Effects of the Topical Administration of Semaglutide on Retinal Neuroinflammation and Vascular Leakage in Experimental Diabetes

被引:16
作者
Simo, Rafael [1 ,2 ]
Bogdanov, Patricia [1 ,2 ]
Ramos, Hugo [1 ,2 ]
Huerta, Jordi [1 ]
Simo-Servat, Olga [1 ,2 ]
Hernandez, Cristina [1 ,2 ]
机构
[1] Univ Autonoma Barcelona, Vall dHebron Res Inst, Diabet & Metab Res Unit, Barcelona 08035, Spain
[2] Inst Salud Carlos III ISCIII, Ctr Invest Biomed Red Diabet & Enfermedades Metab, Madrid 28029, Spain
关键词
diabetic retinopathy; semaglutide; retina; db/db mouse; EXENDIN-4; ANALOG; NEURODEGENERATION; RETINOPATHY; BARRIER;
D O I
10.3390/biomedicines9080926
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 mu L once/daily) or vehicle (PBS; 5 mu 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-kappa B), proinflammatory cytokines (IL-1 beta, 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.
引用
收藏
页数:10
相关论文
共 16 条
[1]  
Anderson PJB, 2008, CLIN OPHTHALMOL, V2, P801
[2]   Exendin-4 alleviates retinal vascular leakage by protecting the blood-retinal barrier and reducing retinal vascular permeability in diabetic Goto-Kakizaki rats [J].
Fan, Yichao ;
Liu, Kun ;
Wang, Qingping ;
Ruan, Yuanyuan ;
Ye, Wen ;
Zhang, Yu .
EXPERIMENTAL EYE RESEARCH, 2014, 127 :104-116
[3]   Topical administration of DPP-IV inhibitors prevents retinal neurodegeneration in experimental diabetes [J].
Hernandez, Cristina ;
Bogdanov, Patricia ;
Sola-Adell, Cristina ;
Sampedro, Joel ;
Valeri, Marta ;
Genis, Xavier ;
Simo-Servat, Olga ;
Garcia-Ramirez, Marta ;
Simo, Rafael .
DIABETOLOGIA, 2017, 60 (11) :2285-2298
[4]   Topical Administration of GLP-1 Receptor Agonists Prevents Retinal Neurodegeneration in Experimental Diabetes [J].
Hernandez, Cristina ;
Bogdanov, Patricia ;
Corraliza, Lidia ;
Garcia-Ramirez, Marta ;
Sola-Adell, Cristina ;
Arranz, Jose A. ;
Arroba, Ana I. ;
Valverde, Angela M. ;
Simo, Rafael .
DIABETES, 2016, 65 (01) :172-187
[5]   Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes [J].
Marso, Steven P. ;
Bain, Stephen C. ;
Consoli, Agostino ;
Eliaschewitz, Freddy G. ;
Jodar, Esteban ;
Leiter, Lawrence A. ;
Lingvay, Ildiko ;
Rosenstock, Julio ;
Seufert, Jochen ;
Warren, Mark L. ;
Woo, Vincent ;
Hansen, Oluf ;
Holst, Anders G. ;
Pettersson, Jonas ;
Vilsboll, Tina .
NEW ENGLAND JOURNAL OF MEDICINE, 2016, 375 (19) :1834-1844
[6]   Brain uptake pharmacokinetics of incretin receptor agonists showing promise as Alzheimer's and Parkinson's disease therapeutics [J].
Salameh, Therese S. ;
Rhea, Elizabeth M. ;
Talbot, Konrad ;
Banks, William A. .
BIOCHEMICAL PHARMACOLOGY, 2020, 180
[7]   New Insights into the Mechanisms of Action of Topical Administration of GLP-1 in an Experimental Model of Diabetic Retinopathy [J].
Sampedro, Joel ;
Bogdanov, Patricia ;
Ramos, Hugo ;
Sola-Adell, Cristina ;
Turch, Mireia ;
Valeri, Marta ;
Simo-Servat, Olga ;
Lagunas, Carmen ;
Simo, Rafael ;
Hernandez, Cristina .
JOURNAL OF CLINICAL MEDICINE, 2019, 8 (03)
[8]   Functional and Structural Findings of Neurodegeneration in Early Stages of Diabetic Retinopathy: Cross-sectional Analyses of Baseline Data of the EUROCONDOR Project [J].
Santos, Ana Rita ;
Ribeiro, Luisa ;
Bandello, Francesco ;
Lattanzio, Rosangela ;
Egan, Catherine ;
Frydkjaer-Olsen, Ulrik ;
Garcia-Arumi, Jose ;
Gibson, Jonathan ;
Grauslund, Jakob ;
Harding, Simon P. ;
Lang, Gabriele E. ;
Massin, Pascale ;
Midena, Edoardo ;
Scanlon, Peter ;
Aldington, Stephen J. ;
Simao, Silvia ;
Schwartz, Christian ;
Ponsati, Berta ;
Porta, Massimo ;
Costa, Miguel Angelo ;
Hernandez, Cristina ;
Cunha-Vaz, Jose ;
Simo, Rafael .
DIABETES, 2017, 66 (09) :2503-2510
[9]   Effects of Topically Administered Neuroprotective Drugs in Early Stages of Diabetic Retinopathy: Results of the EUROCONDOR Clinical Trial [J].
Simo, Rafael ;
Hernandez, Cristina ;
Porta, Massimo ;
Bandello, Francesco ;
Grauslund, Jakob ;
Harding, Simon P. ;
Aldington, Stephen J. ;
Egan, Catherine ;
Frydkjaer-Olsen, Ulrik ;
Garcia-Arumi, Jose ;
Gibson, Jonathan ;
Lang, Gabriele E. ;
Lattanzio, Rosangela ;
Massin, Pascale ;
Midena, Edoardo ;
Ponsati, Berta ;
Ribeiro, Luisa ;
Scanlon, Peter ;
Lobo, Conceicao ;
Costa, Miguel Angelo ;
Cunha-Vaz, Jose ;
Garcia-Ramirez, M. ;
van Reck, E. ;
Gil, E. ;
Morillas, M. ;
Cunha-Vaz, J. ;
Ribeiro, L. ;
Lobo, C. ;
Costa, M. A. ;
Nunes, S. ;
Figueira, J. ;
Pereira-Marques, I. ;
Neves, C. ;
Schwartz, C. ;
Porta, M. ;
Trento, M. ;
Durando, O. ;
Merlo, S. ;
Bandello, F. ;
Lattanzio, R. ;
Zucchiatti, I. ;
Grauslund, J. ;
Frydkjaer-Olsen, U. ;
Harding, S. P. ;
Scanlon, P. ;
Aldington, S. J. ;
Jones, V. ;
Johnson, L. ;
Carter, S. ;
Spurway, J. .
DIABETES, 2019, 68 (02) :457-463
[10]   Neurodegeneration in diabetic retinopathy: does it really matter? [J].
Simo, Rafael ;
Stitt, Alan W. ;
Gardner, Thomas W. .
DIABETOLOGIA, 2018, 61 (09) :1902-1912