53742396d919a053bc274ca4f1b88a48 256708.pdf 12fc48a8919a4d54b0ec11ff0d25dff092388cff 256708.pdf 1b08e5cf28cabb5d930adf90e32804129b491222c0929082b3dcb6b526bbcf36 256708.pdf Title: Effects of the Topical Administration of Semaglutide on Retinal Neuroinflammation and Vascular Leakage in Experimental Diabetes Subject: Background: An unexpected increase in the rate of severe diabetic retinopathy was observed in the Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN)-6 clinical trial. Although this effect was attributed to a rapid decrease in blood glucose levels, a direct deleterious effect of semaglutide on the retina could not be ruled out. In order to shed light on this issue, we have performed a study aimed at testing the direct effect of semaglutide administered by eye drops on retinal neuroinflammation and microvascular abnormalities using the db/db mouse model. Methods: Eye drops containing semaglutide (0.33 mg/mL; 5 L once/daily) or vehicle (PBS; 5 L once daily) were administered for 15 days. Results: We found that semaglutide significantly reduced glial activation, as well as the retinal expression of Nuclear factor kB (NF-B), proinflammatory cytokines (IL-1, IL-6, IL-18) and Intercellular Adhesion Molecule (ICAM)-1. In addition, semaglutide prevented the apoptosis of cells from the retinal ganglion layer and activated the protein kinase B (AKT) pathway. Finally, a dramatic decrease in vascular leakage was observed in db/db mice treated with semaglutide. All these findings were observed without any change in blood glucose levels and, therefore, can be directly attributed to semaglutide. Conclusions: These experimental findings point to a beneficial rather than a deleterious effect of semaglutide on the retina of subjects with diabetes. Keywords: diabetic retinopathy; semaglutide; retina; db/db mouse Author: Rafael Simó, Patricia Bogdanov, Hugo Ramos, Jordi Huerta, Olga Simó-Servat and Cristina Hernández Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Sat Jul 31 08:33:06 2021 CEST ModDate: Sat Jul 31 09:36:02 2021 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 10 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2509025 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- GFKJOY+VnURWPalladioL Type 1 Custom yes yes no 10 0 QPZFHW+EURM10 Type 1 Builtin yes yes no 15 0 YMEERC+URWPalladioL-Ital Type 1 Custom yes yes no 19 0 THBYWB+URWPalladioL-Bold Type 1 Custom yes yes no 24 0 QJOEHG+URWPalladioL-Roma Type 1 Custom yes yes no 28 0 ENXZUH+VnURWPalladioL-Bold Type 1 Custom yes yes no 32 0 EBFBTV+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 40 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 62 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 66 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 70 0 YFFKLH+CMSY10 Type 1 Builtin yes yes no 82 0 MPUDFL+PazoMath Type 1 Builtin yes yes no 89 0 CRJHCU+PazoMath-Italic Type 1 Builtin yes yes no 93 0 FPSCEX+PalatinoLinotype,Italic CID TrueType Identity-H yes yes yes 108 0 FPSCEX+PalatinoLinotype,Bold CID TrueType Identity-H yes yes yes 114 0 FPVMJW+PalatinoLinotype CID TrueType Identity-H yes yes yes 120 0 FPSCEX+PalatinoLinotype,Italic CID TrueType Identity-H yes yes yes 132 0 FPSCEX+PalatinoLinotype,Bold CID TrueType Identity-H yes yes yes 138 0 FPVMJW+PalatinoLinotype CID TrueType Identity-H yes yes yes 144 0 FPSCEX+PalatinoLinotype,Italic CID TrueType Identity-H yes yes yes 163 0 FPSCEX+PalatinoLinotype,Bold CID TrueType Identity-H yes yes yes 169 0 FPVMJW+PalatinoLinotype CID TrueType Identity-H yes yes yes 175 0 FPSCEX+PalatinoLinotype,Italic CID TrueType Identity-H yes yes yes 192 0 FPSCEX+PalatinoLinotype,Bold CID TrueType Identity-H yes yes yes 198 0 FPVMJW+PalatinoLinotype CID TrueType Identity-H yes yes yes 204 0 FPSCEX+PalatinoLinotype,Italic CID TrueType Identity-H yes yes yes 221 0 FPSCEX+PalatinoLinotype,Bold CID TrueType Identity-H yes yes yes 227 0 FPVMJW+PalatinoLinotype CID TrueType Identity-H yes yes yes 233 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2022-06-30 02:28:23 CEST RepresentationInformation: 256708.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2022-04-08 10:44:58 CEST Size: 2509025 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 350 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4923ab24 Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Children: Item: Title: Animals Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Item: Title: Interventional Study Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: Neurovascular Damage Assessment Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Mechanism of Action Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: RNA Isolation and Quantitative RT-PCR assay Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Western Blotting Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Immunohistochemical Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Statistical Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Children: Item: Title: Effect of Semaglutide on Neurovascular Unit Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Mechanisms of Action Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Info: Title: Effects of the Topical Administration of Semaglutide on Retinal Neuroinflammation and Vascular Leakage in Experimental Diabetes Author: Rafael Simó, Patricia Bogdanov, Hugo Ramos, Jordi Huerta, Olga Simó-Servat and Cristina Hernández Subject: Background: An unexpected increase in the rate of severe diabetic retinopathy was observed in the Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN)-6 clinical trial. Although this effect was attributed to a rapid decrease in blood glucose levels, a direct deleterious effect of semaglutide on the retina could not be ruled out. In order to shed light on this issue, we have performed a study aimed at testing the direct effect of semaglutide administered by eye drops on retinal neuroinflammation and microvascular abnormalities using the db/db mouse model. Methods: Eye drops containing semaglutide (0.33 mg/mL; 5 L once/daily) or vehicle (PBS; 5 L once daily) were administered for 15 days. Results: We found that semaglutide significantly reduced glial activation, as well as the retinal expression of Nuclear factor kB (NF-B), proinflammatory cytokines (IL-1, IL-6, IL-18) and Intercellular Adhesion Molecule (ICAM)-1. In addition, semaglutide prevented the apoptosis of cells from the retinal ganglion layer and activated the protein kinase B (AKT) pathway. Finally, a dramatic decrease in vascular leakage was observed in db/db mice treated with semaglutide. All these findings were observed without any change in blood glucose levels and, therefore, can be directly attributed to semaglutide. Conclusions: These experimental findings point to a beneficial rather than a deleterious effect of semaglutide on the retina of subjects with diabetes. 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