Topical administration of GLP-1 eyedrops improves retinal ganglion cell function by facilitating presynaptic GABA release in early experimental diabetes
Diabetic retinopathy is a prominent cause of blindness in adults, with early retinal ganglion cell loss contributing to visual dysfunction or blindness. In the brain, defects in γ-aminobutyric acid synaptic transmission are associated with pathophysiological and neurodegenerative disorders, whereas...
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Wolters Kluwer Medknow Publications
2026-02-01
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| Series: | Neural Regeneration Research |
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| Online Access: | https://journals.lww.com/10.4103/NRR.NRR-D-24-00001 |
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| author | Yu-Qi Shao Yong-Chen Wang Lu Wang Hang-Ze Ruan Yun-Feng Liu Ti-Hui Zhang Shi-Jun Weng Xiong-Li Yang Yong-Mei Zhong |
| author_facet | Yu-Qi Shao Yong-Chen Wang Lu Wang Hang-Ze Ruan Yun-Feng Liu Ti-Hui Zhang Shi-Jun Weng Xiong-Li Yang Yong-Mei Zhong |
| author_sort | Yu-Qi Shao |
| collection | DOAJ |
| description | Diabetic retinopathy is a prominent cause of blindness in adults, with early retinal ganglion cell loss contributing to visual dysfunction or blindness. In the brain, defects in γ-aminobutyric acid synaptic transmission are associated with pathophysiological and neurodegenerative disorders, whereas glucagon-like peptide-1 has demonstrated neuroprotective effects. However, it is not yet clear whether diabetes causes alterations in inhibitory input to retinal ganglion cells and whether and how glucagon-like peptide-1 protects against neurodegeneration in the diabetic retina through regulating inhibitory synaptic transmission to retinal ganglion cells. In the present study, we used the patch-clamp technique to record γ-aminobutyric acid subtype A receptor–mediated miniature inhibitory postsynaptic currents in retinal ganglion cells from streptozotocin-induced diabetes model rats. We found that early diabetes (4 weeks of hyperglycemia) decreased the frequency of GABAergic miniature inhibitory postsynaptic currents in retinal ganglion cells without altering their amplitude, suggesting a reduction in the spontaneous release of γ-aminobutyric acid to retinal ganglion cells. Topical administration of glucagon-like peptide-1 eyedrops over a period of 2 weeks effectively countered the hyperglycemia-induced downregulation of GABAergic mIPSC frequency, subsequently enhancing the survival of retinal ganglion cells. Concurrently, the protective effects of glucagon-like peptide-1 on retinal ganglion cells in diabetic rats were eliminated by topical administration of exendin-9-39, a specific glucagon-like peptide-1 receptor antagonist, or SR95531, a specific antagonist of the γ-aminobutyric acid subtype A receptor. Furthermore, extracellular perfusion of glucagon-like peptide-1 was found to elevate the frequencies of GABAergic miniature inhibitory postsynaptic currents in both ON- and OFF-type retinal ganglion cells. This elevation was shown to be mediated by activation of the phosphatidylinositol-phospholipase C/inositol 1,4,5-trisphosphate receptor/Ca2+/protein kinase C signaling pathway downstream of glucagon-like peptide-1 receptor activation. Moreover, multielectrode array recordings revealed that glucagon-like peptide-1 functionally augmented the photoresponses of ON-type retinal ganglion cells. Optomotor response tests demonstrated that diabetic rats exhibited reductions in visual acuity and contrast sensitivity that were significantly ameliorated by topical administration of glucagon-like peptide-1. These results suggest that glucagon-like peptide-1 facilitates the release of γ-aminobutyric acid onto retinal ganglion cells through the activation of glucagon-like peptide-1 receptor, leading to the de-excitation of retinal ganglion cell circuits and the inhibition of excitotoxic processes associated with diabetic retinopathy. Collectively, our findings indicate that the γ-aminobutyric acid system has potential as a therapeutic target for mitigating early-stage diabetic retinopathy. Furthermore, the topical administration of glucagon-like peptide-1 eyedrops represents a non-invasive and effective treatment approach for managing early-stage diabetic retinopathy. |
| format | Article |
| id | doaj-art-85a4b9ae31d94ce487e0fd2db32336c7 |
| institution | DOAJ |
| issn | 1673-5374 1876-7958 |
| language | English |
| publishDate | 2026-02-01 |
| publisher | Wolters Kluwer Medknow Publications |
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| series | Neural Regeneration Research |
| spelling | doaj-art-85a4b9ae31d94ce487e0fd2db32336c72025-08-20T03:07:28ZengWolters Kluwer Medknow PublicationsNeural Regeneration Research1673-53741876-79582026-02-0121280081010.4103/NRR.NRR-D-24-00001Topical administration of GLP-1 eyedrops improves retinal ganglion cell function by facilitating presynaptic GABA release in early experimental diabetesYu-Qi ShaoYong-Chen WangLu WangHang-Ze RuanYun-Feng LiuTi-Hui ZhangShi-Jun WengXiong-Li YangYong-Mei ZhongDiabetic retinopathy is a prominent cause of blindness in adults, with early retinal ganglion cell loss contributing to visual dysfunction or blindness. In the brain, defects in γ-aminobutyric acid synaptic transmission are associated with pathophysiological and neurodegenerative disorders, whereas glucagon-like peptide-1 has demonstrated neuroprotective effects. However, it is not yet clear whether diabetes causes alterations in inhibitory input to retinal ganglion cells and whether and how glucagon-like peptide-1 protects against neurodegeneration in the diabetic retina through regulating inhibitory synaptic transmission to retinal ganglion cells. In the present study, we used the patch-clamp technique to record γ-aminobutyric acid subtype A receptor–mediated miniature inhibitory postsynaptic currents in retinal ganglion cells from streptozotocin-induced diabetes model rats. We found that early diabetes (4 weeks of hyperglycemia) decreased the frequency of GABAergic miniature inhibitory postsynaptic currents in retinal ganglion cells without altering their amplitude, suggesting a reduction in the spontaneous release of γ-aminobutyric acid to retinal ganglion cells. Topical administration of glucagon-like peptide-1 eyedrops over a period of 2 weeks effectively countered the hyperglycemia-induced downregulation of GABAergic mIPSC frequency, subsequently enhancing the survival of retinal ganglion cells. Concurrently, the protective effects of glucagon-like peptide-1 on retinal ganglion cells in diabetic rats were eliminated by topical administration of exendin-9-39, a specific glucagon-like peptide-1 receptor antagonist, or SR95531, a specific antagonist of the γ-aminobutyric acid subtype A receptor. Furthermore, extracellular perfusion of glucagon-like peptide-1 was found to elevate the frequencies of GABAergic miniature inhibitory postsynaptic currents in both ON- and OFF-type retinal ganglion cells. This elevation was shown to be mediated by activation of the phosphatidylinositol-phospholipase C/inositol 1,4,5-trisphosphate receptor/Ca2+/protein kinase C signaling pathway downstream of glucagon-like peptide-1 receptor activation. Moreover, multielectrode array recordings revealed that glucagon-like peptide-1 functionally augmented the photoresponses of ON-type retinal ganglion cells. Optomotor response tests demonstrated that diabetic rats exhibited reductions in visual acuity and contrast sensitivity that were significantly ameliorated by topical administration of glucagon-like peptide-1. These results suggest that glucagon-like peptide-1 facilitates the release of γ-aminobutyric acid onto retinal ganglion cells through the activation of glucagon-like peptide-1 receptor, leading to the de-excitation of retinal ganglion cell circuits and the inhibition of excitotoxic processes associated with diabetic retinopathy. Collectively, our findings indicate that the γ-aminobutyric acid system has potential as a therapeutic target for mitigating early-stage diabetic retinopathy. Furthermore, the topical administration of glucagon-like peptide-1 eyedrops represents a non-invasive and effective treatment approach for managing early-stage diabetic retinopathy.https://journals.lww.com/10.4103/NRR.NRR-D-24-00001diabetic retinopathyglucagon-like peptide-1inhibitory synaptic transmissionminiature inhibitory postsynaptic currentsneurodegenerationneuroprotectionpatch-clamp recordingprotein kinase csignaling pathwayvisual function |
| spellingShingle | Yu-Qi Shao Yong-Chen Wang Lu Wang Hang-Ze Ruan Yun-Feng Liu Ti-Hui Zhang Shi-Jun Weng Xiong-Li Yang Yong-Mei Zhong Topical administration of GLP-1 eyedrops improves retinal ganglion cell function by facilitating presynaptic GABA release in early experimental diabetes Neural Regeneration Research diabetic retinopathy glucagon-like peptide-1 inhibitory synaptic transmission miniature inhibitory postsynaptic currents neurodegeneration neuroprotection patch-clamp recording protein kinase c signaling pathway visual function |
| title | Topical administration of GLP-1 eyedrops improves retinal ganglion cell function by facilitating presynaptic GABA release in early experimental diabetes |
| title_full | Topical administration of GLP-1 eyedrops improves retinal ganglion cell function by facilitating presynaptic GABA release in early experimental diabetes |
| title_fullStr | Topical administration of GLP-1 eyedrops improves retinal ganglion cell function by facilitating presynaptic GABA release in early experimental diabetes |
| title_full_unstemmed | Topical administration of GLP-1 eyedrops improves retinal ganglion cell function by facilitating presynaptic GABA release in early experimental diabetes |
| title_short | Topical administration of GLP-1 eyedrops improves retinal ganglion cell function by facilitating presynaptic GABA release in early experimental diabetes |
| title_sort | topical administration of glp 1 eyedrops improves retinal ganglion cell function by facilitating presynaptic gaba release in early experimental diabetes |
| topic | diabetic retinopathy glucagon-like peptide-1 inhibitory synaptic transmission miniature inhibitory postsynaptic currents neurodegeneration neuroprotection patch-clamp recording protein kinase c signaling pathway visual function |
| url | https://journals.lww.com/10.4103/NRR.NRR-D-24-00001 |
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