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Topical administration of somatostatin prevents retinal neurodegeneration in experimental diabetes.

ABSTRACT: Retinal neurodegeneration is an early event in the pathogenesis of diabetic retinopathy (DR). Somatostatin (SST) is an endogenous neuroprotective peptide that is downregulated in the diabetic eye. The aim of the study was to test the usefulness of topical administration of SST in preventing retinal neurodegeneration. For this purpose, rats with streptozotocin-induced diabetes mellitus (STZ-DM) were treated with either SST eye drops or vehicle for 15 days. Nondiabetic rats treated with vehicle served as a control group. Functional abnormalities were assessed by electroretinography (ERG), and neurodegeneration was assessed by measuring glial activation and the apoptotic rate. In addition, proapoptotic (FasL, Bid, and activation of caspase-8 and caspase-3) and survival signaling pathways (BclxL) were examined. Intraretinal concentrations of glutamate and its main transporter glutamate/aspartate transporter (GLAST) were also determined. Treatment with SST eye drops prevented ERG abnormalities, glial activation, apoptosis, and the misbalance between proapoptotic and survival signaling detected in STZ-DM rats. In addition, SST eye drops inhibited glutamate accumulation in the retina and GLAST downregulation induced by diabetes mellitus. We conclude that topical administration of SST has a potent effect in preventing retinal neurodegeneration induced by diabetes mellitus. In addition, our findings open up a new preventive pharmacological strategy targeted to early stages of DR.

SUBMITTER: Hernandez C

PROVIDER: S-EPMC3712066 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Topical administration of somatostatin prevents retinal neurodegeneration in experimental diabetes.

Hernández Cristina C García-Ramírez Marta M Corraliza Lidia L Fernández-Carneado Jimena J Farrera-Sinfreu Josep J Ponsati Berta B González-Rodríguez Agueda A González-Rodríguez Agueda A Valverde Angela M AM Simó Rafael R

Diabetes 20130308 7

Retinal neurodegeneration is an early event in the pathogenesis of diabetic retinopathy (DR). Somatostatin (SST) is an endogenous neuroprotective peptide that is downregulated in the diabetic eye. The aim of the study was to test the usefulness of topical administration of SST in preventing retinal neurodegeneration. For this purpose, rats with streptozotocin-induced diabetes mellitus (STZ-DM) were treated with either SST eye drops or vehicle for 15 days. Nondiabetic rats treated with vehicle se ...[more]

PMID: 23474487

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Project description:ImportanceEfforts are underway to incorporate retinal neurodegeneration in the diabetic retinopathy severity scale. However, there is no established measure to quantify diabetic retinal neurodegeneration (DRN).ObjectiveWe compared total retinal, macular retinal nerve fiber layer (mRNFL) and ganglion cell-inner plexiform layer (GC-IPL) thickness among participants with and without diabetes (DM) in a population-based cohort.Design/setting/participantsCross-sectional analysis, using the UK Biobank data resource. Separate general linear mixed models (GLMM) were created using DM and glycated hemoglobin as predictor variables for retinal thickness. Sub-analyses included comparing thickness measurements for patients with no/mild diabetic retinopathy (DR) and evaluating factors associated with retinal thickness in participants with and without diabetes. Factors found to be significantly associated with DM or thickness were included in a multiple GLMM.ExposureDiagnosis of DM was determined via self-report of diagnosis, medication use, DM-related complications or glycated hemoglobin level of ≥ 6.5%.Main outcomes and measuresTotal retinal, mRNFL and GC-IPL thickness.Results74,422 participants (69,985 with no DM; 4,437 with DM) were included. Median age was 59 years, 46% were men and 92% were white. Participants with DM had lower total retinal thickness (-4.57 μm, 95% CI: -5.00, -4.14; p<0.001), GC-IPL thickness (-1.73 μm, 95% CI: -1.86, -1.59; p<0.001) and mRNFL thickness (-0.68 μm, 95% CI: -0.81, -0.54; p<0.001) compared to those without DM. After adjusting for co-variates, in the GLMM, total retinal thickness was 1.99 um lower (95% CI: -2.47, -1.50; p<0.001) and GC-IPL was 1.02 μm lower (95% CI: -1.18, -0.87; p<0.001) among those with DM compared to without. mRNFL was no longer significantly different (p = 0.369). GC-IPL remained significantly lower, after adjusting for co-variates, among those with DM compared to those without DM when including only participants with no/mild DR (-0.80 μm, 95% CI: -0.98, -0.62; p<0.001). Total retinal thickness decreased 0.40 μm (95% CI: -0.61, -0.20; p<0.001), mRNFL thickness increased 0.20 μm (95% CI: 0.14, 0.27; p<0.001) and GC-IPL decreased 0.26 μm (95% CI: -0.33, -0.20; p<0.001) per unit increase in A1c after adjusting for co-variates. Among participants with diabetes, age, DR grade, ethnicity, body mass index, glaucoma, spherical equivalent, and visual acuity were significantly associated with GC-IPL thickness.ConclusionGC-IPL was thinner among participants with DM, compared to without DM. This difference persisted after adjusting for confounding variables and when considering only those with no/mild DR. This confirms that GC-IPL thinning occurs early in DM and can serve as a useful marker of DRN.

Project description:Purpose: Neuropeptide signaling has been reported to impact neurogenesis in the central nervous system. However, these studies have typically been conducted using pharmacological agents in ex vivo preparations, and in vivo evidence for their developmental function is generally lacking. The goal of this study is to identify the impact of somatostatin signaling on retinal neurogenesis and development both ex vivo and in vivo. Methods: Mouse retinal explants grown ex vivo from E14-P0 and treated with a range of doses of agonist for the somatostatin receptor Sstr2 were multiplexed according to the MULTI-seq protocol and used to generate a single scRNA-seq expression library. Retinas from P0 littermates representing an allelic series (+/+, +/-, -/-) of Sstr2 KO mice were mutliplexed according to the MULTI-seq protocol and used to generate a single scRNA-seq expression library. Retinas from P14 littermates representing an allelic series (+/+, +/-, -/-) of Sstr2 KO mice were mutliplexed according to the MULTI-seq protocol and used to generate a single scRNA-seq expression library. Sequencing was performed on an illumina sequencer. Bcl files were analyzed by Cellranger. Samples were deconvoluted with the deMULTIplex r package and clustering and gene expression analysis were performed with the Seurat and Monocle2 r packages. Results: Cell type proportions were found to be impacted by Sstr2 signaling ex vivo with increasing levels of Sstr2 agonist found to decrease photoreceptor proportion and increase primary progenitor proportion. Sstr2 KO was not found to have an impact on cell type proportion in vivo at either P0 or P14. Sstr2 pharmacologic manipulation and Sstr2 KO did produce complementary gene expression changes in neurogenic progenitors indicating that somatostatin signaling downregulates neurogenesis. Conclusions: Our study demonstrates a role for somatostatin in retinal development by downregulating neurogenesis in neurogenic progenitors. However, it also demonstrates that somatostatin signaling is dispensable for in vivo retinal development and likely redundant with other cell extrinsic signals released during the same period.

Dataset Information

Topical administration of somatostatin prevents retinal neurodegeneration in experimental diabetes.

Publications

Topical administration of somatostatin prevents retinal neurodegeneration in experimental diabetes.

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