascular unit prior to the clinical observation of microangiopathy. Currently, treatment success is limited as it is often initiated far too late and after significant neurodegeneration has occurred. This forward-thinking approach of earlier detection and treatment with a wider array of possible therapies broadens the physician's armamentarium and increases the opportunity for prevention and early treatment of diabetic retinopathy with preservation of good vision, as well the prevention of similar destructive processes occurring among other organs.
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Affiliation(s)
- Stephen H. Sinclair
- Sinclair Retina Associates, Media, PA, United States
- Main Line Health System, Media, PA, United States
- *Correspondence: Stephen H. Sinclair
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18
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Zhu H, Zhang W, Zhao Y, Shu X, Wang W, Wang D, Yang Y, He Z, Wang X, Ying Y. GSK3β-mediated tau hyperphosphorylation triggers diabetic retinal neurodegeneration by disrupting synaptic and mitochondrial functions. Mol Neurodegener 2018; 13:62. [PMID: 30466464 PMCID: PMC6251088 DOI: 10.1186/s13024-018-0295-z] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 11/14/2018] [Indexed: 12/28/2022] Open
Abstract
Background Although diabetic retinopathy (DR) has long been considered as a microvascular disorder, mounting evidence suggests that diabetic retinal neurodegeneration, in particular synaptic loss and dysfunction of retinal ganglion cells (RGCs) may precede retinal microvascular changes. Key molecules involved in this process remain poorly defined. The microtubule-associated protein tau is a critical mediator of neurotoxicity in Alzheimer’s disease (AD) and other neurodegenerative diseases. However, the effect of tau, if any, in the context of diabetes-induced retinal neurodegeneration has yet to be ascertained. Here, we investigate the changes and putative roles of endogeneous tau in diabetic retinal neurodegeneration. Methods To this aim, we combine clinically used electrophysiological techniques, i.e. pattern electroretinogram and visual evoked potential, and molecular analyses in a well characterized high-fat diet (HFD)-induced mouse diabetes model in vivo and primary retinal ganglion cells (RGCs) in vitro. Results We demonstrate for the first time that tau hyperphosphorylation via GSK3β activation causes vision deficits and synapse loss of RGCs in HFD-induced DR, which precedes retinal microvasculopathy and RGCs apoptosis. Moreover, intravitreal administration of an siRNA targeting to tau or a specific inhibitor of GSK3β reverses synapse loss and restores visual function of RGCs by attenuating tau hyperphosphorylation within a certain time frame of DR. The cellular mechanisms by which hyperphosphorylated tau induces synapse loss of RGCs upon glucolipotoxicity include i) destabilizing microtubule tracks and impairing microtubule-dependent synaptic targeting of cargoes such as mRNA and mitochondria; ii) disrupting synaptic energy production through mitochondria in a GSK3β-dependent manner. Conclusions Our study proposes mild retinal tauopathy as a new pathophysiological model for DR and tau as a novel therapeutic target to counter diabetic RGCs neurodegeneration occurring before retinal vasculature abnormalities. Electronic supplementary material The online version of this article (10.1186/s13024-018-0295-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Huazhang Zhu
- Department of Physiology, School of Basic Medical Sciences, Center for Diabetes, Obesity and Metabolism, Shenzhen University Health Sciences Center, Shenzhen, 518060, Guangdong, China
| | - Weizhen Zhang
- Department of Physiology, School of Basic Medical Sciences, Center for Diabetes, Obesity and Metabolism, Shenzhen University Health Sciences Center, Shenzhen, 518060, Guangdong, China.,Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, 100191, China
| | - Yingying Zhao
- Department of Physiology, School of Basic Medical Sciences, Center for Diabetes, Obesity and Metabolism, Shenzhen University Health Sciences Center, Shenzhen, 518060, Guangdong, China
| | - Xingsheng Shu
- Department of Physiology, School of Basic Medical Sciences, Center for Diabetes, Obesity and Metabolism, Shenzhen University Health Sciences Center, Shenzhen, 518060, Guangdong, China
| | - Wencong Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510064, Guangdong, China
| | - Dandan Wang
- Department of Physiology, School of Basic Medical Sciences, Center for Diabetes, Obesity and Metabolism, Shenzhen University Health Sciences Center, Shenzhen, 518060, Guangdong, China
| | - Yangfan Yang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510064, Guangdong, China
| | - Zhijun He
- Department of Physiology, School of Basic Medical Sciences, Center for Diabetes, Obesity and Metabolism, Shenzhen University Health Sciences Center, Shenzhen, 518060, Guangdong, China
| | - Xiaomei Wang
- Department of Physiology, School of Basic Medical Sciences, Center for Diabetes, Obesity and Metabolism, Shenzhen University Health Sciences Center, Shenzhen, 518060, Guangdong, China
| | - Ying Ying
- Department of Physiology, School of Basic Medical Sciences, Center for Diabetes, Obesity and Metabolism, Shenzhen University Health Sciences Center, Shenzhen, 518060, Guangdong, China.
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19
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Tanvir Z, Nelson RF, DeCicco-Skinner K, Connaughton VP. One month of hyperglycemia alters spectral responses of the zebrafish photopic electroretinogram. Dis Model Mech 2018; 11:dmm.035220. [PMID: 30158110 PMCID: PMC6215424 DOI: 10.1242/dmm.035220] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Accepted: 08/22/2018] [Indexed: 12/12/2022] Open
Abstract
Prolonged hyperglycemia can alter retinal function, ultimately resulting in blindness. Adult zebrafish adults exposed to alternating conditions of 2% glucose/0% glucose display a 3× increase in blood sugar levels. After 4 weeks of treatment, electroretinograms (ERGs) were recorded from isolated, perfused, in vitro eyecups. Control animals were exposed to alternating 2% mannitol/0% mannitol (osmotic control) or to alternating water (0% glucose/0% glucose; handling control). Two types of ERGs were recorded: (1) native ERGs measured using white-light stimuli and medium without synaptic blockers; and (2) spectral ERGs measured with an AMPA/kainate receptor antagonist, isolating photoreceptor-to-ON-bipolar-cell synapses, and a spectral protocol that separated red (R), green (G), blue (B) and UV cone signals. Retinas were evaluated for changes in layer thickness and for the inflammatory markers GFAP and Nf-κB (RelA or p65). In native ERGs, hyperglycemic b- and d-waves were lower in amplitude than the b- and d-waves of mannitol controls. Alteration of waveshape became severe, with b-waves becoming more transient and ERG responses showing more PIII-like (a-wave) characteristics. For spectral ERGs, waveshape appeared similar in all treatment groups. However, a1- and b2-wave implicit times were significantly longer, and amplitudes were significantly reduced, in response to hyperglycemic treatment, owing to the functional reduction in signals from R, G and B cones. Nf-κB increased significantly in hyperglycemic retinas, but the increase in GFAP was not significant and retinal layer thickness was unaffected. Thus, prolonged hyperglycemia triggers an inflammatory response and functional deficits localized to specific cone types, indicating the rapid onset of neural complications in the zebrafish model of diabetic retinopathy. Summary: Zebrafish can be used to examine diabetic complications, including vision loss. Here, in zebrafish, we show that prolonged (4 week) hyperglycemia causes an inflammatory response associated with functional deficits localized to specific cone types.
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Affiliation(s)
- Zaid Tanvir
- Department of Biology, American University, 4400 Massachusetts Ave NW, Washington, DC 20016, USA
| | - Ralph F Nelson
- Neural Circuitry Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 5625 Fisher's Lane, Rockville, MD 20852, USA
| | - Kathleen DeCicco-Skinner
- Department of Biology, American University, 4400 Massachusetts Ave NW, Washington, DC 20016, USA
| | - Victoria P Connaughton
- Department of Biology, American University, 4400 Massachusetts Ave NW, Washington, DC 20016, USA
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20
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Chakravarthy H, Devanathan V. Molecular Mechanisms Mediating Diabetic Retinal Neurodegeneration: Potential Research Avenues and Therapeutic Targets. J Mol Neurosci 2018; 66:445-461. [PMID: 30293228 DOI: 10.1007/s12031-018-1188-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Accepted: 09/25/2018] [Indexed: 12/16/2022]
Abstract
Diabetic retinopathy (DR) is a devastating complication of diabetes with a prevalence rate of 35%, and no effective treatment options. Since the most visible clinical features of DR are microvascular irregularities, therapeutic interventions often attempt to reduce microvascular injury, but only after permanent retinal damage has ensued. However, recent data suggests that diabetes initially affects retinal neurons, leading to neurodegeneration as an early occurrence in DR, before onset of the more noticeable vascular abnormalities. In this review, we delineate the sequence of initiating events leading to retinal degeneration in DR, considering neuronal dysfunction as a primary event. Key molecular mechanisms and potential biomarkers associated with retinal neuronal degeneration in diabetes are discussed. In addition to glial reactivity and inflammation in the diabetic retina, the contribution of neurotrophic factors, cell adhesion molecules, apoptosis markers, and G protein signaling to neurodegenerative pathways warrants further investigation. These studies could complement recent developments in innovative treatment strategies for diabetic retinopathy, such as targeting retinal neuroprotection, promoting neuronal regeneration, and attempts to re-program other retinal cell types into functional neurons. Indeed, several ongoing clinical trials are currently attempting treatment of retinal neurodegeneration by means of such novel therapeutic avenues. The aim of this article is to highlight the crucial role of neurodegeneration in early retinopathy progression, and to review the molecular basis of neuronal dysfunction as a first step toward developing early therapeutic interventions that can prevent permanent retinal damage in diabetes. ClinicalTrials.gov: NCT02471651, NCT01492400.
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Affiliation(s)
- Harshini Chakravarthy
- Department of Biology, Indian Institute of Science Education and Research (IISER), Transit campus: C/o. Sree Rama Engineering College Campus, Karakambadi Road, Mangalam, Tirupati, 517507, India
| | - Vasudharani Devanathan
- Department of Biology, Indian Institute of Science Education and Research (IISER), Transit campus: C/o. Sree Rama Engineering College Campus, Karakambadi Road, Mangalam, Tirupati, 517507, India.
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21
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Kim MK, Aung MH, Mees L, Olson DE, Pozdeyev N, Iuvone PM, Thule PM, Pardue MT. Dopamine Deficiency Mediates Early Rod-Driven Inner Retinal Dysfunction in Diabetic Mice. Invest Ophthalmol Vis Sci 2018; 59:572-581. [PMID: 29372256 PMCID: PMC5788047 DOI: 10.1167/iovs.17-22692] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Purpose Electroretinograms (ERGs) are abnormal in diabetic retinas before the appearance of vascular lesions, providing a possible biomarker for diabetic vision loss. Previously, we reported that decreased retinal dopamine (DA) levels in diabetic rodents contributed to early visual and retinal dysfunction. In the current study, we examined whether oscillatory potentials (OPs) could serve as a potential marker for detecting early inner retinal dysfunction due to retinal DA deficiency. Methods Retinal function was tested with dark-adapted ERGs, taken at 3, 4, and 5 weeks after diabetes induction with streptozotocin. Electrical responses were analyzed and correlations were made with previously reported retinal DA levels. The effect of restoring systemic DA levels or removing DA from the retina in diabetic mice on OPs was assessed using L-3,4-dihydroxyphenylalanine (L-DOPA) treatments and retina-specific tyrosine hydroxylase (Th) knockout mice (rTHKO), respectively. Results Diabetic animals had significantly delayed OPs compared to control animals in response to dim, but not bright, flash stimuli. L-DOPA treatment preserved OP implicit time in diabetic mice. Diabetic rTHKO mice had further delayed OPs compared to diabetic mice with normal retinal Th, with L-DOPA treatment also providing benefit. Decreasing retinal DA levels significantly correlated with increasing OP delays mediated by rod pathways. Conclusions Our data suggest that inner retinal dysfunction in early-stage diabetes is mediated by rod-pathway deficits and DA deficiencies. OP delays may be used to determine the earliest functional deficits in diabetic retinopathy and to establish an early treatment window for DA therapies that may prevent progressive vision loss.
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Affiliation(s)
- Moon K Kim
- Department of Ophthalmology, Emory University, Atlanta, Georgia, United States
| | - Moe H Aung
- Neuroscience, Emory University, Atlanta, Georgia, United States
| | - Lukas Mees
- Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States.,Center for Visual and Neurocognitive Rehabilitation, Atlanta Veterans Affairs Medical Center, Decatur, Georgia, United States
| | - Darin E Olson
- Division of Endocrinology, Metabolism and Lipids, Emory University, Atlanta, Georgia, United States.,Medical Service, Atlanta Veterans Affairs Medical Center, Decatur, Georgia, United States
| | - Nikita Pozdeyev
- Department of Ophthalmology, Emory University, Atlanta, Georgia, United States.,Department of Pharmacology, Emory University, Atlanta, Georgia, United States
| | - P Michael Iuvone
- Department of Ophthalmology, Emory University, Atlanta, Georgia, United States.,Neuroscience, Emory University, Atlanta, Georgia, United States.,Department of Pharmacology, Emory University, Atlanta, Georgia, United States
| | - Peter M Thule
- Division of Endocrinology, Metabolism and Lipids, Emory University, Atlanta, Georgia, United States.,Medical Service, Atlanta Veterans Affairs Medical Center, Decatur, Georgia, United States
| | - Machelle T Pardue
- Department of Ophthalmology, Emory University, Atlanta, Georgia, United States.,Neuroscience, Emory University, Atlanta, Georgia, United States.,Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States.,Center for Visual and Neurocognitive Rehabilitation, Atlanta Veterans Affairs Medical Center, Decatur, Georgia, United States
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22
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Effect of intravitreal injection of ranibizumab on retinal ganglion cells and microvessels in the early stage of diabetic retinopathy in rats with streptozotocin-induced diabetes. Exp Ther Med 2017; 13:3360-3368. [PMID: 28587414 PMCID: PMC5450683 DOI: 10.3892/etm.2017.4431] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2015] [Accepted: 12/09/2016] [Indexed: 11/05/2022] Open
Abstract
The aim of the present study was to investigate the effect of intravitreal injection of ranibizumab on retinal ganglion cells and microvessels at the early stage of diabetic retinopathy (DR) in rats with streptozotocin-induced diabetes mellitus (DM). DM was induced by a single intraperitoneal injection of 60 mg/kg body weight streptozotocin. A total of 80 diabetic rats were randomly assigned to four treatment groups (n=20 in each group) and were treated with an oculus dexter intravitreal injection of ranibizumab. Groups A and B were injected with ranibizumab two and four weeks after DM-induction, respectively, while groups a and b (controls) were injected with phosphate-buffered saline at the same time points. In addition, 20 normal rats were assigned to group N (blank control; without intraocular injection). Vitreous humors were isolated for vascular endothelial growth factor (VEGF)-A ELISA and retinas were obtained for hematoxylin and eosin staining, periodic acid-Schiff staining and fluorescence imaging techniques at six and eight weeks after the onset of DM. At six and eight weeks, a significantly increased in retinal ganglion cells (RGCs) was observed in group A compared with group a (P<0.01), and in group B compared with group b (P<0.01). In addition, there was a significant difference in the RGC level between groups A and B at six weeks after DM induction (P<0.01), but not at eight weeks (P>0.05). VEGF-A concentrations in rat vitreous humors were significantly lower in groups A and B compared with groups a and b at six and eight weeks after DM induction (P<0.01). Furthermore, the ratio of endotheliocytes to pericytes in groups A and B was significantly lower compared with groups a and b at six and eight weeks (P<0.05). Furthermore, it was also demonstrated that type IV collagen-positive strands were not present in group A during the eight-week observation period, which was significantly different from groups a, b and B (P<0.01). In conclusion, intravitreal injection of ranibizumab at a very early stage of DR in streptozotocin-induced DM rats slowed the progression of DR by reducing vascular regression or damage and maintaining RGC numbers, as well as reducing VEGF-A concentrations.
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Abstract
Diabetes mellitus represents a growing international public health issue with a near quadrupling in its worldwide prevalence since 1980. Though it has many known microvascular complications, vision loss from diabetic retinopathy is one of the most devastating for affected individuals. In addition, there is increasing evidence to suggest that diabetic patients have a greater risk for glaucoma as well. Though the pathophysiology of glaucoma is not completely understood, both diabetes and glaucoma appear to share some common risk factors and pathophysiologic similarities with studies also reporting that the presence of diabetes and elevated fasting glucose levels are associated with elevated intraocular pressure-the primary risk factor for glaucomatous optic neuropathy. While no study has completely addressed the possibility of detection bias, most recent epidemiologic evidence suggests that diabetic populations are likely enriched with glaucoma patients. As the association between diabetes and glaucoma becomes better defined, routine evaluation for glaucoma in diabetic patients, particularly in the telemedicine setting, may become a reasonable consideration to reduce the risk of vision loss in these patients.
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Affiliation(s)
- Brian J Song
- Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, 243 Charles Street, Boston, MA, 02114, USA.
| | - Lloyd Paul Aiello
- Beetham Eye Institute, Joslin Diabetes Center, Harvard Medical School, 1 Joslin Place, Boston, MA, 02115, USA
| | - Louis R Pasquale
- Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, 243 Charles Street, Boston, MA, 02114, USA
- Channing Division of Network Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA, 02215, USA
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Kancherla S, Kohler WJ, van der Merwe Y, Chan KC. In Vivo Evaluation of the Visual Pathway in Streptozotocin-Induced Diabetes by Diffusion Tensor MRI and Contrast Enhanced MRI. PLoS One 2016; 11:e0165169. [PMID: 27768755 PMCID: PMC5074510 DOI: 10.1371/journal.pone.0165169] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Accepted: 10/07/2016] [Indexed: 02/07/2023] Open
Abstract
Visual function has been shown to deteriorate prior to the onset of retinopathy in some diabetic patients and experimental animal models. This suggests the involvement of the brain's visual system in the early stages of diabetes. In this study, we tested this hypothesis by examining the integrity of the visual pathway in a diabetic rat model using in vivo multi-modal magnetic resonance imaging (MRI). Ten-week-old Sprague-Dawley rats were divided into an experimental diabetic group by intraperitoneal injection of 65 mg/kg streptozotocin in 0.01 M citric acid, and a sham control group by intraperitoneal injection of citric acid only. One month later, diffusion tensor MRI (DTI) was performed to examine the white matter integrity in the brain, followed by chromium-enhanced MRI of retinal integrity and manganese-enhanced MRI of anterograde manganese transport along the visual pathway. Prior to MRI experiments, the streptozotocin-induced diabetic rats showed significantly smaller weight gain and higher blood glucose level than the control rats. DTI revealed significantly lower fractional anisotropy and higher radial diffusivity in the prechiasmatic optic nerve of the diabetic rats compared to the control rats. No apparent difference was observed in the axial diffusivity of the optic nerve, the chromium enhancement in the retina, or the manganese enhancement in the lateral geniculate nucleus and superior colliculus between groups. Our results suggest that streptozotocin-induced diabetes leads to early injury in the optic nerve when no substantial change in retinal integrity or anterograde transport along the visual pathways was observed in MRI using contrast agent enhancement. DTI may be a useful tool for detecting and monitoring early pathophysiological changes in the visual system of experimental diabetes non-invasively.
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Affiliation(s)
- Swarupa Kancherla
- NeuroImaging Laboratory, University of Pittsburgh, Pittsburgh, PA, United States of America
- UPMC Eye Center, Ophthalmology and Visual Science Research Center, Department of Ophthalmology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - William J. Kohler
- NeuroImaging Laboratory, University of Pittsburgh, Pittsburgh, PA, United States of America
- UPMC Eye Center, Ophthalmology and Visual Science Research Center, Department of Ophthalmology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Yolandi van der Merwe
- NeuroImaging Laboratory, University of Pittsburgh, Pittsburgh, PA, United States of America
- UPMC Eye Center, Ophthalmology and Visual Science Research Center, Department of Ophthalmology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America
- Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA, United States of America
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America
- Louis J. Fox Center for Vision Restoration, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Kevin C. Chan
- NeuroImaging Laboratory, University of Pittsburgh, Pittsburgh, PA, United States of America
- UPMC Eye Center, Ophthalmology and Visual Science Research Center, Department of Ophthalmology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America
- Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA, United States of America
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America
- Louis J. Fox Center for Vision Restoration, University of Pittsburgh, Pittsburgh, PA, United States of America
- Center for the Neural Basis of Cognition, University of Pittsburgh and Carnegie Mellon University, Pittsburgh, PA, United States of America
- Department of Electrical and Electronic Engineering, The University of Hong Kong, Hong Kong, China
- * E-mail:
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Jadhav V, Luo Q, M. Dominguez J, Al-Sabah J, Chaqour B, Grant MB, Bhatwadekar AD. Per2-Mediated Vascular Dysfunction Is Caused by the Upregulation of the Connective Tissue Growth Factor (CTGF). PLoS One 2016; 11:e0163367. [PMID: 27662578 PMCID: PMC5035004 DOI: 10.1371/journal.pone.0163367] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Accepted: 09/07/2016] [Indexed: 01/08/2023] Open
Abstract
Period 2-mutant mice (Per2m/m), which possess a circadian dysfunction, recapitulate the retinal vascular phenotype similar to diabetic retinopathy (DR). The vascular dysfunction in Per2m/m is associated with an increase in connective tissue growth factor (CTGF/CCN2). At the molecular level, CTGF gene expression is dependent on the canonical Wnt/β-catenin pathway. The nuclear binding of β-catenin to a transcription factor, lymphoid enhancer binding protein (Lef)/ T-cell factor (TCF/LEF), leads to downstream activation of CTGF. For this study, we hypothesized that the silencing of Per2 results in nuclear translocation and subsequent transactivation of the CTGF gene. To test this hypothesis, we performed immunofluorescence labeling for CTGF in retinal sections from wild-type (WT) and Per2m/m mice. Human retinal endothelial cells (HRECs) were transfected with siRNA for Per2, and the protein expression of CTGF and β-catenin was evaluated. The TCF/LEF luciferase reporter (TOPflash) assay was performed to validate the involvement of β-catenin in the activation of CTGF. Per2m/m retinas exhibited an increased CTGF immunostaining in ganglion cell layer and retinal endothelium. Silencing of Per2 using siRNA resulted in an upregulation of CTGF and β-catenin. The TOPflash assay revealed an increase in luminescence for HRECs transfected with Per2 siRNA. Our studies show that loss of Per2 results in an activation of CTGF via nuclear entry of β-catenin. Our study provides novel insight into the understanding of microvascular dysfunction in Per2m/m mice.
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Affiliation(s)
- Vaishnavi Jadhav
- Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
| | - Qianyi Luo
- Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
| | - James M. Dominguez
- Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
| | - Jude Al-Sabah
- Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
| | - Brahim Chaqour
- Department of Cell Biology, Suny Downstate Medical Center, Brooklyn, New York, United States of America
| | - Maria B. Grant
- Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
| | - Ashay D. Bhatwadekar
- Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
- * E-mail:
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26
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Wang J, Chen S, Zhang X, Huang W, Jonas JB. Intravitreal triamcinolone acetonide, retinal microglia and retinal ganglion cell apoptosis in the optic nerve crush model. Acta Ophthalmol 2016; 94:e305-11. [PMID: 25708663 DOI: 10.1111/aos.12698] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2014] [Accepted: 01/12/2015] [Indexed: 01/20/2023]
Abstract
PURPOSE To evaluate the effect of intravitreal triamcinolone acetonide (TA) on the activation of retinal microglia cells (RMGCs) and survival of retinal ganglion cells (RGCs) in an optic nerve crush (ONC) model. METHODS Adult female Sprague-Dawley rats underwent a standardized ONC and either received an intravitreal injection of TA (TA group) or of phosphate-buffered saline (PBS, PBS group) in the right eyes. At 1, 3, 7, 14 and 28 days after the ONC, the animals were killed. The retinas were examined by immunohistochemistry, light microscopy, Western blot or retrograde labelling of RGCs by fluorogold injected into the superior colliculi. RESULTS The TA group as compared to the PBS control group showed a significantly (p < 0.0001) lower density of activated RMGCs, at 14 days [4.2 ± 1.6 versus 9.3 ± 2.2 cells/high-power microscopic field (HPF)] and at 28 days (2.3 ± 1.1 versus 4.4 ± 1.5 cells/HPF), and with a significantly lower expression of inflammatory factors. Central density of RGCs as stained by haematoxylin-eosin or by fluorogold was significantly (all p < 0.05) more reduced in the PBS group than in the TA group at days 14 and 28 after baseline. The survival rate (cell density in the study eye as compared to cell density in the contralateral unaffected eye) was significantly higher in the TA group than in the PBS group on days 14 (58% versus 45%; p = 0.003) and 28 (52% versus 41%; p = 0.022). CONCLUSIONS Intravitreal TA as compared to intravitreal PBS was associated with a lower density of activated RMGCs and a higher density of surviving RGCs in an ONC model.
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Affiliation(s)
- Jiawei Wang
- State Key Laboratory of Ophthalmology; Zhongshan Ophthalmic Center; Sun Yat-Sen University; Guangzhou China
| | - Shida Chen
- State Key Laboratory of Ophthalmology; Zhongshan Ophthalmic Center; Sun Yat-Sen University; Guangzhou China
| | - Xiulan Zhang
- State Key Laboratory of Ophthalmology; Zhongshan Ophthalmic Center; Sun Yat-Sen University; Guangzhou China
| | - Wenbin Huang
- State Key Laboratory of Ophthalmology; Zhongshan Ophthalmic Center; Sun Yat-Sen University; Guangzhou China
| | - Jost B. Jonas
- Department of Ophthalmology; Medical Faculty Mannheim of the Ruprecht-Karls-University; Heidelberg Germany
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Pharmacology of the retinal pigment epithelium, the interface between retina and body system. Eur J Pharmacol 2016; 787:84-93. [PMID: 27044435 DOI: 10.1016/j.ejphar.2016.03.066] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Revised: 03/14/2016] [Accepted: 03/31/2016] [Indexed: 12/12/2022]
Abstract
The retinal pigment epithelium (RPE) is a close, interactive partner to the photoreceptors as well as an interface with the endothelium of the choroid and thus with the body's circulatory system. To fulfill these roles, the RPE communicates with neighboring tissue by secretion of a large variety of factors and is able to react to secreted factors via a plethora of transmembrane receptors. Clinically relevant local pharmacological effects are caused by anti-VEGF-A treatment in choroidal neovascularization or by carboanhydrase inhibitors reducing fluid accumulation in the macula. Being exposed to the bloodstream, the RPE reacts to systemic disease, such as diabetes or hypertension, but also to systemic pharmacological intervention, for example to hypotensive drugs acting on the renin-angiotensin-system. Sustained pharmacological treatments, in particular, cause side effects at the RPE with consequences for both RPE function and photoreceptor survival. Among these are systemic inhibition of angiotensin-converting enzyme, insulin treatment in diabetes and anti-VEGF-A therapy. Given the special anatomical and functional relationships of the RPE, pharmacological intervention targeting either the eye or the body systemically should take potential alteration of RPE and subsequently photoreceptor function into account.
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28
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Hernández C, Dal Monte M, Simó R, Casini G. Neuroprotection as a Therapeutic Target for Diabetic Retinopathy. J Diabetes Res 2016; 2016:9508541. [PMID: 27123463 PMCID: PMC4830713 DOI: 10.1155/2016/9508541] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Revised: 02/29/2016] [Accepted: 03/16/2016] [Indexed: 02/07/2023] Open
Abstract
Diabetic retinopathy (DR) is a multifactorial progressive disease of the retina and a leading cause of vision loss. DR has long been regarded as a vascular disorder, although neuronal death and visual impairment appear before vascular lesions, suggesting an important role played by neurodegeneration in DR and the appropriateness of neuroprotective strategies. Upregulation of vascular endothelial growth factor (VEGF), the main target of current therapies, is likely to be one of the first responses to retinal hyperglycemic stress and VEGF may represent an important survival factor in early phases of DR. Of central importance for clinical trials is the detection of retinal neurodegeneration in the clinical setting, and spectral domain optical coherence tomography seems the most indicated technique. Many substances have been tested in animal studies for their neuroprotective properties and for possible use in humans. Perhaps, the most intriguing perspective is the use of endogenous neuroprotective substances or nutraceuticals. Together, the data point to the central role of neurodegeneration in the pathogenesis of DR and indicate neuroprotection as an effective strategy for treating this disease. However, clinical trials to determine not only the effectiveness and safety but also the compliance of a noninvasive route of drug administration are needed.
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Affiliation(s)
- Cristina Hernández
- CIBERDEM (CIBER de Diabetes y Enfermedades Metabolicas Asociadas) and Diabetes and Metabolism Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autonoma de Barcelona, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain
- *Cristina Hernández: and
| | - Massimo Dal Monte
- Department of Biology, University of Pisa, Via San Zeno 31, 56127 Pisa, Italy
- Interdepartmental Research Center Nutrafood “Nutraceuticals and Food for Health”, University of Pisa, Via del Borghetto 80, 56124 Pisa, Italy
| | - Rafael Simó
- CIBERDEM (CIBER de Diabetes y Enfermedades Metabolicas Asociadas) and Diabetes and Metabolism Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autonoma de Barcelona, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain
| | - Giovanni Casini
- Department of Biology, University of Pisa, Via San Zeno 31, 56127 Pisa, Italy
- Interdepartmental Research Center Nutrafood “Nutraceuticals and Food for Health”, University of Pisa, Via del Borghetto 80, 56124 Pisa, Italy
- *Giovanni Casini:
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29
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Diabetic retinopathy: recent advances towards understanding neurodegeneration and vision loss. SCIENCE CHINA-LIFE SCIENCES 2015; 58:541-9. [DOI: 10.1007/s11427-015-4856-x] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/24/2014] [Accepted: 02/02/2015] [Indexed: 12/22/2022]
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Nivison-Smith L, O'Brien BJ, Truong M, Guo CX, Kalloniatis M, Acosta ML. Vinpocetine modulates metabolic activity and function during retinal ischemia. Am J Physiol Cell Physiol 2015; 308:C737-49. [PMID: 25696811 DOI: 10.1152/ajpcell.00291.2014] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2014] [Accepted: 02/17/2015] [Indexed: 12/18/2022]
Abstract
Vinpocetine protects against a range of degenerative conditions and insults of the central nervous system via multiple modes of action. Little is known, however, of its effects on metabolism. This may be highly relevant, as vinpocetine is highly protective against ischemia, a process that inhibits normal metabolic function. This study uses the ischemic retina as a model to characterize vinpocetine's effects on metabolism. Vinpocetine reduced the metabolic demand of the retina following ex vivo hypoxia and ischemia to normal levels based on lactate dehydrogenase activity. Vinpocetine delivered similar effects in an in vivo model of retinal ischemia-reperfusion, possibly through increasing glucose availability. Vinpocetine's effects on glucose also appeared to improve glutamate homeostasis in ischemic Müller cells. Other actions of vinpocetine following ischemia-reperfusion, such as reduced cell death and improved retinal function, were possibly a combination of the drug's actions on metabolism and other retinal pathways. Vinpocetine's metabolic effects appeared independent of its other known actions in ischemia, as it recovered retinal function in a separate metabolic model where the glutamate-to-glutamine metabolic pathway was inhibited in Müller cells. The results of this study indicate that vinpocetine mediates ischemic damage partly through altered metabolism and has potential beneficial effects as a treatment for ischemia of neuronal tissues.
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Affiliation(s)
- Lisa Nivison-Smith
- School of Optometry and Vision Science, University of New South Wales, Sydney, Australia
| | - Brendan J O'Brien
- Department of Optometry and Vision Science, University of Auckland, Auckland, New Zealand
| | - Mai Truong
- Department of Optometry and Vision Science, University of Auckland, Auckland, New Zealand
| | - Cindy X Guo
- Department of Optometry and Vision Science, University of Auckland, Auckland, New Zealand
| | - Michael Kalloniatis
- School of Optometry and Vision Science, University of New South Wales, Sydney, Australia; Department of Optometry and Vision Science, University of Auckland, Auckland, New Zealand; Centre for Eye Health, University of New South Wales, Sydney, Australia; and
| | - Monica L Acosta
- Department of Optometry and Vision Science, University of Auckland, Auckland, New Zealand; New Zealand National Eye Centre, University of Auckland, Auckland, New Zealand
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31
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Abstract
Although photoreceptors account for most of the mass and metabolic activity of the retina, their role in the pathogenesis of diabetic retinopathy has been largely overlooked. Recent studies suggest that photoreceptors might play a critical role in the diabetes-induced degeneration of retinal capillaries, and thus can no longer be ignored. The present review summarizes diabetes-induced alterations in photoreceptor structure and function, and provides a rationale for further study of a role of photoreceptors in the pathogenesis of the retinopathy.
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Affiliation(s)
- Timothy S Kern
- Case Western Reserve University, Department of Medicine and Center for Diabetes Research Cleveland, Ohio, USA ; Veterans Administration Medical Center Research Service 151 Cleveland, Ohio, USA
| | - Bruce A Berkowitz
- Wayne State University School of Medicine, Departments of Anatomy and Cell Biology and Ophthalmology Detroit, Michigan, USA
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32
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Zhou X, Bedggood P, Metha A. Improving high resolution retinal image quality using speckle illumination HiLo imaging. BIOMEDICAL OPTICS EXPRESS 2014; 5:2563-79. [PMID: 25136486 PMCID: PMC4132989 DOI: 10.1364/boe.5.002563] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Revised: 06/30/2014] [Accepted: 06/30/2014] [Indexed: 05/15/2023]
Abstract
Retinal image quality from flood illumination adaptive optics (AO) ophthalmoscopes is adversely affected by out-of-focus light scatter due to the lack of confocality. This effect is more pronounced in small eyes, such as that of rodents, because the requisite high optical power confers a large dioptric thickness to the retina. A recently-developed structured illumination microscopy (SIM) technique called HiLo imaging has been shown to reduce the effect of out-of-focus light scatter in flood illumination microscopes and produce pseudo-confocal images with significantly improved image quality. In this work, we adopted the HiLo technique to a flood AO ophthalmoscope and performed AO imaging in both (physical) model and live rat eyes. The improvement in image quality from HiLo imaging is shown both qualitatively and quantitatively by using spatial spectral analysis.
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Pardue MT, Barnes CS, Kim MK, Aung MH, Amarnath R, Olson DE, Thulé PM. Rodent Hyperglycemia-Induced Inner Retinal Deficits are Mirrored in Human Diabetes. Transl Vis Sci Technol 2014; 3:6. [PMID: 24959388 DOI: 10.1167/tvst.3.3.6] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2014] [Accepted: 04/28/2014] [Indexed: 02/05/2023] Open
Abstract
PURPOSE To evaluate the utility of low luminance stimuli to functionally probe inner retinal rod pathways in the context of diabetes mellitus in both rat and human subjects. METHODS Inner retinal dysfunction was assessed using oscillatory potential (OP) delays in diabetic rats. Scotopic electroretinograms (ERGs) in response to a series of increasing flash luminances were recorded from streptozotocin (STZ)-treated and control Sprague-Dawley rats after 7, 14, 20, and 29 weeks of hyperglycemia. We then evaluated OP delays in human diabetic subjects with (DR) and without (DM) diabetic retinopathy using the International Society for Clinical Electrophysiology in Vision (ISCEV) standard scotopic protocol and two additional dim test flashes. RESULTS Beginning 7 weeks after STZ, OP implicit times in diabetic rats were progressively delayed in response to dim, but not bright stimuli. In many diabetic subjects the standard ISCEV dim flash failed to illicit measureable OPs. However, OPs became measurable using a brighter, nonstandard dim flash (Test Flash 1, -1.43 log cd s/m2), and exhibited prolonged implicit times in the DM group compared with control subjects (CTRL). CONCLUSIONS Delays in scotopic OP implicit times are an early response to hyperglycemia in diabetic rats. A similar, inner retinal, rod-driven response was detected in diabetic human subjects without diabetic retinopathy, only when a nonstandard ISCEV flash intensity was employed during ERG testing. TRANSLATIONAL RELEVANCE The addition of a dim stimulus to standard ISCEV flashes with assessment of OP latency during ERG testing may provide a detection method for early retinal dysfunction in diabetic patients.
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Affiliation(s)
- Machelle T Pardue
- Rehab R&D Center of Excellence, Veterans Affairs Medical Center, Decatur, GA ; Department of Ophthalmology, Emory University, Atlanta, GA ; Neuroscience Program, Emory University, Atlanta, GA
| | - Claire S Barnes
- Rehab R&D Center of Excellence, Veterans Affairs Medical Center, Decatur, GA ; Department of Ophthalmology, Emory University, Atlanta, GA
| | - Moon K Kim
- Rehab R&D Center of Excellence, Veterans Affairs Medical Center, Decatur, GA ; Department of Ophthalmology, Emory University, Atlanta, GA
| | - Moe H Aung
- Neuroscience Program, Emory University, Atlanta, GA
| | - Raj Amarnath
- Rehab R&D Center of Excellence, Veterans Affairs Medical Center, Decatur, GA
| | - Darin E Olson
- Medical Service, Veterans Affairs Medical Center, Decatur, GA ; Division of Endocrinology, Metabolism, & Lipids, Emory University, Atlanta, GA
| | - Peter M Thulé
- Medical Service, Veterans Affairs Medical Center, Decatur, GA ; Division of Endocrinology, Metabolism, & Lipids, Emory University, Atlanta, GA
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34
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Abcouwer SF, Gardner TW. Diabetic retinopathy: loss of neuroretinal adaptation to the diabetic metabolic environment. Ann N Y Acad Sci 2014; 1311:174-90. [PMID: 24673341 DOI: 10.1111/nyas.12412] [Citation(s) in RCA: 174] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Diabetic retinopathy (DR) impairs vision of patients with type 1 and type 2 diabetes, associated with vascular dysfunction and occlusion, retinal edema, hemorrhage, and inappropriate growth of new blood vessels. The recent success of biologic treatments targeting vascular endothelial growth factor (VEGF) demonstrates that treating the vascular aspects in the later stages of the disease can preserve vision in many patients. It would also be highly desirable to prevent the onset of the disease or arrest its progression at a stage preceding the appearance of overt microvascular pathologies. The progression of DR is not necessarily linear but may follow a series of steps that evolve over the course of multiple years. Abundant data suggest that diabetes affects the entire neurovascular unit of the retina, with an early loss of neurovascular coupling, gradual neurodegeneration, gliosis, and neuroinflammation occurring before observable vascular pathologies. In this article, we consider the pathology of DR from the point of view that diabetes causes measurable dysfunctions in the complex integral network of cell types that produce and maintain human vision.
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Affiliation(s)
- Steven F Abcouwer
- Department of Ophthalmology and Visual Sciences, University of Michigan Kellogg Eye Center, Ann Arbor, Michigan
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35
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Yu J, Wang L, Weng SJ, Yang XL, Zhang DQ, Zhong YM. Hyperactivity of ON-type retinal ganglion cells in streptozotocin-induced diabetic mice. PLoS One 2013; 8:e76049. [PMID: 24069457 PMCID: PMC3777880 DOI: 10.1371/journal.pone.0076049] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2013] [Accepted: 08/19/2013] [Indexed: 11/29/2022] Open
Abstract
Impairment of visual function has been detected in the early stage of diabetes but the underlying neural mechanisms involved are largely unknown. Morphological and functional alterations of retinal ganglion cells, the final output neurons of the vertebrate retina, are thought to be the major cause of visual defects in diabetes but direct evidence to support this notion is limited. In this study we investigated functional changes of retinal ganglion cells in a type 1-like diabetic mouse model. Our results demonstrated that the spontaneous spiking activity of ON-type retinal ganglion cells was increased in streptozotocin-diabetic mice after 3 to 4 months of diabetes. At this stage of diabetes, no apoptotic signals or cell loss were detected in the ganglion cell layer of the retina, suggesting that the functional alterations in ganglion cells occur prior to massive ganglion cell apoptosis. Furthermore, we found that the increased activity of ON-type ganglion cells was mainly a result of reduced inhibitory signaling to the cells in diabetes. This novel mechanism provides insight into how visual function is impaired in diabetic retinopathy.
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Affiliation(s)
- Jun Yu
- Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China
| | - Lu Wang
- Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China
| | - Shi-Jun Weng
- Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China
| | - Xiong-Li Yang
- Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China
| | - Dao-Qi Zhang
- Eye Research Institute, Oakland University, Rochester, Michigan, United States of America
| | - Yong-Mei Zhong
- Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China
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36
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Identifying cell class specific losses from serially generated electroretinogram components. BIOMED RESEARCH INTERNATIONAL 2013; 2013:796362. [PMID: 24089688 PMCID: PMC3781995 DOI: 10.1155/2013/796362] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2013] [Accepted: 07/08/2013] [Indexed: 11/18/2022]
Abstract
Purpose. Processing of information through the cellular layers of the retina occurs in a serial manner. In the electroretinogram (ERG), this complicates interpretation of inner retinal changes as dysfunction may arise from “upstream” neurons or may indicate a direct loss to that neural generator. We propose an approach that addresses this issue by defining ERG gain relationships. Methods. Regression analyses between two serial ERG parameters in a control cohort of rats are used to define gain relationships. These gains are then applied to two models of retinal disease. Results. The PIIIamp to PIIamp gain is unity whereas the PIIamp to pSTRamp and PIIamp to nSTRamp gains are greater than unity, indicating “amplification” (P < 0.05). Timing relationships show amplification between PIIIit to PIIit and compression for PIIit to pSTRit and PIIit to nSTRit, (P < 0.05). Application of these gains to ω-3-deficiency indicates that all timing changes are downstream of photoreceptor changes, but a direct pSTR amplitude loss occurs (P < 0.05). Application to diabetes indicates widespread inner retinal dysfunction which cannot be attributed to outer retinal changes (P < 0.05). Conclusions. This simple approach aids in the interpretation of inner retinal ERG changes by taking into account gain characteristics found between successive ERG components of normal animals.
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Zhou X, Bedggood P, Metha A. Limitations to adaptive optics image quality in rodent eyes. BIOMEDICAL OPTICS EXPRESS 2012; 3:1811-24. [PMID: 22876346 PMCID: PMC3409701 DOI: 10.1364/boe.3.001811] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2012] [Revised: 06/08/2012] [Accepted: 06/14/2012] [Indexed: 05/18/2023]
Abstract
Adaptive optics (AO) retinal image quality of rodent eyes is inferior to that of human eyes, despite the promise of greater numerical aperture. This paradox challenges several assumptions commonly made in AO imaging, assumptions which may be invalidated by the very high power and dioptric thickness of the rodent retina. We used optical modeling to compare the performance of rat and human eyes under conditions that tested the validity of these assumptions. Results showed that AO image quality in the human eye is robust to positioning errors of the AO corrector and to differences in imaging depth and wavelength compared to the wavefront beacon. In contrast, image quality in the rat eye declines sharply with each of these manipulations, especially when imaging off-axis. However, some latitude does exist to offset these manipulations against each other to produce good image quality.
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38
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Wright WS, McElhatten RM, Busu C, Amit SY, Leskova W, Aw TY, Harris NR. Influence of glutathione on the electroretinogram in diabetic and non-diabetic rats. Curr Eye Res 2012; 36:831-7. [PMID: 21851169 DOI: 10.3109/02713683.2011.589021] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
AIMS The purpose of this study was to investigate the influence of glutathione on the electroretinogram (ERG) in diabetic and non-diabetic rats. MATERIALS AND METHODS Streptozotocin (STZ: 60 mg/kg) was injected into male RCC Wistar rats to induce hyperglycemia, with buffer instead of STZ injected into age-matched non-diabetic controls. After 8 weeks, ERG measurements were obtained at seven different scotopic flash intensities on the two groups of anesthetized, dark-adapted rats (controls, STZ). Following ERG measurements, eyes were enucleated for measurements of retinal/vitreous GSH and glutathione disulfide (GSSG). RESULTS Diabetic rats produced delayed b-wave ERG signals (increased implicit times), but had normal a-wave and b-wave amplitudes, a-wave implicit times, and oscillatory potentials. No differences were observed in retinal GSH or GSSG between controls and diabetics; however, correlations between GSH and all ERG parameters (with the exception of b-wave implicit times) were noted, and were not significantly altered by the presence of hyperglycemia. CONCLUSIONS GSH is likely to play an important role in retinal function as assessed by the ERG, with this role not substantially altered in rats diabetic for 8 weeks.
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Affiliation(s)
- William S Wright
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130, USA
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39
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Xiao C, He M, Nan Y, Zhang D, Chen B, Guan Y, Pu M. Physiological effects of superoxide dismutase on altered visual function of retinal ganglion cells in db/db mice. PLoS One 2012; 7:e30343. [PMID: 22272340 PMCID: PMC3260298 DOI: 10.1371/journal.pone.0030343] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2011] [Accepted: 12/14/2011] [Indexed: 01/04/2023] Open
Abstract
Background 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. Methodology/Principal Findings In vitro extracellular single-unit recordings from RGCs in wholemount retinas were performed. The receptive field size, luminance threshold, and contrast gain of the RGCs were investigated. Although ON- and OFF-RGCs showed a different time course of RF size reduction, by 20 wk, the RF of ON- and OFF-RGCs were similarly affected. The LT of ON-RGCs was significantly elevated in 12 and 20 wk db/db mice compared to the LT of OFF-RGCs. The diabetic injury also affected contrast gains of ON- and OFF-RGCs differently. The generation of reactive oxidative species (ROS) in fresh retina was estimated by dihydroethidium. Superoxide dismutase (SOD) (300 unit/ml) was applied in Ames medium to the retina, and visual responses of RGCs were recorded for five hours. ROS generation in the retinas of db/db mice increased at 8wk and continued to progress at 20 wk of ages. In vitro application of SOD improved visual functions in 20 wk db/db mice but the SOD treatment affected ON- and OFF-RGCs differently in db/m retina. Conclusions/Significance The altered visual functions of RGCs were characterized by the reduced RF center size, elevated LT, and attenuated contrast gain in 12 and 20 wk db/db mice, respectively. These altered visual functions could, at least partly, be due to oxidative stress since in vitro application of SOD effectively improves visual functions.
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Affiliation(s)
- Chunxia Xiao
- Department of Anatomy, School of Basic Medical Sciences, Peking University, Beijing, China
- Key Laboratory on Machine Perception, Peking University, Beijing, China
- Key Laboratory for Visual Impairment and Restore, Peking University, Beijing, China
| | - Meihua He
- Department of Anatomy, School of Basic Medical Sciences, Peking University, Beijing, China
- Key Laboratory on Machine Perception, Peking University, Beijing, China
- Key Laboratory for Visual Impairment and Restore, Peking University, Beijing, China
| | - Yan Nan
- Department of Anatomy, School of Basic Medical Sciences, Peking University, Beijing, China
- Key Laboratory on Machine Perception, Peking University, Beijing, China
- Key Laboratory for Visual Impairment and Restore, Peking University, Beijing, China
| | - Dongjuan Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Baiyu Chen
- Department of Anatomy, School of Basic Medical Sciences, Peking University, Beijing, China
- Key Laboratory on Machine Perception, Peking University, Beijing, China
| | - Youfei Guan
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
- * E-mail: (MP); (YG)
| | - Mingliang Pu
- Department of Anatomy, School of Basic Medical Sciences, Peking University, Beijing, China
- Key Laboratory on Machine Perception, Peking University, Beijing, China
- Key Laboratory for Visual Impairment and Restore, Peking University, Beijing, China
- * E-mail: (MP); (YG)
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40
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Berkowitz BA, Bissig D, Ye Y, Valsadia P, Kern TS, Roberts R. Evidence for diffuse central retinal edema in vivo in diabetic male Sprague Dawley rats. PLoS One 2012; 7:e29619. [PMID: 22253747 PMCID: PMC3256169 DOI: 10.1371/journal.pone.0029619] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2011] [Accepted: 12/01/2011] [Indexed: 12/27/2022] Open
Abstract
Background Investigations into the mechanism of diffuse retinal edema in diabetic subjects have been limited by a lack of animal models and techniques that co-localized retinal thickness and hydration in vivo. In this study we test the hypothesis that a previously reported supernormal central retinal thickness on MRI measured in experimental diabetic retinopathy in vivo represents a persistent and diffuse edema. Methodology/Principal Findings In diabetic and age-matched control rats, and in rats experiencing dilutional hyponatremia (as a positive edema control), whole central retinal thickness, intraretinal water content and apparent diffusion coefficients (ADC, ‘water mobility’) were measured in vivo using quantitative MRI methods. Glycated hemoglobin and retinal thickness ex vivo (histology) were also measured in control and diabetic groups. In the dilutional hyponatremia model, central retinal thickness and water content were supernormal by quantitative MRI, and intraretinal water mobility profiles changed in a manner consistent with intracellular edema. Groups of diabetic (2, 3, 4, 6, and 9 mo of diabetes), and age-matched controls were then investigated with MRI and all diabetic rats showed supernormal whole central retinal thickness. In a separate study in 4 mo diabetic rats (and controls), MRI retinal thickness and water content metrics were significantly greater than normal, and ADC was subnormal in the outer retina; the increase in retinal thickness was not detected histologically on sections of fixed and dehydrated retinas from these rats. Conclusions/Significance Diabetic male Sprague Dawley rats demonstrate a persistent and diffuse retinal edema in vivo, providing, for the first time, an important model for investigating its pathogenesis and treatment. These studies also validate MRI as a powerful approach for investigating mechanisms of diabetic retinal edema in future experimental and clinical investigations.
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Affiliation(s)
- Bruce A Berkowitz
- Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, Michigan, United States of America.
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Wong VHY, Vingrys AJ, Bui BV. Glial and neuronal dysfunction in streptozotocin-induced diabetic rats. J Ocul Biol Dis Infor 2011; 4:42-50. [PMID: 23275800 DOI: 10.1007/s12177-011-9069-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2011] [Accepted: 12/02/2011] [Indexed: 11/29/2022] Open
Abstract
Neuronal dysfunction has been noted very soon after the induction of diabetes by streptozotocin injection in rats. It is not clear from anatomical evidence whether glial cell dysfunction accompanies the well-documented neuronal deficit. Here, we isolate the Müller cell driven slow-P3 component of the full-field electroretinogram and show that it is attenuated at 4 weeks following the onset of streptozotocin-hyperglycaemia. We also found a concurrent reduction in the sensitivity of the phototransduction cascade, as well as in the components of the electroretinogram known to indicate retinal ganglion cell and amacrine cell integrity. Our data support the idea that neuronal and Müller cell dysfunction occurs at the same time in streptozotocin-induced hyperglycaemia.
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Affiliation(s)
- Vickie H Y Wong
- Department of Optometry and Vision Sciences, University of Melbourne, Parkville, 3010 Victoria Australia
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42
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Wong VHY, Bui BV, Vingrys AJ. Clinical and experimental links between diabetes and glaucoma. Clin Exp Optom 2010; 94:4-23. [PMID: 21091536 DOI: 10.1111/j.1444-0938.2010.00546.x] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Glaucoma is a leading cause of blindness. It is a multifactorial condition, the risk factors for which are increasingly well defined from large-scale epidemiological studies. One risk factor that remains controversial is the presence of diabetes. It has been proposed that diabetic eyes are at greater risk of injury from external stressors, such as elevated intraocular pressure. Alternatively, diabetes may cause ganglion cell loss, which becomes additive to a glaucomatous ganglion cell injury. Several clinical trials have considered whether a link exists between diabetes and glaucoma. In this review, we outline these studies and consider the causes for their lack of concordant findings. We also review the biochemical and cellular similarities between the two conditions. Moreover, we review the available literature that attempts to answer the question of whether the presence of diabetes increases the risk of developing glaucoma. At present, laboratory studies provide robust evidence for an association between diabetes and glaucoma.
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Affiliation(s)
- Vickie H Y Wong
- Department of Optometry and Vision Sciences, The University of Melbourne, Parkville, VIC 3010, Australia
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