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Structure-Function Relationships in the Rodent Streptozotocin-Induced Model for Diabetic Retinopathy: A Systematic
Inesa Lelyte1,2, Zubair Ahmed2,3, Simon Kaja4,5
1Research and Development Division, Experimentica Ltd., Kuopio, Finland.
Abstract:
The streptozotocin (STZ)-induced rodent model is one of the most commonly employed models in preclinical drug discovery for diabetic retinopathy (DR). However, standardization and validation of experimental readouts are largely lacking. The aim of this systematic review was to identify and compare the most useful readouts of STZ-induced DR and provide recommendations for future study design based on our findings. We performed a systematic search using 2 major databases, PubMed and EMBASE. Only articles describing STZ-induced DR describing both functional and structural readouts were selected. We also assessed the risk of bias and analyzed qualitative data in the selected studies. We identified 21 studies that met our inclusion/exclusion criteria, using either rats or mice and study periods of 2 to 24 weeks. Glucose level thresholds used to define hyperglycemia were inconsistent between studies, however, most studies used either 250 or 300.6 mg/dL as a defining criterion for hyperglycemia. All included studies performed electroretinography (ERG) and reported a reduction in a-, b-, or c-wave and/or oscillatory potential amplitudes. Spectral-domain optical coherence tomography and fluorescein angiography, as well as immunohistochemical and histopathological analyses showed reductions in retinal thickness, vascular changes, and presence of inflammation. Risk of bias assessment showed that all studies had a high risk of bias due to lack of reporting or correctly following procedures. Our systematic review highlights that ERG represents the most consistent functional readout in the STZ model. However, due to the high risk of bias, caution must be used when interpreting these studies.
Insights
The streptozotocin (STZ)-induced rodent model for diabetic retinopathy (DR) lacks standardized readouts. Electroretinography (ERG) is the most consistent functional measure, but high bias risk necessitates cautious interpretation in preclinical drug discovery.
Area of Science:
- Ophthalmology
- Preclinical Research
- Diabetology
Background:
- The streptozotocin (STZ)-induced rodent model is widely used for diabetic retinopathy (DR) research.
- Significant variability exists in experimental readouts and standardization within this model.
- This limits the reliability and comparability of preclinical drug discovery findings.
Purpose of the Study:
- To systematically review and compare functional and structural readouts in STZ-induced DR rodent models.
- To identify the most effective readouts for assessing DR progression and treatment efficacy.
- To provide recommendations for improving future study designs and reducing bias.
Main Methods:
- Systematic literature search of PubMed and EMBASE databases.
- Inclusion of studies reporting both functional and structural readouts in STZ-induced DR models.
- Assessment of risk of bias and qualitative analysis of selected studies.
Main Results:
- Twenty-one studies using rats or mice (2-24 weeks) were included.
- Electroretinography (ERG) consistently showed reduced wave amplitudes across studies.
- Structural analyses revealed retinal thinning, vascular changes, and inflammation; however, high risk of bias was noted in all studies.
Conclusions:
- Electroretinography (ERG) is the most reliable functional readout in STZ-induced DR models.
- Inconsistent hyperglycemia criteria and high risk of bias necessitate careful interpretation of current findings.
- Standardization of readouts and improved study conduct are crucial for advancing DR preclinical research.
