Mechanisms behind Retinal Ganglion Cell Loss in Diabetes and Therapeutic Approach

Diabetes produces several changes in the body triggered by high glycemia. Some of these changes include altered metabolism, structural changes in blood vessels and chronic inflammation. The eye and particularly the retinal ganglion cells (RGCs) are not spared, and the changes eventually lead to cell loss and visual function impairment. Understanding the mechanisms resulting in RGC damage and loss from diabetic retinopathy is essential to find an effective treatment. This review focuses mainly on the signaling pathways and molecules involved in RGC loss and the potential therapeutic approaches for the prevention of this cell death. Throughout the manuscript it became evident that multiple factors of different kind are responsible for RGC damage. This shows that new therapeutic agents targeting several factors at the same time are needed. Alpha-1 antitrypsin as an anti-inflammatory agent may become a suitable option for the treatment of RGC loss because of its beneficial interaction with several signaling pathways involved in RGC injury and inflammation. In conclusion, alpha-1 antitrypsin may become a potential therapeutic agent for the treatment of RGC loss and processes behind diabetic retinopathy.

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mTOR-dependent dysregulation of autophagy contributes to the retinal ganglion cell loss in streptozotocin-induced diabetic retinopathy

10.21203/rs.3.rs-56279/v1 ◽

2020 ◽

Author(s):

Sanjar Batirovich Madrakhimov ◽

Jin Young Yang ◽

Jin Ha Kim ◽

Jung Woo Han ◽

Tae Kwann Park

Keyword(s):

Diabetic Retinopathy ◽

Ganglion Cell ◽

Ganglion Cells ◽

Neuronal Cell ◽

Cell Loss ◽

Retinal Ganglion ◽

Diabetic Mice ◽

Tissue Samples ◽

Glucose Transporter 1 ◽

Apoptosis Pathway

Abstract Background: Neurodegeneration, an early event in the pathogenesis of diabetic retinopathy (DR), precedes clinically detectable microvascular damage. Autophagy dysregulation is considered a potential cause of neuronal cell loss, however underlying mechanisms remain unclear. The mechanistic target of rapamycin (mTOR) integrates diverse environmental signals to coordinate biological processes, including autophagy. Here, we investigated the role of mTOR signaling in neuronal cell death in diabetic retinopathy. Methods: Diabetes was induced by a single intraperitoneal injection of streptozotocin and tissue samples were harvested at 1, 2, 3, 4, and 6 months of diabetes. Early-stage of diabetic retinopathy was investigated in 1-month-diabetic mice treated with phlorizin or rapamycin. The effect of autophagy modulation on retinal ganglion cells was investigated in 3-months-diabetic mice treated with phlorizin or MHY1485. Tissue samples obtained from treated/untreated diabetic mice and age-matched controls were used for Western blot and histologic analysis.Results: mTOR-related proteins and glucose transporter 1 (GLUT1) was upregulated at 1 month and downregulated in the following period up to 6 months. Diabetes-induced neurodegeneration was characterized by an increase of apoptotic marker – cleaved caspase 3, a decrease of the total number of cells, and NeuN immunoreactivity in the ganglion cell layer (GCL), as well as an increase of autophagic protein. Insulin-independent glycemic control restored the mTOR pathway activity and GLUT1 expression, along with a decrease of autophagic and apoptotic proteins in 3-months-diabetic mice neuroretina. However, blockade of autophagy using MHY1485 resulted in a more protective effect on ganglion cells compared with phlorizin treatment. Conclusion: Collectively, our study describes the mechanisms of neurodegeneration through the hyperglycemia/ mTOR/ autophagy/ apoptosis pathway.

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mTOR-dependent dysregulation of autophagy contributes to the retinal ganglion cell loss in streptozotocin-induced diabetic retinopathy

10.21203/rs.3.rs-56279/v2 ◽

2020 ◽

Author(s):

Sanjar Batirovich Madrakhimov ◽

Jin Young Yang ◽

Jin Ha Kim ◽

Jung Woo Han ◽

Tae Kwann Park

Keyword(s):

Diabetic Retinopathy ◽

Ganglion Cell ◽

Ganglion Cells ◽

Neuronal Cell ◽

Cell Loss ◽

Retinal Ganglion ◽

Diabetic Mice ◽

Tissue Samples ◽

Glucose Transporter 1 ◽

Subcutaneous Injections

Abstract Background: Neurodegeneration, an early event in the pathogenesis of diabetic retinopathy (DR), precedes clinically detectable microvascular damage. Autophagy dysregulation is considered a potential cause of neuronal cell loss, however underlying mechanisms remain unclear. The mechanistic target of rapamycin (mTOR) integrates diverse environmental signals to coordinate biological processes, including autophagy. Here, we investigated the role of mTOR signaling in neuronal cell death in diabetic retinopathy. Methods: Diabetes was induced by a single intraperitoneal injection of streptozotocin and tissue samples were harvested at 1, 2, 3, 4, and 6 months of diabetes. Early-stage of diabetic retinopathy was investigated in 1-month-diabetic mice treated with phlorizin (two daily subcutaneous injections at a dose of 200 mg/kg of body weight during the last 7 full days of the experiment and the morning of the 8th day, 3 h before sacrifice) or rapamycin (daily intraperitoneal injections, at a dose of 3mg/kg for the same period as for phlorizin treatment). The effect of autophagy modulation on retinal ganglion cells was investigated in 3-months-diabetic mice treated with phlorizin (two daily subcutaneous injections during the last 10 full days of the experiment and the morning of the 11th day, 3 h before sacrifice) or MHY1485 (daily i.p. injections, at a dose of 10 mg/kg for the same period as for phlorizin treatment). Tissue samples obtained from treated/untreated diabetic mice and age-matched controls were used for Western blot and histologic analysis.Results: mTOR-related proteins and glucose transporter 1 (GLUT1) was upregulated at 1 month and downregulated in the following period up to 6 months. Diabetes-induced neurodegeneration was characterized by an increase of apoptotic marker – cleaved caspase 3, a decrease of the total number of cells, and NeuN immunoreactivity in the ganglion cell layer (GCL), as well as an increase of autophagic protein. Insulin-independent glycemic control restored the mTOR pathway activity and GLUT1 expression, along with a decrease of autophagic and apoptotic proteins in 3-months-diabetic mice neuroretina. However, blockade of autophagy using MHY1485 resulted in a more protective effect on ganglion cells compared with phlorizin treatment. Conclusion: Collectively, our study describes the mechanisms of neurodegeneration through the hyperglycemia/ mTOR/ autophagy/ apoptosis pathway.

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mTOR-dependent dysregulation of autophagy contributes to the retinal ganglion cell loss in streptozotocin-induced diabetic retinopathy

Cell Communication and Signaling ◽

10.1186/s12964-020-00698-4 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Sanjar Batirovich Madrakhimov ◽

Jin Young Yang ◽

Jin Ha Kim ◽

Jung Woo Han ◽

Tae Kwann Park

Keyword(s):

Diabetic Retinopathy ◽

Ganglion Cell ◽

Ganglion Cells ◽

Neuronal Cell ◽

Cell Loss ◽

Retinal Ganglion ◽

Diabetic Mice ◽

Tissue Samples ◽

Glucose Transporter 1 ◽

Subcutaneous Injections

Abstract Background Neurodegeneration, an early event in the pathogenesis of diabetic retinopathy (DR), precedes clinically detectable microvascular damage. Autophagy dysregulation is considered a potential cause of neuronal cell loss, however underlying mechanisms remain unclear. The mechanistic target of rapamycin (mTOR) integrates diverse environmental signals to coordinate biological processes, including autophagy. Here, we investigated the role of mTOR signaling in neuronal cell death in DR. Methods Diabetes was induced by a single intraperitoneal injection of streptozotocin and tissue samples were harvested at 1, 2, 3, 4, and 6 months of diabetes. Early-stage of DR was investigated in 1-month-diabetic mice treated with phlorizin (two daily subcutaneous injections at a dose of 200 mg/kg of body weight during the last 7 full days of the experiment and the morning of the 8th day, 3 h before sacrifice) or rapamycin (daily intraperitoneal injections, at a dose of 3 mg/kg for the same period as for phlorizin treatment). The effect of autophagy modulation on retinal ganglion cells was investigated in 3-months-diabetic mice treated with phlorizin (two daily subcutaneous injections during the last 10 full days of the experiment and the morning of the 11th day, 3 h before sacrifice) or MHY1485 (daily i.p. injections, at a dose of 10 mg/kg for the same period as for phlorizin treatment). Tissue samples obtained from treated/untreated diabetic mice and age-matched controls were used for Western blot and histologic analysis. Results mTOR-related proteins and glucose transporter 1 (GLUT1) was upregulated at 1 month and downregulated in the following period up to 6 months. Diabetes-induced neurodegeneration was characterized by an increase of apoptotic marker—cleaved caspase 3, a decrease of the total number of cells, and NeuN immunoreactivity in the ganglion cell layer, as well as an increase of autophagic protein. Insulin-independent glycemic control restored the mTOR pathway activity and GLUT1 expression, along with a decrease of autophagic and apoptotic proteins in 3-months-diabetic mice neuroretina. However, blockade of autophagy using MHY1485 resulted in a more protective effect on ganglion cells compared with phlorizin treatment. Conclusion Collectively, our study describes the mechanisms of neurodegeneration through the hyperglycemia/ mTOR/ autophagy/ apoptosis pathway.

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Melatonin As a Modulator of Degenerative and Regenerative Signaling Pathways in Injured Retinal Ganglion Cells

Current Pharmaceutical Design ◽

10.2174/1381612825666190829151314 ◽

2019 ◽

Vol 25 (28) ◽

pp. 3057-3073 ◽

Cited By ~ 6

Author(s):

Kobra B. Juybari ◽

Azam Hosseinzadeh ◽

Habib Ghaznavi ◽

Mahboobeh Kamali ◽

Ahad Sedaghat ◽

...

Keyword(s):

Optic Nerve ◽

Mitochondrial Dysfunction ◽

Signaling Pathways ◽

Retinal Ganglion Cells ◽

Molecular Mechanisms ◽

Nitrosative Stress ◽

Ganglion Cells ◽

Axon Growth ◽

Nerve Fibers ◽

Retinal Ganglion

Optic neuropathies refer to the dysfunction or degeneration of optic nerve fibers caused by any reasons including ischemia, inflammation, trauma, tumor, mitochondrial dysfunction, toxins, nutritional deficiency, inheritance, etc. Post-mitotic CNS neurons, including retinal ganglion cells (RGCs) intrinsically have a limited capacity for axon growth after either trauma or disease, leading to irreversible vision loss. In recent years, an increasing number of laboratory evidence has evaluated optic nerve injuries, focusing on molecular signaling pathways involved in RGC death. Trophic factor deprivation (TFD), inflammation, oxidative stress, mitochondrial dysfunction, glutamate-induced excitotoxicity, ischemia, hypoxia, etc. have been recognized as important molecular mechanisms leading to RGC apoptosis. Understanding these obstacles provides a better view to find out new strategies against retinal cell damage. Melatonin, as a wide-spectrum antioxidant and powerful freeradical scavenger, has the ability to protect RGCs or other cells against a variety of deleterious conditions such as oxidative/nitrosative stress, hypoxia/ischemia, inflammatory processes, and apoptosis. In this review, we primarily highlight the molecular regenerative and degenerative mechanisms involved in RGC survival/death and then summarize the possible protective effects of melatonin in the process of RGC death in some ocular diseases including optic neuropathies. Based on the information provided in this review, melatonin may act as a promising agent to reduce RGC death in various retinal pathologic conditions.

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Dynamic Expression of HDAC3 in db/db Mouse RGCs and Its Relationship with Apoptosis and Autophagy

Journal of Diabetes Research ◽

10.1155/2020/6086780 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Yuhong Fu ◽

Ying Wang ◽

Xinyuan Gao ◽

Huiyao Li ◽

Yue Yuan

Keyword(s):

Diabetic Retinopathy ◽

Ganglion Cell ◽

Retinal Ganglion Cells ◽

Retinal Ganglion Cell ◽

Ganglion Cells ◽

Control Group ◽

Diabetic Patients ◽

Retinal Ganglion ◽

Glucose Levels ◽

Dynamic Expression

Background. Diabetic retinopathy (DR) is a severe complication of diabetes mellitus. DR is considered as a neurovascular disease. Retinal ganglion cell (RGC) loss plays an important role in the vision function disorder of diabetic patients. Histone deacetylase3 (HDAC3) is closely related to injury repair and nerve regeneration. The correlation between HDAC3 and retinal ganglion cells in diabetic retinopathy is still unclear yet. Methods. To investigate the chronological sequence of the abnormalities of retinal ganglion cells in diabetic retinopathy, we choose 15 male db/db mice (aged 8 weeks, 12 weeks, 16 weeks, 18 weeks, and 25 weeks; each group had 3 mice) as diabetic groups and 3 male db/m mice (aged 8 weeks) as the control group. In this study, we examined the morphological and immunohistochemical changes of HDAC3, Caspase3, and LC3B in a sequential manner by characterizing the process of retinal ganglion cell variation. Results. Blood glucose levels and body weights of db/db mice were significantly higher than that of the control group, P<0.01. Compared with the control group, the number of retinal ganglion cells decreased with the duration of disease increasing. HDAC3 expression gradually increased in RGCs of db/db mice. Caspase3 expression gradually accelerated in RGCs of db/db mice. LC3B expression dynamically changed in RGCs of db/db mice. HDAC3 was positively correlated with Caspase3 expression (r=0.7424), P<0.01. HDAC3 was positively correlated with LC3B expression (r=0.7336), P<0.01. Discussion. We clarified the dynamic expression changes of HDAC3, Caspase3, and LC3B in retinal ganglion cells of db/db mice. Our results suggest the HDAC3 expression has a positive correlation with apoptosis and autophagy.

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Otologic Histopathology of Fabry's Disease

Annals of Otology Rhinology & Laryngology ◽

10.1177/000348948909800509 ◽

1989 ◽

Vol 98 (5) ◽

pp. 359-363 ◽

Cited By ~ 43

Author(s):

Patricia A. Schachern ◽

Michael M. Paparella ◽

Donald A. Shea ◽

Tae H. Yoon

Keyword(s):

Temporal Bone ◽

Ganglion Cells ◽

Spiral Ganglion ◽

Cell Loss ◽

The Body ◽

Spiral Ligament ◽

Fabry’S Disease ◽

Fabry's Disease ◽

Temporal Bones ◽

Spiral Ganglia

Fabry's disease is a rare progressive X-linked recessive disorder of glycosphingolipid metabolism. The accumulation of glycosphingolipids occurs in virtually all areas of the body, including the endothelial, perithelial, and smooth-muscle cells of blood vessels, the ganglion cells of the autonomic nervous system, and the glomeruli and tubules of the kidney. Although otologic symptoms have been described in these patients, to our knowledge there have been no temporal bone histopathologic reports. We describe the clinical histories, audiometric results, and temporal bone findings of two patients with this rare disorder. Both patients demonstrated a bilateral sloping sensorineural hearing loss audiometrically. Middle ear findings of seropurulent effusions and hyperplastic mucosa were seen in all four temporal bones. Strial and spiral ligament atrophy in all turns, and hair cell loss mainly in the basal turns, were also common findings. The number of spiral ganglion cells was reduced in all temporal bones; however, evidence of glycosphingolipid accumulation was not observed in the spiral ganglia.

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Retinal Neuropathy in IGT Stage of OLETF Rats: Another Characteristic Change of Diabetic Retinopathy

Journal of Diabetes Research ◽

10.1155/2021/3181347 ◽

2021 ◽

Vol 2021 ◽

pp. 1-19

Author(s):

Zhenhong Guo ◽

Xiaoyue Sun ◽

Juhong Yang ◽

Jinlan Xie ◽

Feifei Zhong ◽

...

Keyword(s):

Diabetic Retinopathy ◽

Glucose Tolerance ◽

Ganglion Cells ◽

Normal Glucose Tolerance ◽

Characteristic Change ◽

Retinal Ganglion ◽

Oletf Rats ◽

Significant Damage ◽

Normal Glucose ◽

Retinal Structure

Aims. We investigated the changes of retinal structure in normal glucose tolerance (NGT), impaired glucose tolerance (IGT), diabetes mellitus (DM), and diabetic kidney disease (DKD) stages in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Methods. We assigned OLETF rats to four groups based on their OGTT results and 24 h urinary microalbumin (24 h UMA) levels: NGT, IGT, DM, and DKD groups. We observed the structural and the corresponding pathological changes and quantified the expression of HIF-1α, iNOS, NF-κB, VEGF, ICAM-1, and occludin in the retina. Results. Significant damage to the retinal structure, especially in retinal ganglion cells (RGCs), was observed in the IGT stage. The expression of HIF-1α, iNOS, NF-κB, VEGF, and ICAM-1 was significantly upregulated, while that of occludin was downregulated. Conclusion. Significant retinal neuropathy occurs in the IGT stage. Inflammation and hypoxia may damage the blood retina barrier (BRB), leading to diabetic retinopathy.

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