Neurodegeneration In Diabetic Retinopathy Research Articles

Retinal neurodegeneration in diabetic retinopathy with systemic hypertension.

To identify the impact of hypertension (HTN) on inner retinal layer thickness in patients with diabetic retinopathy (DR). In this retrospective cross-sectional study, participants were divided into three groups: type 2 diabetes patients without DR (DM group), patients with DR (DR group), and patients with both DR and HTN (DR+HTN group). The peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell-inner plexiform layer (GC-IPL) thicknesses, measured using optical coherence tomography, were compared among the groups. A total of 470 eyes were enrolled: 224 eyes in the DM group, 131 eyes in the DR group, and 115 eyes in the DR+HTN group. The mean RNFL thicknesses were 95.0 ± 7.7, 92.5 ± 10.1, and 89.2 ± 11.2μm, and the mean GC-IPL thicknesses were 84.0 ± 5.7, 82.0 ± 7.6, and 79.2 ± 8.1μm in each group, respectively (all P < 0.001). In the DR+HTN group, the DR stage showed a significant association with pRNFL (B = - 5.38, P = 0.014) and GC-IPL (B = - 5.18, P = 0.001) thicknesses in multivariate analyses. Subgroup analyses revealed that pRNFL (P = 0.007) and GC-IPL (P = 0.005) thicknesses decreased significantly as DR progressed only in the DR+HTN group. Patients with both DR and HTN exhibited much thinner pRNFL and GC-IPL, compared with patients with DR only. These results may have been related to the amplified diabetic retinal neurodegeneration and synergistic impact of ischemia in DR patients with concurrent HTN. Additionally, the progression of DR resulted in more severe inner retinal damage when combined with HTN.

Neurodegeneration in diabetic retinopathy: An insight on its main signalling pathways

Aims/Purpose: In the latest years neurodegeneration has been considered as one of the main pathological processes involved in proliferative diabetic retinopathy's (PDR) onset and progression. We aimed to increase the understanding on the role of the main signalling molecules that participate in this phenomenon, including apoptotic, excitotoxic and neurotrophic factor pathways.Methods: Participants of both sexes were selected and programmed for vitrectomy by its diabetes mellitus 2 (DM2)‐derived vitreoretinal complications (PDR group, PDRG; n = 20), or by suffering macular hole, epiretinal membrane or rhegmatogenous retinal detachment (as the surrogate control group, SCG; n = 26). Vitreous body (VIT) and plasma (PLS) samples were collected and processed to determine the glutamate, caspase‐3 (CAS‐3) and brain‐derived neurotrophic factor (BDNF) levels. Next‐Generation Sequencing (NGS) techniques were applied to characterize the miRNA expression pattern in both groups.Results: Significantly higher VIT glutamate (p &lt; 0.05) and CAS‐3 (p &lt; 0.05), and significantly lower BDNF (p &lt; 0.05) levels were detected in the PDRG. Significantly higher PLS glutamate (p &lt; 0.05) and CAS‐3 (p &lt; 0.05) levels were found in diabetics. However, PLS levels of BDNF showed no differences between groups (p = 0.80). NGS analysis showed a different miRNA expression pattern between both groups.Conclusions: Diabetes‐induced changes in retinal neurons/glia may be the key to discover preclinical biomarkers for better managing diabetic eyes. Glutamate, caspase‐3 and BDNF, playing important roles in the neurodegenerative processes occurring in PDR, are pivotal candidates to identify diabetics at high risk of sight‐threatening complications. Additionally, certain miRNAs could be playing an important role in these signalling pathways, being involved in PDR's neurodegenerative phenomenon.

Exploring Neuroprotective Effects of Topical Brimonidine in Experimental Diabetic Retinopathy.

Diabetic retinopathy is a leading cause of blindness worldwide, characterized by neurovascular dysfunction. This study aimed to investigate the impact of brimonidine, a selective adrenoceptor agonist, on diabetic retinal neurodegeneration, recognizing the critical role of neurodegeneration in diabetic retinopathy. Streptozotocin-induced diabetes was established in adult male Sprague-Dawley rats to mimic diabetic retinopathy. Rats, except non-diabetic control rats, received topical applications of 0.15% brimonidine tartrate (treatment group) or balanced salt solution (diabetic control group) twice daily following diabetes induction. Each group comprised six randomly assigned animals. Retinal samples were analyzed using immunofluorescence staining, apoptosis assay, and western blot. Topical brimonidine treatment reduced apoptosis of retinal ganglion cells at 8 weeks after induction of diabetes (p<0.05). Glial activation induced by diabetes was reduced by brimonidine treatment. Immunoblot and immunofluorescence assay revealed that the decrease in phospho- protein kinase B (AKT) level resulting from diabetes was also attenuated by brimonidine (p<0.05). Furthermore, brimonidine alleviated the decrease in anti-apoptotic proteins [BCL2 apoptosis regulator (BCL2) and BCL-xl] induced by diabetes (p<0.05). Elevation of phospho-p38 mitogen-activated protein kinase (p38MAPK) and p53 in diabetic rats were reduced by brimonidine (p<0.05). Additionally, brimonidine treatment attenuated the upregulation of the pro-apoptotic molecule BCL-2 associated X in retinas of diabetic rats (p<0.05). These findings suggest that topical brimonidine treatment may protect retinal ganglion cells in experimental diabetes by modulating the AKT pathway and reducing pro-apoptotic p38MAPK levels. This presents a potential neuroprotective approach in diabetes, offering the advantage of localized treatment without the added burden of oral medication.

On implications of somatostatin in diabetic retinopathy.

Somatostatin, a naturally produced neuroprotective peptide, depresses excitatory neurotransmission and exerts anti-proliferative and anti-inflammatory effects on the retina. In this review, we summarize the progress of somatostatin treatment of diabetic retinopathy through analysis of relevant studies published from February 2019 to February 2023 extracted from the PubMed and Google Scholar databases. Insufficient neuroprotection, which occurs as a consequence of declined expression or dysregulation of retinal somatostatin in the very early stages of diabetic retinopathy, triggers retinal neurovascular unit impairment and microvascular damage. Somatostatin replacement is a promising treatment for retinal neurodegeneration in diabetic retinopathy. Numerous pre-clinical and clinical trials of somatostatin analog treatment for early diabetic retinopathy have been initiated. In one such trial (EUROCONDOR), topical administration of somatostatin was found to exert neuroprotective effects in patients with pre-existing retinal neurodysfunction, but had no impact on the onset of diabetic retinopathy. Overall, we concluded that somatostatin restoration may be especially beneficial for the growing population of patients with early-stage retinopathy. In order to achieve early prevention of diabetic retinopathy initiation, and thereby salvage visual function before the appearance of moderate non-proliferative diabetic retinopathy, several issues need to be addressed. These include the needs to: a) update and standardize the retinal screening scheme to incorporate the detection of early neurodegeneration, b) identify patient subgroups who would benefit from somatostatin analog supplementation, c) elucidate the interactions of somatostatin, particularly exogenously-delivered somatostatin analogs, with other retinal peptides in the context of hyperglycemia, and d) design safe, feasible, low cost, and effective administration routes.

Serum levels of cytokines in patients with retinal neurodegeneration in diabetic retinopathy on the background of type 2 diabetes mellitus

The aim of the present study was to determine the serum level of IL-1, TNF- IL-17A, INF-, IL-10 in patients with retinal neurodegeneration against the background of type 2 diabetes mellitus. The study included 80 patients with type 2 diabetes mellitus, which were divided into 4 groups depending on the presence of vascular symptoms of diabetic retinopathy and retinal neurodegeneration. The level of cytokines was determined using solid-phase ELISA. In groups of patients with retinal neurodegeneration, a significant (p0.05) increase in IL-1 and a decrease in IL-10 were detected. The presence of vascular changes in the retina did not affect the level of cytokines studied. The identified changes show the role of systemic imbalance between pro- and anti-inflammatory cytokines in the induction of retinal neurodegeneration in diabetic retinopathy. Further study of this problem is required in order to search for possible immune markers of retinal neurodegeneration in patients with type 2 diabetes.

IL-33 regulates Müller cell-mediated retinal inflammation and neurodegeneration in diabetic retinopathy.

Diabetic retinopathy (DR) is characterised by dysfunction of the retinal neurovascular unit, leading to visual impairment and blindness. Müller cells are key components of the retinal neurovascular unit and diabetes has a detrimental impact on these glial cells, triggering progressive neurovascular pathology of DR. Amongst many factors expressed by Müller cells, interleukin-33 (IL-33) has an established immunomodulatory role, and we investigated the role of endogenous IL-33 in DR. The expression of IL-33 in Müller cells increased during diabetes. Wild-type and Il33-/- mice developed equivalent levels of hyperglycaemia and weight loss following streptozotocin-induced diabetes. Electroretinogram a- and b-wave amplitudes, neuroretina thickness, and the numbers of cone photoreceptors and ganglion cells were significantly reduced in Il33-/- diabetic mice compared with those in wild-type counterparts. The Il33-/- diabetic retina also exhibited microglial activation, sustained gliosis, and upregulation of pro-inflammatory cytokines and neurotrophins. Primary Müller cells from Il33-/- mice expressed significantly lower levels of neurotransmitter-related genes (Glul and Slc1a3) and neurotrophin genes (Cntf, Lif, Igf1 and Ngf) under high-glucose conditions. Our results suggest that deletion of IL-33 promotes inflammation and neurodegeneration in DR, and that this cytokine is critical for regulation of glutamate metabolism, neurotransmitter recycling and neurotrophin secretion by Müller cells.

Role of cytokines, neuropeptids and matrix metalloproteinases in the immunopathogenesis of retinal neurodegeneration in diabetic retinopathy

Currently, diabetic retinopathy (DR) is considered both a vascular lesion, as well as a neurodegenerative disease. The normal functioning of the glia and retinal neurons depends on the balance between the cytokine system, neurotrophic factors and matrix metalloproteinases. The disorders that occur in these systems are assigned an important role in many neurodegenerative processes. The purpose of the present study was to determine the levels of IL-1, IL-17A, TNF, IFN, IL-10, TGF-1, TGF-2, TGF-3, MMP- 2, MMP-7, MMP-9, TIMP-1, TIMP-2, S100b protein, BDNF and NGF in the serum of patients with type 2 diabetes mellitus with signs of retinal neurodegeneration, and to identify additional immunological markers for diagnosis and prediction of their clinical course. The study included 80 patients with endocrinogically verified diagnosis of type 2 diabetes. All subjects were examined at an optical coherent tomograph RTVue-100 (USA), and the volume of focal loss of retinal ganglion cells (FLV) was determined. According to its results, the patients of the main group were divided into 2 subgroups. The first group included 22 persons in whom the FLV indexes did not show significant differences from the controls. The second group included 58 patients with a significantly larger FLV volume. In the subgroup of patients with high level of focal GCS loss, a significant increase in the level of IL-1 and IL-10 deficiency was revealed in comparison with the controls, and the subgroup without significant losses of GCS over the entire observation period. TGF-3 deficiency was found in patients of subgroup 2 versus controls and subgroup 1. An imbalance in the tissue proteolysis system was revealed, MMP-9 and TIMP-2 levels were elevated, and MMP-7 levels were decreased in both subgroups compared to controls. When analyzing serum contents of neurospecific proteins in the group of patients with OCT signs of retinal neurodegeneration, high levels of the S100b protein and NGF were revealed, in contrast to the control group and subgroup 1.

Role of neuroproteins in retinal neurodegeneration in diabetic retinopathy

Aim. To evaluate the serum levels of S100b protein, brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) in patients with type 2 diabetes mellitus, as well as to establish a correlation between the studied parameters and retinal neurodegeneration.Methods. In total, 80 patients with confirmed type 2 diabetes (experimental group) and 30 healthy volunteers (control group) were included in the study. All patients were examined using an RTVue-100 optic coherence tomography scanner (Optovue, USA) and a MAIA microperimeter (CenterVue, Italy). The serum levels of S100b, BDNF, and NGF were determined by a sandwich-type solid-phase enzyme immunoassay using reagents produced by R&amp;D Diagnostics Inc. (USA).Results. The serum level of S100b protein was found to be significantly (p = 0.001) higher in the experimental group, comprising 56.86 (31,12–104,02) pg/ml, compared to that in the control group of 45.19 (37.27–51.79) pg/ml. Conversely, the brain-derived neurotrophic factor (BDNF) showed a significant (p = 0.02) decrease to the level of 27.38 (25.15–29.12) pg/ml in the experimental group compared to the level of 30.19 (27.38–32.14) pg/ml in the control group. The serum level of nerve growth factor (NGF) in the experimental group was found to be 7.53 (5.63–10.54) pg/ml, thereby exceeding significantly (p = 0.02) the level of 5.96 (4.77–8.13) pg/ml in the control group.Conclusions. The results obtained indicate an imbalance in the serum levels of the studied neuroproteins in patients with type 2 diabetes mellitus and retinal neurodegeneration signs. The identified variations require further research in order to determine the feasibility of their use as additional criteria for predicting the development of retinal neurodegeneration in such patients.

Neuroinflammation and neurodegeneration in diabetic retinopathy.

Diabetic retinopathy (DR) is the most common complication of diabetes and has been historically regarded as a microangiopathic disease. Now, the paradigm is shifting toward a more comprehensive view of diabetic retinal disease (DRD) as a tissue-specific neurovascular complication, in which persistently high glycemia causes not only microvascular damage and ischemia but also intraretinal inflammation and neuronal degeneration. Despite the increasing knowledge on the pathogenic pathways involved in DR, currently approved treatments are focused only on its late-stage vasculopathic complications, and a single molecular target, vascular endothelial growth factor (VEGF), has been extensively studied, leading to drug development and approval. In this review, we discuss the state of the art of research on neuroinflammation and neurodegeneration in diabetes, with a focus on pathophysiological studies on human subjects, in vivo imaging biomarkers, and clinical trials on novel therapeutic options.

Association between renal function and retinal neurodegeneration in Chinese patients with type 2 diabetes mellitus.

Chronic kidney disease (CKD) and diabetic retinopathy (DR) are two serious complications of diabetes. However, the association between retinal neurodegeneration in DR and renal function decline is still unclear. Our objective was to evaluate the association by measure estimated glomerular filtration rate (eGFR), macular ganglion cell-inner plexiform layer (GC-IPL), and ganglion cell complex (GCC) thickness in patients with type 2 diabetes mellitus (T2DM). We analyzed the baseline data of the Guangzhou Diabetic Eye Study. T2DM patients from communities in Guangzhou were enrolled and all participants went through ophthalmic and general examinations. The thickness of the macular GC-IPL and GCC in their right eyes were measured by swept-source optical coherence tomography. CKD was defined as eGFR <60 mL/min/1.73 m2. One thousand three hundred and nine patients were included (mean age 64.4±7.6 years, 59.1% female), and fifty-eight (4.4%) of them had CKD. Average macular GC-IPL thickness was significantly thinner in CKD patients (96.5±9.1 µm) than non-CKD patients (101.3±9.2 µm) (P<0.01). Average macular GCC thickness was also significantly thinner in CKD patients (123.5±13.2 µm) than non-CKD patients (129.9±12.8 µm) (P<0.01). The significant thinning of macular GC-IPL and GCC thickness presented in every gird in the macula (all, P<0.05) except for central grid (P≥0.05). In the patients without DR, the eGFR was linearly correlated with the average macular GC-IPL thickness [β=0.07 (95% CI, 0.02-0.12), P<0.01] and GCC thickness [β=0.09 (95% CI, 0.03-0.16), P<0.01] after adjustment for age, sex, axial length, intraocular pressure (IOP) and combination of hypertension. However, no linear correlation was found between eGFR and macular GC-IPL or GCC thickness in DR patients. Renal function decrease is associated with the thinning of the macular GC-IPL and GCC in T2DM patients, suggesting the potential value of ganglion cell lose to detect early function decline in the kidney in diabetic patients, especially in patients without DR.

Advance of neurodegeneration in diabetic retinopathy

Advance of neurodegeneration in diabetic retinopathy

Recent Developments in Diabetic Retinal Neurodegeneration: A Literature Review.

Neurodegeneration plays a significant role in the complex pathology of diabetic retinopathy. Evidence suggests the onset of neurodegeneration occurs early on in the disease, and so a greater understanding of the process is essential for prompt detection and targeted therapies. Neurodegeneration is a common pathway of assorted processes, including activation of inflammatory pathways, reduction of neuroprotective factors, DNA damage, and apoptosis. Oxidative stress and formation of advanced glycation end products amplify these processes and are elevated in the setting of hyperglycemia, hyperlipidemia, and glucose variability. These key pathophysiologic mechanisms are discussed, as well as diagnostic modalities and novel therapeutic avenues, with an emphasis on recent discoveries. The aim of this article is to highlight the crucial role of neurodegeneration in diabetic retinopathy and to review the molecular basis for this neuronal dysfunction, its diagnostic features, and the progress currently made in relevant therapeutic interventions.

Plate-based Large-scale Cultivation of Caenorhabditis elegans: Sample Preparation for the Study of Metabolic Alterations in Diabetes.

Culturing Caenorhabditis elegans (C. elegans) in a large-scale manner on agar plates can be time-consuming and difficult. This protocol describes a simple and inexpensive method to obtain a large number of animals for the isolation of proteins to proceed with a western blot, mass spectrometry, or further proteomics analyses. Furthermore, an increase of nematode numbers for immunostainings and the integration of multiple analyses under the same culturing conditions can easily be achieved. Additionally, a transfer between plates with different experimental conditions is facilitated. Common techniques in plate culture involve the transfer of a single C. elegans using a platinum wire and the transfer of populated agar chunks using a scalpel. However, with increasing nematode numbers, these techniques become overly time-consuming. This protocol describes the large-scale culture of C. elegans including numerous steps to minimize the impact of the sample preparation on the physiology of the worm. Fluid and shear stress can alter the lifespan of and metabolic processes in C. elegans, thus requiring a detailed description of the critical steps in order to retrieve reliable and reproducible results. C. elegans is a model organism, consisting of neuronal cells for up to one-third, but lacking blood vessels, thus providing the possibility to investigate solely neuronal alterations independent of vascular control. Recently, early neurodegeneration in diabetic retinopathy was found prior to vascular alterations. Thus, C. elegans is of special interest for studying general mechanisms of diabetic complications. For example, an increased formation of advanced glycation end products (AGEs) and reactive oxygen species (ROS) is observed, which are reproducibly found in C. elegans. Protocols to handle samples of adequate size for a broader spectrum of investigations are presented here, exemplified by the study of diabetes-induced biochemical alterations. In general, this protocol can be useful for studies requiring large C. elegans numbers and in which liquid culture is not suitable.

Loss-of-function mutation of serine racemase attenuates retinal ganglion cell loss in diabetic mice

Consistent results suggest the promoting roles of serine racemase (SR)/D-serine in retinal neurodegeneration in diabetic retinopathy (DR). However, the direct evidence connecting SR deficiency with retinal neuroprotection in genetic model of diabetes mellitus has not been reported. In this investigation, we explore the effect of absence of functional SR on the degeneration of retinal ganglion cells (RGCs) with a diabetic murine model, Ins2Akita mice. We established a murine strain with double mutation, termed Ins2Akita-Srr, by mating heterozygous Ins2Akita mice with homozygous Srrochre269 mice. Ins2Akita retained less RGC in posterior, middle, and peripheral retinae than the counterpart from non-diabetic sibling mice at the age of five or seven months. Ins2Akita-Srr mice retained more RGC in middle and peripheral--but not in posterior-- retinae than the counterpart from Ins2Akita sibling mice at the age of five months. By contrast, at the age of seven months, Ins2Akita-Srr mice contained more RGC in peripheral, middle, and posterior retinae than the counterpart from Ins2Akita. RGCs were identified with retrograde labeling in vivo or with immunolabeling against a RGC-specific transcription factor, Brn3a, in retinal flat mounts. Correspondingly, the aqueous humor of Ins2Akita-Srr contained less amount of D-serine than sibling Ins2Akita mice. Thus, SR deficiency significantly prevented RGC loss in diabetic mice. We conclude that D-serine is a critical factor in the degeneration of RGC in DR. Targeting SR expression or activity may be a strategy for ameliorating RGC loss in DR.

Neurodegeneration in diabetic retinopathy: Potential for novel therapies

The complex pathology of diabetic retinopathy (DR) affects both vascular and neural tissue. The characteristics of neurodegeneration are well-described in animal models but have more recently been confirmed in the clinical setting, mostly by using non-invasive imaging approaches such as spectral domain optical coherence tomography (SD-OCT). The most frequent observations report loss of tissue in the nerve fiber layer and inner plexiform layer, confirming earlier findings from animal models. In several cases the reduction in inner retinal layers is reported in patients with little evidence of vascular lesions or macular edema, suggesting that degenerative loss of neural tissue in the inner retina can occur after relatively short durations of diabetes. Animal studies also suggest that neurodegeneration leading to retinal thinning is not limited to cell death and tissue loss but also includes changes in neuronal morphology, reduced synaptic protein expression and alterations in neurotransmission, including changes in expression of neurotransmitter receptors as well as neurotransmitter release, reuptake and metabolism. The concept of neurodegeneration as an early component of DR introduces the possibility to explore alternative therapies to prevent the onset of vision loss, including neuroprotective therapies and drugs targeting individual neurotransmitter systems, as well as more general neuroprotective approaches to preserve the integrity of the neural retina. In this review we consider some of the evidence for progressive retinal neurodegeneration in diabetes, and explore potential neuroprotective therapies.

Neurodegeneration in Diabetic Retinopathy: Current Concepts and Therapeutic Implications.

Neurodegeneration in Diabetic Retinopathy: Current Concepts and Therapeutic Implications.

Neuroprotective effects of quercetin in diabetic rat retina.

Diabetic retinopathy (DR) is a severe complication of diabetes and the leading cause of blindness among working adults worldwide. DR is being widely recognized as a neurodegenerative disease of the retina, since, retinal neurons are damaged soon after diabetes onset. Diabetes-induced oxidative stress is considered as central factor that dysregulates neurotrophic factors and activates apoptosis, thereby damages neurons in the diabetic retina. Flavonoids being a powerful antioxidant have been considered to protect neurons in diabetic retina. The purpose of this study was to analyze the beneficial effects of flavonoid, quercetin to protect neurons in the diabetic rat retina. We quantitated the expression levels of BDNF, NGF, TrkB, synaptophysin, Akt, Bcl-2, cytochrome c and caspase-3 using Western blotting techniques in the diabetic retina with and without quercetin treatments and compared with non-diabetic rats. In addition, we employed ELISA techniques to determine the level of BDNF. Caspase-3 activity and the level of glutathione were analyzed by biochemical methods. Our results indicate that quercetin treatment to diabetic rats caused a significant increase in the level of neurotrophic factors and inhibited the level of cytochrome c and caspase-3 activity in the diabetic retina. Furthermore, the level of an anti-apoptotic protein Bcl-2 was augmented in quercetin treated diabetic retina. Thus, quercetin, may protect the neuronal damage in diabetic retina by ameliorating the levels of neurotrophic factors and also by inhibiting the apoptosis of neurons. Therefore, this study suggests that quercetin can be a suitable therapeutic agent to prevent neurodegeneration in diabetic retinopathy.

H-NMR based serum metabolomic signatures imperative in retinalneurodegeneration and development of Diabetic Retinopathy

Aim: To identify serum metabolomic fingerprints using 1H NMR in Diabetic Retinopathy (DR). Methods and Materials: 1H-NMR was performed on 32 subjects [11 type 2 diabetic patients each without DR (group A) and with DR (group B) along with 10 control (group C)]. Results:The study unraveled 1H-NMR based serum metabolomic fingerprints of diabetic retinopathy showed significant variations in Ribitol, D-glucose, Fructose-6-phosphate, Uridine Diphosphate-N-acetyl glucosamine and Glycerophosphocholine. The study envisaged that abnormal polyol metabolism and accumulation of ribitol contributory to development of diabetic retinopathy.Presence of Uridine Diphosphate-N-acetylglucosamine in blood has been also confirmed its probable role in progressive neurodegeneration in diabetic retinopathy. NMR spectra also indicated that downregulation of glycerophosphocholine is directly related to retinol metabolism and subsequent unusual chromophore synthesis facilitating retinal degeneration. Conclusion:Five metabolomic fingerprints have been identified and found to be unique in Diabetic Retinopathy (DR).

Neuroprotection as a Therapeutic Target for Diabetic Retinopathy.

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.

Aralia elata Prevents Neuronal Death by Downregulating Tonicity Response Element Binding Protein in Diabetic Retinopathy

Background/Aims: The present study addresses the role of tonicity response element binding protein (TonEBP) in retinal ganglion cell (RGC) death in diabetic retinopathy and the impact of Aralia elata extract on the TonEBP/RGC interaction. Methods: Diabetes was induced in C57BL/6 mice by intraperitoneal injection of streptozotocin (STZ). Control mice received phosphate-buffered saline. After five injections of STZ or saline buffer, A. elata extract was administered by daily oral tube feeding for 7 weeks. All mice were killed at 2 months after the last injection of STZ or saline and the extent of cell death together with the protein expression levels of TonEBP, aldose reductase (AR) and nuclear factor-kappa B (NF-κB) were examined. Results: Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive signals were colocalized with TonEBP-immunoreactive RGCs. The apoptotic cell death of RGCs and the expression levels of TonEBP, AR and NF-κB were significantly increased in the retinas of diabetic mice compared with controls at 2 months after the induction of diabetes. However, these changes were effectively blocked by the administration of A. elata extract. Conclusions: These results indicate that A. elata prevents diabetes-induced RGC apoptosis and downregulates TonEBP expression. Therefore, A. elata extract may have therapeutic potential to prevent diabetes-induced retinal neurodegeneration in diabetic retinopathy.