Research Applications for Striatech Products

Diabetic Retinopathy: Early Functional Visual Biomarkers in Preclinical Metabolic-Retinal Models

The leading cause of preventable blindness in working-age adults. Neurodegeneration of the inner retina precedes or parallels the classical microvascular pathology, opening a functional biomarker window before fundoscopic lesions appear.

Introduction

Animal Models

Research Questions

Measurement Modalities

Publications

Journal Clubs

Introduction

What Is Diabetic Retinopathy?

Diabetic retinopathy (DR) is the leading cause of preventable blindness in working-age adults and is classically staged by its vascular manifestations – from early non-proliferative microaneurysms and pericyte dropout through proliferative neovascularisation and diabetic macular oedema (DME). However, a growing body of evidence has shifted this view: neurodegeneration and neural dysfunction in the inner retina precede, or occur in parallel with, clinically visible microvascular pathology rather than simply following from it (Zhou et al, 2023, Cells | Simó et al, 2022, Asia Pac J Ophthalmol (Phila).). Chronic hyperglycaemia drives overlapping cascades – oxidative stress, mitochondrial dysfunction, microglia activation, and STING-pathway innate immune signalling – that converge on the retinal neurovascular unit and produce progressive dysfunction of retinal ganglion cells (RGCs) and inner retinal neurons before overt vascular lesions appear on fundoscopy.

Also see:

Vascular and Metabolic Disease: addresses the full neurovascular spectrum of DR alongside stroke and ischaemic retinal disease
Neuroinflammation and Autoimmune CNS Disease: covers the shared microglial and cytokine-driven mechanisms that also underpin inflammatory retinopathy and CNS demyelinating disease
Further related applications are: Vascular and Metabolic Disease and Neuroinflammation and Autoimmune CNS Disease

Animal Models

Common Animal Models for Diabetic Retinopathy Research

Streptozotocin (STZ) mouse and rat – type 1 diabetes model: Single or multiple intraperitoneal STZ injections ablate pancreatic beta cells, inducing stable hyperglycaemia within 48-72 hours. DR features – pericyte loss, inner blood-retinal barrier (iBRB) breakdown, microglial activation, and RGC dysfunction – develop over weeks to months. Optomotor-based visual acuity and contrast sensitivity decline is detectable from approximately 8-12 weeks post-induction and can be tracked longitudinally in the same animals without terminal procedures (Holden et al, 2024, J Neurochem.). The STZ model is the most widely used rodent DR paradigm.
db/db mouse (BKS.Cg-Lepr^db/db) – type 2 diabetes model: Genetic leptin receptor deficiency produces obesity, insulin resistance, and sustained hyperglycaemia on a type 2 metabolic syndrome background. Retinal neurovascular changes develop more slowly than in the STZ model but more closely replicate the metabolic context of human type 2 DR. Optomotor-based visual acuity decline is trackable across the natural disease progression, and the db/db model has been used to assess the synergistic impact of dyslipidaemia on retinal function by combining hyperglycaemia with poloxamer-induced hypercholesterolaemia (Johnston et al, 2023, Sci Rep.). A cross-model longitudinal comparison of db/db, Ins2^Akita, and STZ mice confirmed visual acuity loss and retinal thinning across all three paradigms, with functional and structural changes correlating with blood glucose levels (Sheskey et al, 2021, Invest Ophthalmol Vis Sci.).
Ins2^Akita mouse – spontaneous type 1 diabetes model: A point mutation in the insulin-2 gene causes misfolding and ER stress in pancreatic beta cells, leading to progressive hyperglycaemia from approximately four weeks of age. This model avoids the chemical toxicity concerns of STZ and replicates a more physiologically spontaneous onset of hyperglycaemia. Visual acuity loss is detectable by optomotor testing across the disease time course alongside retinal thinning (Sheskey et al, 2021, Invest Ophthalmol Vis Sci.).
Inflammatory retinopathy model (metabolic/vascular overlap): Models in which inflammatory retinopathy is induced in a metabolic or vascular disease context, combining elements of the DR pathobiology with innate immune activation. Such models are directly relevant to the immunomodulatory arm of DR research and have been used to test whether immune suppression translates to preserved optomotor performance (Kinuthia et al, 2025, JCI Insight).

Research Questions

How Can Striatech Tools support Your Study?

Select a question that matches your research objective to see which instruments are relevant, what challenge they address, and what the published evidence shows.

How Does Chronic Hyperglycaemia Alter Optomotor-Measured Visual Acuity and Contrast Sensitivity Over Time in Diabetic Rodent Models?

Audience A - Vision-focused

Quick Answer

Chronic hyperglycaemia produces a progressive, measurable decline in both spatial visual acuity and contrast sensitivity that can be tracked longitudinally in the same animals using the OptoDrum. In STZ rodent models, functional deficits are detectable weeks before overt microvascular pathology, making repeated non-invasive optomotor testing a sensitive early endpoint for diabetic retinal disease progression.

The challenge

A central question in preclinical DR research is when and how fast the visual system deteriorates relative to structural vascular changes. Historically, functional endpoints in rodent DR studies relied on terminal or labour-intensive procedures – electroretinography (ERG) under anaesthesia, histological retinal flat-mounts, or post-mortem quantification of pericyte loss – that could not be repeated serially in the same cohort without confounding effects. This made it difficult to establish precise time courses of functional decline or to use the same animals for longitudinal monitoring of both disease progression and treatment response.

The "neurodegeneration-first" hypothesis proposes that retinal neural dysfunction and RGC layer loss can precede clinically visible microvascular lesions in diabetic retinas, and emerging histological evidence supports the view that neural loss and capillary dropout can occur in spatially dissociated patterns rather than as a direct consequence of local vascular dropout alone (Yang et al, 2024, Diabetes). Non-invasive longitudinal functional endpoints are therefore essential for capturing this early neural phase of DR.

Also see: Vascular and Metabolic Disease, and Neuroinflammation.

How Striatech products help

OptoDrum

Measures photopic spatial visual acuity (cycles per degree) and contrast sensitivity via the optomotor reflex in awake, freely moving rodents. Non-invasive and fully automated, enabling repeated measurements in the same animals across the full DR time course – weekly if required – without anaesthesia or surgical intervention. Both eyes can be assessed independently. Validated for detecting progressive visual decline in STZ rodent models from approximately 8-12 weeks post-induction.

ScotopicKit

Extends OptoDrum testing into the scotopic (low-light, rod-mediated) domain. Early DR involves dysfunction of rod photoreceptors and inner retinal circuits before cone pathways are significantly affected; scotopic visual acuity and contrast sensitivity provide additional sensitivity for detecting early-stage disease. Used in conjunction with DarkAdapt for standardised dark-adaptation prior to testing.

DarkAdapt

Provides a fully light-tight, ventilated housing environment for reliable dark-adaptation prior to scotopic OptoDrum and ScotopicKit testing. Ensures reproducible dark-adapted states across longitudinal time points.

AcuiSee

Measures visual acuity via operant conditioning, engaging cortical visual processing pathways. Complements OptoDrum's subcortical OMR readout where suprathreshold visual discrimination or cortical processing deficits are of interest in the diabetic visual pathway.

Non-aversive Animal Platform

Reduces handling stress during testing, particularly relevant for diabetic rodents that may show reduced mobility, lethargy, or altered stress responses with disease progression. Calmer animals produce more reproducible optomotor responses.

Evidence from the Literature

Remlinger et al (2023) Neurol. Neuroimmunol. Neuroinflamm.
Feature →
Holden et al (2024) J Neurochem.
OptoDrum was used to track visual acuity and contrast sensitivity longitudinally in a rodent model of chronic hyperglycaemia, establishing a time course of progressive functional visual deterioration that parallels retinal neuroinflammatory and neurovascular changes.
Sheskey et al. (2021) Ophthalmol Vis Sci.
Longitudinal comparison of visual acuity (optokinetic tracking) and retinal structure (OCT) across db/db, Ins2^Akita, and STZ mouse models over 1.5-9 months. All three models showed progressive vision loss and retinal thinning correlated with blood glucose. Demonstrates cross-model generalisability of the optomotor endpoint in DR research.
Aung et al. (2013) Invest Ophthalmol Vis Sci.
Demonstrated detectable optokinetic tracking deficits in STZ-induced diabetic rats within the first month of hyperglycaemia, preceding or concurrent with ERG changes, establishing the sensitivity of the OMR as an early functional endpoint in DR.

How Does Innate Immune Activation and Blood-Retinal Barrier Breakdown Drive Early Visual Acuity Loss in Diabetic Retinopathy?

Audience A - Vision-focused

Audience B - CNS/Systemic

Quick Answer

Activation of the cGAS-STING innate immune pathway in retinal microglia drives inner blood-retinal barrier (iBRB) breakdown and measurable visual acuity loss in diabetic retinopathy models. OptoDrum directly quantifies the functional visual consequence of this neurovascular event, linking a molecular mechanism to a whole-animal behavioural endpoint.

The challenge

The inner blood-retinal barrier – formed by tight junctions between retinal vascular endothelial cells, reinforced by pericytes, Muller glia end-feet, and microglia – is the primary physical barrier protecting the neuroretina from inflammatory and vascular perturbations. Its breakdown is a defining early event in DR that precedes overt clinical retinopathy and is now recognised as driven not only by VEGF-mediated vascular permeability but also by innate immune activation via the cGAS-STING pathway. Mitochondrial DNA released under hyperglycaemic stress activates cGAS in retinal cells, generating cyclic GMP-AMP (cGAMP), which activates STING and triggers an interferon and NF-κB inflammatory cascade.

A key open question has been whether this molecular vascular mechanism produces a detectable, quantifiable deficit in whole-animal visual function – and whether in vivo functional endpoints can capture this deficit before histological or clinical evidence of advanced retinopathy. Non-invasive functional measurement is also critical for testing whether STING-pathway inhibitors or P2RX7 blockers can preserve functional vision as well as structural barrier integrity.

Also see: Neuroinflammation, Retinal Degeneration and Retinal Ganglion Cell Pathology.

How Striatech products help

OptoDrum

Measures the subcortical optomotor reflex as a functional readout of the RGC-to-brainstem visual pathway. Because the OMR depends on intact photoreceptor, bipolar, and RGC signalling through to the accessory optic system, it is sensitive to inner retinal dysfunction caused by iBRB breakdown and associated neurovascular injury. Provides the in vivo behavioural endpoint that connects cGAMP-mediated vascular pathology to a whole-animal functional consequence.

AcuiSee

Assesses cortical visual processing via operant discrimination, providing a complementary endpoint where suprathreshold perceptual consequences of iBRB-related inner retinal damage are of interest.

Non-aversive Animal Platform

Minimises handling stress in diabetic animals, which may be particularly relevant when testing animals at early inflammatory stages where stress-related confounders could obscure subtle functional deficits.

Evidence from the Literature

Remlinger et al (2023) Neurol. Neuroimmunol. Neuroinflamm.
Feature →
Ge et al (2025) J Neuroinflammation.
OptoDrum was used as the primary in vivo functional endpoint in this study, demonstrating that cGAMP-driven iBRB disruption via P2RX7-mediated microglial transport produces measurable visual acuity loss in a diabetic retinopathy model.
Liu et al. (2023) JCI Insight.
Demonstrated that STING expression is upregulated in DR patients and animal models, and that STING-KO animals are protected against retinal endothelial senescence, capillary degeneration, and inflammation in early DR. Provides mechanistic context for the cGAMP iBRB findings.
Bianco et al. (2022) Front. Aging Neurosci.
Comprehensive review of the shifting paradigm from DR as a pure vasculopathy to a neurovascular complication in which persistent innate immune activation (microglial, complement, and cytokine cascades) drives both neural and vascular degeneration.

Does Immunomodulatory Treatment Preserve Visual Function in Inflammatory and Diabetic Retinopathy Models?

Audience A - Vision-focused

Audience B - CNS/Systemic

Quick Answer

Yes. In an inflammatory retinopathy model with metabolic and vascular overlap, immunomodulatory treatment that suppresses the retinal immune environment produces a measurable, behaviourally meaningful gain in optomotor-assessed visual acuity, as confirmed by OptoDrum. This validates the OMR as an endpoint for evaluating immunotherapeutic interventions in DR-relevant models.

The challenge

Current standard-of-care treatments for DR – anti-VEGF agents (ranibizumab, aflibercept, faricimab), pan-retinal photocoagulation (PRP) for proliferative disease, and corticosteroid implants for DME – are largely restricted to advanced stages of disease and do not adequately address the early neuroretinal and neuroinflammatory component. In preclinical drug development, demonstrating that an anti-inflammatory or immunomodulatory treatment produces not only structural retinal protection but also functional visual benefit is critical for translation. Functional endpoint validation requires a non-invasive, repeatable readout that can be applied before and after treatment in the same animals.

The mechanistic overlap between DR neuroinflammation and the immune cascades in autoimmune CNS disease (shared microglial activation pathways, cytokine profiles overlapping with EAE and MS models) means that immunomodulatory strategies developed for CNS neuroinflammation may have direct translational relevance for DR. For context on these shared immune mechanisms, see: Neuroinflammation and Autoimmune CNS Disease.

How Striatech products help

OptoDrum

Measures visual acuity and contrast sensitivity via the subcortical optomotor reflex before, during, and after immunomodulatory treatment in the same animals. As a non-invasive endpoint, OptoDrum enables within-animal treatment-effect quantification without requiring histological sacrifice at each time point, supporting both efficacy assessment and longitudinal therapeutic window characterisation.

AcuiSee

Provides a cortical visual processing endpoint for evaluating whether treatment-mediated structural retinal protection translates to improvements in higher-order visual perception and discrimination, complementing the subcortical OMR readout.

Non-aversive Animal Platform

Supports reliable, low-stress optomotor testing in animals undergoing repeated treatment and measurement cycles, reducing procedural variability across extended treatment studies.

Evidence from the Literature

Remlinger et al (2023) Neurol. Neuroimmunol. Neuroinflamm.
Feature →
Kinuthia et al (2025) JCI Insight.
OptoDrum was used as the primary in vivo functional endpoint to confirm that immunomodulatory treatment targeting the retinal immune environment preserves visual acuity in an inflammatory retinopathy model with metabolic and vascular overlap. This study demonstrates that OMR-based visual monitoring captures the functional benefit of immunotherapy even in retinopathy paradigms that are not primarily demyelinating.
Kaštelan et al. (2025) Molecules.
Comprehensive review of anti-inflammatory and neuroprotective pharmacological strategies in DR, including anti-VEGF, corticosteroids, and polyphenol-based neuroprotection.
Simó et al. (2021) Pharmaceutics.
Reviews evidence for neurovascular unit impairment as a primary therapeutic target in early DR, including pharmacological strategies with dual neuroprotective and vasculotropic activity. Highlights that neuroprotection is not always the primary event and that patient phenotyping is recommended before selecting monotherapy approaches.

Which Functional Visual Endpoints Detect Early Neural Dysfunction in Diabetic Retinopathy Before Microvascular Lesions Are Visible?

Audience A - Vision-focused

Quick Answer

Retinal neural dysfunction in diabetes – including inner retinal RGC layer changes, reduced oscillatory potentials, and progressive optomotor performance decline – precedes clinically detectable microvascular pathology in both human patients and rodent models. The optomotor reflex measured by OptoDrum is a sensitive, non-invasive, repeatable endpoint that captures this early neuroretinal phase and is directly validated in STZ and related chronic-hyperglycaemia models.

The challenge

The clinical staging of DR (ETDRS severity scale) is based on fundoscopic vascular signs and does not capture the early neurodegenerative phase of the disease. Patients with diabetes but no visible retinopathy already show measurable retinal thinning on OCT, oscillatory potential delays on full-field ERG, and reduced contrast sensitivity on psychophysical testing (McAnany et al, 2021, Surv Ophthalmol.). The challenge in preclinical DR research is to validate rodent model endpoints that are sensitive enough to detect this early neural phase and specific enough to differentiate it from later vascular-driven dysfunction.

Available non-invasive functional endpoints in rodents include: the optomotor reflex (spatial acuity and contrast sensitivity, subcortical), operant visual discrimination (cortical acuity), the full-field ERG (photoreceptor and inner nuclear layer function), and the pattern ERG (RGC-specific response). Each endpoint captures a different layer of the retinal visual processing hierarchy. The optomotor reflex has the practical advantages of requiring no anaesthesia, no animal training, and no electrode contact with the eye, making it uniquely suited to longitudinal repeated-measures designs across extended DR disease time courses.

Also see: Retinal Ganglion Cell Pathology and Retinal Degeneration.

How Striatech products help

OptoDrum

Measures spatial visual acuity (cycles per degree) and contrast sensitivity via the subcortical optomotor reflex in awake, freely moving rodents. Detects inner retinal dysfunction arising from early DR-associated neurodegeneration, RGC loss, and neurovascular injury without anaesthesia or terminal procedures. Fully automated; measurements take approximately 4 minutes per animal. Enables dense longitudinal sampling across the DR disease time course.

ScotopicKit

Isolates rod-photoreceptor-mediated visual acuity and contrast sensitivity under near-dark conditions. Rod pathways show early dysfunction in diabetes (impaired dark adaptation, scotopic sensitivity loss), providing an additional sensitive endpoint for pre-vascular neuroretinal change.

DarkAdapt

Enables standardised, complete dark-adaptation prior to scotopic OMR testing, ensuring reproducible rod-pathway isolation across repeated longitudinal measurements.

AcuiSee

Measures cortical visual acuity via operant forced-choice discrimination. Provides a psychophysical complement to the OMR, capturing visual cortex processing changes that the subcortical optomotor reflex does not assess. Relevant when DR-associated visual cortex remodelling or suprathreshold perceptual changes are the outcome of interest.

Evidence from the Literature

Remlinger et al (2023) Neurol. Neuroimmunol. Neuroinflamm.
Feature →
Holden et al (2024) J Neurochem.
Longitudinal OptoDrum-based characterisation of visual acuity and contrast sensitivity decline in a chronic hyperglycaemia model, establishing that OMR-detectable functional changes precede or co-occur with retinal neuroinflammatory and neurovascular histological changes.
McAnany et al. (2021) Surv Ophthalmol.
Reviews clinical ERG evidence that neural dysfunction (oscillatory potential delays, inner retinal amplitude reductions, photoreceptor function changes) is detectable before vascular lesions appear in diabetic patients. Provides the clinical translational rationale for early functional endpoint sensitivity in preclinical DR studies.
Zhou et al. (2023) Cells.
Zhou and Chen – Review of structural and functional changes in DR, discussing the evidence for early neuronal dysfunction and neurodegeneration preceding vascular pathology and covering the molecular mediators (oxidative stress, proinflammatory cytokines, mitochondrial dysfunction) relevant to preclinical model characterisation.

Product Fit

Summary: Striatech Products supporting your research questions

Research Question	OptoDrum	ScotopicKit	AcuiSee	DarkAdapt	Non-aversive platform
Longitudinal visual decline (hyperglycaemia time course)	Yes	Yes	Yes	Yes	Yes
iBRB breakdown and visual acuity loss (innate immune/STING)	Yes		Yes		Yes
Immunomodulatory treatment efficacy	Yes	Yes	Yes	Yes	Yes
Early neural dysfunction (pre-vascular endpoints)	Yes	Yes	Yes	Yes	Yes

Measurement Modalities

Measuring Functional Visual Outcomes in Diabetic Retinopathy: How Do Available Methods Compare?

Modality	Invasiveness	Longitudinal repeatability	Anaesthesia required	Animal training required	Endpoint captured	3Rs impact
OptoDrum (OMR)	Non-invasive	High – daily if required	No	No	Subcortical acuity and contrast sensitivity (photopic; scotopic with ScotopicKit)	Supports Reduction (replaces terminal endpoints) and Refinement (no handling stress with non-aversive platform)
AcuiSee (operant)	Non-invasive	High	No	Yes (10-14 days)	Cortical visual acuity and contrast sensitivity; forced-choice discrimination	Supports Refinement; training phase adds time
Full-field ERG	Minimal (electrode contact)	Moderate – anaesthesia limits frequency	Yes	No	Photoreceptor (a-wave), inner nuclear layer/bipolar cells (b-wave), oscillatory potentials (inner retinal amacrine/RGC)	Anaesthetic agents may confound longitudinal data; each session requires recovery
Pattern ERG (PERG)	Minimal	Moderate	Yes (or head-fixed)	No	RGC-specific inner retinal function	As for full-field ERG; more targeted to RGC layer
Fundus imaging / OCT	Non-invasive (mydriasis required)	High	Usually (or head-fixed)	No	Structural – retinal layer thickness, vascular changes, neovascularisation	Structural only; does not capture functional visual deficit directly
Fluorescein angiography	Invasive (intravenous or intraperitoneal dye injection)	Low – dye toxicity limits frequency	Yes	No	Vascular permeability, iBRB integrity, neovascularisation	Invasive; not ideal for dense longitudinal monitoring

Striatech's OptoDrum and AcuiSee are best used as complementary functional endpoints alongside ERG and structural imaging rather than replacements. The OMR uniquely supports dense longitudinal functional sampling without anaesthetic confounds, making it the most practical choice for tracking the early visual function time course in diabetic rodent models across multi-week or multi-month disease progression studies.

Supported by Striatech Products

Publications on Diabetic Retinopathy

JCI Insight (Jul 01, 2025) Immunomodulation of inflammatory responses preserves retinal integrity in murine models of pericyte-depletion retinopathy

Kinuthia UM, Moehle C, Adams RH, Langmann T

DOI: 10.1172/jci.insight.184465 >>

Featured image for “Immunomodulation of inflammatory responses preserves retinal integrity in murine models of pericyte-depletion retinopathy”

Kinuthia et al. investigated the role of microglia-driven inflammatory responses in diabetic retinopathy (DR) using two mouse models that mimic key features of human DR. Both models showed compromised blood-retina barrier integrity, increased secretion of angiogenic and inflammatory factors, and sustained microglia reactivity accompanied by upregulation of disease-associated genes. Treatment with minocycline was not sufficient to preserve visual acuity, measured with Striatech’s OptoDrum, but it attenuated these inflammatory responses and preserved retinal vascular and structural integrity.

The loss of integrity of the blood retina barrier (BRB) is a key pathological hallmark of vision-threatening complications in diabetic retinopathy (DR). Although DR is considered a microvascular disease, mounting evidence from mouse models and patients show that inflammation is closely connected with microvasculopathy. Inflammatory responses during retinal pathophysiology are often orchestrated by microglia, resident innate immune cells of the retina. However, the precise role of microglia activity during DR pathogenesis remains elusive. Here, we used an anti-PDGFRβ antibody and inducible endothelial cell-specific PDGFB-KO during postnatal development of retinal vasculature to reproduce a key feature of DR pathology in mice. In addition, we applied a minocycline therapy to modulate retinal inflammation. Postnatal depletion of pericytes or loss of PDGFB in retinal vessels altered BRB integrity and triggered secretion of angiogenic and inflammatory factors with concomitant microglia reactivity, which was sustained in retinas of adult mice. Microglia reactivity was accompanied by upregulation of disease-associated genes. Notably, minocycline attenuated the cycle of inflammatory responses in young and mature retinas, thereby preserving retinal vascular and structural integrity in mice. Together, our findings suggest that immunomodulation of microglia-driven inflammatory responses preserves retinal vasculature and maintains BRB integrity in 2 different mouse models of human DR.

Related Products:

OptoDrum

Applications:
Diabetic Retinopathy
·
Neuroinflammation
·
Neuroinflammation and Autoimmune CNS Disease
·
Retinal Degeneration
·
Retinal Dystrophy
·
Retinal Ganglion Cell Pathology
·
Vascular and Metabolic Disease: Diabetic Retinopathy and Stroke
>

Journal of Neuroinflammation (Mar 01, 2025) cGAMP promotes inner blood-retinal barrier breakdown through P2RX7-mediated transportation into micrglia

Ge X, Zhu X, Liu W, Li M, Zhang Z, Zou M, Deng M, Cui H, Chen Z, Wang L, Hu X, Ju R, Tang X, Ding X, Gong L

DOI: 10.1186/s12974-025-03391-w >>

Featured image for “cGAMP promotes inner blood-retinal barrier breakdown through P2RX7-mediated transportation into microglia”

In diabetic retinopathy, the breakdown of the inner blood-retinal barrier leads to retinal degeneration. This study explores the contribution of a key player in immune signaling, the cGAS-STING pathway. Researchers found elevated levels of cGAMP, an endogenous STING activator, both in patients with proliferative diabetic retinopathy and in diabetic mice. cGAMP is transported into retinal microglia via the P2RX7 receptor. This triggers damage to the inner blood-retinal barrier, neuronal degeneration, and vision impairment. Blocking P2RX7 reduced STING activation, preserved inner blood-retinal barrier integrity, and improved neuronal survival in diabetic models, highlighting its therapeutic potential. The OptoDrum system was employed to assess visual acuity in mice. This helped quantifying the impact of cGAMP-induced retinal damage on visual behavior.

Background: Impairment of the inner blood-retinal barrier (iBRB) leads to various blinding diseases including diabetic retinopathy (DR). The cGAS-STING pathway has emerged as a driving force of cardiovascular destruction, but its impact on the neurovascular system is unclear. Here, we show that cGAMP, the endogenous STING agonist, causes iBRB breakdown and retinal degeneration thorough P2RX7-mediated transport into microglia. Methods: Extracellular cGAMP and STING pathway were determined in tissue samples from patients with proliferative DR (PDR) and db/db diabetic mice. Histological, molecular, bioinformatic and behavioral analysis accessed effects of cGAMP on iBRB. Single-cell RNA sequencing identified the primary retinal cell type responsive to cGAMP. Specific inhibitors and P2RX7-deficienct mice were used to evaluate P2RX7' role as a cGAMP transporter. The therapeutic effects of P2RX7 inhibitor were tested in db/db mice. Results: cGAMP was detected in the aqueous humor of patients with PDR and elevated in the vitreous humor with STING activation in db/db mouse retinas. cGAMP administration led to STING-dependent iBRB breakdown and neuron degeneration. Microglia were the primary cells responding to cGAMP, essential for cGAMP-induced iBRB breakdown and visual impairment. The ATP-gated P2RX7 transporter was required for cGAMP import and STING activation in retinal microglia. Contrary to previous thought that mouse P2RX7 nonselectively transports cGAMP only at extremely high ATP concentrations, human P2RX7 directly binds to cGAMP and activates STING under physiological conditions. Clinically, cGAMP-induced microglial signature was recapitulated in fibrovascular membranes from patients with PDR, with P2RX7 being predominantly expressed in microglia. Inhibiting P2RX7 reduced cGAMP-STING activation, protected iBRB and improved neuron survival in diabetic mouse retinas. Conclusions: Our study reveals a mechanism for cGAMP-mediated iBRB breakdown and suggests that targeting microglia and P2RX7 may mitigate the deleterious effects of STING activation in retinal diseases linked to iBRB impairment.

Related Products:

OptoDrum

Applications:
Diabetic Retinopathy
·
Neuroinflammation
·
Neurovascular Injury
·
Vascular and Metabolic Disease: Diabetic Retinopathy and Stroke
>

Journal of Neurochemistry (Oct 07, 2024) Chronic hyperglycemia alters retinal astrocyte microstructure and uptake of cholera toxin B in a murine model of diabetes

Holden JM, Bossardet OL, Bou Ghanem G, Calkins DJ, Wareham LK

DOI: 10.1111/jnc.16237 >>

Featured image for “Chronic hyperglycemia alters retinal astrocyte microstructure and uptake of cholera toxin B in a murine model of diabetes”

This study investigated early changes in retinal astrocytes during diabetes using a mouse model of hyperglycemia. The researchers found that astrocytes undergo morphological remodeling in response to high blood sugar levels and intravitreal injury. These changes affect the astrocytes’ interaction with neurons and blood vessels. The study also observed increased uptake of cholera toxin B by astrocytes and increased leukocyte infiltration in the retina under certain conditions. These findings have implications for current diabetic retinopathy treatments involving intravitreal injections.

Astrocytes are the principle glial cells of the central nervous system and play an active role in maintaining proper metabolism in surrounding neurons. Because of their involvement in metabolic control, it is likely that their physiology changes in response to metabolic diseases such as diabetes and associated diabetic retinopathy. Here, we investigated whether microstructural changes in astrocyte morphology occur during the early stages of chronic hyperglycemia that may be indicative of early pathogenic programs. We used MORF3 mice in conjunction with streptozotocin-induced hyperglycemia to investigate the morphology of single retinal astrocytes at an early timepoint in diabetic disease. We report that astrocytes initiate a morphological remodeling program, which depends on both the glycemic background and the presence of intravitreal injury, to alter the amount of the neuronal-associated pad and bristle microstructural motifs. Additionally, hyperglycemia increases astrocyte uptake of cholera toxin B, possibly reflecting changes in glycolipid and glycoprotein biosynthesis. Chronic hyperglycemia coupled with intravitreal injection of cholera toxin B also causes extensive leukocyte infiltration into the retina. Our results have important clinical relevance as current therapies for diabetic retinopathy involve intravitreal injection of pharmaceuticals in individuals with often poorly controlled blood glucose levels.

Related Products:

OptoDrum