Table 1.
Characteristics of the Included Studies
| Study | Species (animal number) | STZ injection | Follow-up time in weeks | Glucose level considered as diabetic (mg/dL) | Functional readouts | In vivo imaging | Postmortem analyses |
|---|---|---|---|---|---|---|---|
| He et al.36,a | Sprague-Dawley rats (n = 30) | Single intraperitoneal injection of STZ (60 mg/kg)+high-fat and high-calorie diet | 4 | 300.6 | Full-field ERG | OCT | Antioxidant parameters: the concentration of antioxidant SOD Inflammatory parameters: levels of proinflammatory cytokines (TNF-α and IL-6) Immunofluorescence and western blot assay: expression VEGF-α, ALDH2, and expression of Nrf2 and Sirt1. |
| Qiu et al.43 | Brown Norway rats (n = 48) | Single intraperitoneal injection of STZ (50 mg/kg) | 8 | >350 | Flash ERG | OCT | Evans Blue extravasation: retinal vascular permeability Leukostasis assay: number of adherent leukocytes Western blot analysis: levels of VEGF, ICAM-1, and β-actin; |
| Sergeys et al.31 | C57BL/6J mice (n varies from 4 to 18 depending on the readout) | 5 sequential daily intraperitoneal injections of STZ (50 mg/kg) | 24 | >250 | Full-field ERG | FA, OCT | Leukostasis assay: number of adherent leukocytes H&E staining: observation of general retinal and the optic nerve head morphology Neurodegeneration: number of RGC (RBPMS) and cholinergic amacrine cell (ChAT); Inflammation and Gliosis: number of macrophages (F4/80); and Muller cell (vimentin) |
| Liao et al.30,b | C57BL/6 mice (n = 25) | 5 sequential daily intraperitoneal injections of STZ (55 mg/kg) + whole-body hypoxia (10% O2) | 4 | >250 | Flash ERG | O CT, FA, FP | H&E staining: morphology of the retina TUNEL assay: morphology of the retina. Number of INL and ONL cells Western blot analysis: expression of inflammatory and junction proteins (BAX, COX-2, iNOS) MTT assay: viability of RPE cells |
| Chang et al.28 | C57BL/6J mice (n = 37) | 3 sequential daily intraperitoneal injections of STZ (100 mg/kg) | 12 | >250 | Flash ERG | FA | Immunofluorescent staining: observation of mitochondrial processes with DRP1, MFN2, and MCU |
| Feng et al.29 | Sprague-Dawley rats (n = 90) | Single intraperitoneal injection of STZ (60 mg/kg) | 4 | >250 | Full-field ERG | No data | BRB breakdown: extravasation of albumin; H&E staining: thicknesses of the IPL, INL and ONL, number of RGC; ELISA: activities of antioxidant enzyme (SOD, GSHPx, GSSGRed, and GSHTrans); and examination of oxidative stress (levels of 4-HNE and 8-OhdG); Western blot analysis: levels of BDNF and synaptophysin |
| Tarchick et al.33,c | Mice with inactivated insulin receptor (IR) B6.129S4 (FVB)-Insrtm1Khn/J (n varies from 9 to 18 depending on the readout) | 3 sequential daily intraperitoneal injections of STZ (55 mg/kg) | 4 | >250 | Flash ERG | No data | Light micrographs: the distance from OLM to ILM, the length of OS, IS, and ONL, and thickness of RPE was measured. DHE staining: measurement of reactive oxygen species |
| Nagai et al.24 | Wistar rats (n = 7) | 2 sequential daily intraperitoneal injections of STZ (100 mg/kg) | 6 | 267.6 | Flash ERG | No data | ELISA: level of VEGF; H&E staining: the distance between RGC to the outer granule layer |
| Deguchi et al.25 | Wistar rats (n = 6) | 2 sequential daily intraperitoneal injections of STZ (100 mg/kg) | 2 | No data | Flash ERG | No data | H&E staining: distance between the GCL and the distal border of the ONL |
| Hernández et al.26 | Sprague-Dawley rats (n = 24) | Single injection of STZ (60 mg/kg) into the tail vein | 2 | >250 | Flash ERG | No data | Assessment of glial activation: expression of GFAP; TUNEL assay: assessment of apoptosis (number of retinal apoptotic cells); Western blot analysis: observation of proapoptotic and survival signaling; Real-time PCR and immunohistochemistry: expression of GLAST. |
| Wang et al.41 | C57BL/6 mice (n = 36) | 3 sequential daily intraperitoneal injections of STZ (75 mg/kg) | 5 | 300.6 | Focal ERG | FA | Leukostasis: number of adherent leukocytes and vascular endothelial cells; Western blot analysis: Levels of GFAP, VEGF and ICAM-1 levels; BRB breakdown: extravasation of albumin; DHE assay: measurement of MDA, SOD, and ROS formation |
| Tarchick et al.33 | C57BL/6J mice (n ≥ 10) | 3 sequential daily intraperitoneal injections of STZ (30 mg/kg) | 4 | ≥250 | dc-ERG | No data | Light microscopy: length of the inner segment, outer segment, and ONL; thickness of RPE; PNA staining: Number of rod and cone photoreceptor nuclei per column |
| Lv et al.38 | BALB/c Mice (n = 25) | 5 sequential daily intraperitoneal injections of STZ (50 mg/kg) | 2 | ≥300.6 | Full-field ERG | No data | H&E staining: The thickness of GCL, INL, ONL, and total retina |
| Zhang et al.34 | Sprague-Dawley rats (n = 24) | Single STZ injection of STZ (30 mg/kg) | 12 | >199.8 | Flash ERG | No data | H&E staining: thickness of total retina, thickness of INL and ONL layers, and cell number in the INL and ONL; TUNEL assay: apoptosis assessment; Immunohistochemistry: expression of Bcl-2, Bax. |
| He et al.37 | Sprague-Dawley rats (n = 40) | Single intraperitoneal injection of STZ (35 mg/kg) | 10.2 | >300.6 | Full-field ERG | OCT | Western blot analysis: expression of VEGF, GFAP, and VCAM-1; Levels of GLU, TC, and TG; Levels of GSH-Px, SOD, and CAT. |
| Liao et al.32 | C57/BL6 mice (n = 40) | 5 sequential daily intraperitoneal injections of STZ (55 mg/kg) | 5 | No data | Flash ERG | FA + FP | Trypsin-digested retinal whole mounts: number of acellular capillaries H&E staining: number of preretinal neovascular cells; Thicknesses of the IPL, INL, OPL, and ONL; RT-qPCR and western blot analysis: expressions of VEGF; levels of proinflammatory cytokines, including TNF-a, IL-1b, IL-6, IL-18, and IL-12; |
| Goharinia et al.35 | Sprague-Dawley rats (n = 8) | Single intraperitoneal injection of STZ (60 mg/kg) | 8 | 300 | Flash ERG | No data | H&E staining: number of RGCs |
| Ren et al.40 | BALB/c mice (n = 20) | Single intraperitoneal injection of STZ (80 mg/kg) | 4 | ≥300.6 | Full-field ERG | No data | H&E staining: the thickness of the whole retina, ONL, INL, and RGC layer; Trx expression. |
| Piano et al.39 | C57BL/6J mice (n = 20) | Single intraperitoneal injection of STZ (150 mg/kg) | 12 | >300.6 | Flash ERG | No data | Cryosections: total retinal thickness; Vascular area: deep plexus vessels; neovascularization; Western blot analysis: rhodopsin and cone-opsin content; TUNEL staining: apoptosis of rod photoreceptors; Western blot analysis: level of Caspase-3 and GAPDH |
| Yee et al.27,d | Sprague-Dawley rats (n = 56) | Single injection of STZ (53 mg/kg) into the tail vein+specific fish oil or safflower oil diet | 20 | 270 | Flash ERG | No data | Toluidine Blue staining: thickness of ONL, INL, IPL layers, and total retina. Retinal fatty acid analysis: identification of fatty acids in retina Immunolabeling: level of GFAP |
| Wang et al.42 | Sprague-Dawley rats (n = 16) | Single intraperitoneal injection of STZ (35 mg/kg) + high-sucrose/high-fat diet | 17 | 300.6 | fVEP | OCT | H&E staining: number of RGC; Expressions of GFAP and number of activated astrocytes; PAS assessment: retinal microvascular changes, ghost pericytes. |
Reasons for study exclusions.
a
No control group (only a group with STZ).
b
STZ administration was combined with whole-body hypoxia (10% O2) for quicker diabetes induction.
c
Mice with inactivated insulin receptor.
d
STZ administration with specific oil diet.
BAX, Bcl-2-associated X protein; BRB, blood–retinal barrier; ChAT, choline acetyltransferase; COX-2, cyclooxygenase-2; DHE, dihydroethidium; DR, diabetic retinopathy; ELISA, enzyme-linked immunosorbent assays; ERG, electroretinography; FA, fluorescein angiography; fVEP, functional visually evoked potentials; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GCL, ganglion cell layer; GFAP, glial fibrillary acidic protein; H&E, Hematoxylin and Eosin; ICAM-1, intercellular adhesion molecule-1; IL, interleukin; INL, inner nuclear layer; iNOS, inducible nitric oxide synthases; IPL, inner plexiform layer; MCU, mitochondrial calcium uniporter; OCT, optical coherence tomography; ONL, outer nuclear layer; OPL outer plexiform layer; PAS, Periodic acid–Schiff; PCR, polymerase chain reaction; RGC, retinal ganglion cell; RT-qPCR, reverse transcription quantitative polymerase chain reaction; SOD, superoxide dismutase; STZ, streptozotocin; TNF-α, tumor necrosis factor-a; VCAM-1, vascular cell adhesion molecule-1; VEGF, vascular endothelial growth factor.