Login Register Cart 0
Current Medicinal Chemistry

Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Translate in Chinese
Research Article

Idebenone Attenuates Diabetic Retinopathy by Modulating Autophagy via Targeting Akt Signaling

Author(s): Zhenqian Yu and Gang Liu*

Volume 33, Issue 1, 2026

Published on: 01 November, 2024

Page: [220 - 231] Pages: 12

DOI: 10.2174/0109298673339172241017114810

Price: $65

Become a Editorial Board Member
Become a Reviewer
Become a Editor
Become a Section Editor

Abstract

Introduction: Diabetic Retinopathy (DR) is a common microvascular issue caused by diabetes. Idebenone (IDE) is a coenzyme Q10 analog and antioxidant that has been utilized in the treatment of neurodegenerative diseases.

Methods: Our goal was to investigate how IDE might treat diabetic retinopathy. An in vivo DR model was established by injecting a single dose of streptozotocin (STZ). Rats were treated with IDE, and their vascular function was measured by ultrasound. The retina structure was checked by haematoxylin and eosin (HE) staining. The expression of biomarkers of autophagy and apoptosis was measured by Western blotting assay. The retina endothelial cell line RF/6A was stimulated with high glucose (HG) and treated with IDE. Cell proliferation and apoptosis were assessed using the Edu assay, TUNEL assay, and flow cytometry, respectively.

Results: Reduced peak systolic velocity (PSV), mean velocity (MV), end-diastolic velocity (EDV), and increased pulsatility index (PI) and resistance index (RI) were observed in diabetic rats; however, these traits were reversed by IDE therapy. IDE alleviated the STZ-induced disordered retina structure. The IDE administration suppressed DR-induced apoptosis and autophagy both in vivo and in vitro. IDE suppressed the activation of Phosphatidylinositol 3 kinase (PI3K) signaling. Activation of PI3K abolished the IDE-alleviated retina damage and cell death.

Conclusion: IDE regulated the autophagy of retina cells to alleviate diabetic retinopathy via regulating the PI3K signaling pathway.

Keywords: Diabetes, apoptosis, PI3 phosphatidylinositol 3 kinase K, microvascular, retinopathy, muller.

« Previous Next »
[1]
Wang, W.; Lo, A.C.Y. Diabetic Retinopathy: Pathophysiology and treatments. Int. J. Mol. Sci., 2018, 19(6), 1816.
[http://dx.doi.org/10.3390/ijms19061816] [PMID: 29925789]
[2]
Lechner, J.; O’Leary, O.E.; Stitt, A.W. The pathology associated with diabetic retinopathy. Vision Res., 2017, 139, 7-14.
[http://dx.doi.org/10.1016/j.visres.2017.04.003] [PMID: 28412095]
[3]
Simó-Servat, O.; Hernández, C.; Simó, R. Diabetic retinopathy in the context of patients with diabetes. Ophthalmic Res., 2019, 62(4), 211-217.
[http://dx.doi.org/10.1159/000499541] [PMID: 31129667]
[4]
Vujosevic, S.; Aldington, S.J.; Silva, P.; Hernández, C.; Scanlon, P.; Peto, T.; Simó, R. Screening for diabetic retinopathy: New perspectives and challenges. Lancet Diabetes Endocrinol., 2020, 8(4), 337-347.
[http://dx.doi.org/10.1016/S2213-8587(19)30411-5] [PMID: 32113513]
[5]
Jenkins, A.J.; Joglekar, M.V.; Hardikar, A.A.; Keech, A.C.; O’Neal, D.N.; Januszewski, A.S. Biomarkers in diabetic retinopathy. Rev. Diabet. Stud., 2015, 12(1-2), 159-195.
[http://dx.doi.org/10.1900/RDS.2015.12.159] [PMID: 26676667]
[6]
Gao, Q. Oxidative stress and autophagy. Adv. Exp. Med. Biol., 2019, 1206, 179-198.
[http://dx.doi.org/10.1007/978-981-15-0602-4_9] [PMID: 31776986]
[7]
Menzies, F.M.; Fleming, A.; Rubinsztein, D.C. Compromised autophagy and neurodegenerative diseases. Nat. Rev. Neurosci., 2015, 16(6), 345-357.
[http://dx.doi.org/10.1038/nrn3961] [PMID: 25991442]
[8]
Heras-Sandoval, D.; Pérez-Rojas, J.M.; Hernández- Damián, J.; Pedraza-Chaverri, J. The role of PI3K/AKT/mTOR pathway in the modulation of autophagy and the clearance of protein aggregates in neurodegeneration. Cell. Signal., 2014, 26(12), 2694-2701.
[http://dx.doi.org/10.1016/j.cellsig.2014.08.019] [PMID: 25173700]
[9]
Kitada, M.; Koya, D. Autophagy in metabolic disease and ageing. Nat. Rev. Endocrinol., 2021, 17(11), 647-661.
[http://dx.doi.org/10.1038/s41574-021-00551-9] [PMID: 34508250]
[10]
Yang, D.; Livingston, M.J.; Liu, Z.; Dong, G.; Zhang, M.; Chen, J.K.; Dong, Z. Autophagy in diabetic kidney disease: Regulation, pathological role and therapeutic potential. Cell. Mol. Life Sci., 2018, 75(4), 669-688.
[http://dx.doi.org/10.1007/s00018-017-2639-1] [PMID: 28871310]
[11]
Tao, T.; Xu, H. Autophagy and obesity and diabetes. Adv. Exp. Med. Biol., 2020, 1207, 445-461.
[http://dx.doi.org/10.1007/978-981-15-4272-5_32] [PMID: 32671767]
[12]
Gueven, N.; Ravishankar, P.; Eri, R.; Rybalka, E. Idebenone: When an antioxidant is not an antioxidant. Redox Biol., 2021, 38, 101812.
[http://dx.doi.org/10.1016/j.redox.2020.101812] [PMID: 33254077]
[13]
Peng, J.; Wang, H.; Gong, Z.; Li, X.; He, L.; Shen, Q.; Pan, J.; Peng, Y. Idebenone attenuates cerebral inflammatory injury in ischemia and reperfusion via dampening NLRP3 inflammasome activity. Mol. Immunol., 2020, 123, 74-87.
[http://dx.doi.org/10.1016/j.molimm.2020.04.013] [PMID: 32438202]
[14]
Higa, R.; Roberti, S.; Mazzucco, M.B.; White, V.; Jawerbaum, A. Effect of the antioxidant idebenone on maternal diabetes-induced embryo alterations during early organogenesis. Reprod. Biomed. Online, 2018, 37(4), 397-408.
[http://dx.doi.org/10.1016/j.rbmo.2018.05.006] [PMID: 29857987]
[15]
Hui, C.; Tomilov, A.; Garcia, C.; Jiang, X.; Fash, D.M.; Khdour, O.M.; Rosso, C.; Filippini, G.; Prato, M.; Graham, J.; Hecht, S.; Havel, P.; Cortopassi, G. Novel idebenone analogs block Shc’s access to insulin receptor to improve insulin sensitivity. Biomed. Pharmacother., 2020, 132, 110823.
[http://dx.doi.org/10.1016/j.biopha.2020.110823] [PMID: 33045613]
[16]
Jintao, Y. Idebenone-loaded wound dressings promote diabetic wound healing through downregulation of Il1b, Nfkb genes and upregulation of Fgf2 gene. Res. Vet. Sci., 2022, 151, 128-137.
[http://dx.doi.org/10.1016/j.rvsc.2022.07.002] [PMID: 35901525]
[17]
Dassano, A.; Loretelli, C.; Fiorina, P. Idebenone and T2D: A new insulin-sensitizing drug for personalized therapy. Pharmacol. Res., 2019, 139, 469-470.
[http://dx.doi.org/10.1016/j.phrs.2018.12.008] [PMID: 30552974]
[18]
Olivares, A.M.; Althoff, K.; Chen, G.F.; Wu, S.; Morrisson, M.A.; DeAngelis, M.M.; Haider, N. Animal models of diabetic retinopathy. Curr. Diab. Rep., 2017, 17(10), 93.
[http://dx.doi.org/10.1007/s11892-017-0913-0] [PMID: 28836097]
[19]
Hammes, H.P. Diabetic retinopathy: Hyperglycaemia, oxidative stress and beyond. Diabetologia, 2018, 61(1), 29-38.
[http://dx.doi.org/10.1007/s00125-017-4435-8] [PMID: 28942458]
[20]
Sabanayagam, C.; Banu, R.; Chee, M.L.; Lee, R.; Wang, Y.X.; Tan, G.; Jonas, J.B.; Lamoureux, E.L.; Cheng, C.Y.; Klein, B.E.K.; Mitchell, P.; Klein, R.; Cheung, C.M.G.; Wong, T.Y. Incidence and progression of diabetic retinopathy: A systematic review. Lancet Diabetes Endocrinol., 2019, 7(2), 140-149.
[http://dx.doi.org/10.1016/S2213-8587(18)30128-1] [PMID: 30005958]
[21]
Lee, H.; Park, J.H.; Hoe, H.S. Idebenone regulates Aβ and LPS-induced neurogliosis and cognitive function through inhibition of NLRP3 inflammasome/IL-1β axis activation. Front. Immunol., 2022, 13, 749336.
[http://dx.doi.org/10.3389/fimmu.2022.749336] [PMID: 35222363]
[22]
Shastri, S.; Shinde, T.; Sohal, S.S.; Gueven, N.; Eri, R. Idebenone protects against acute murine colitis via antioxidant and anti-inflammatory mechanisms. Int. J. Mol. Sci., 2020, 21(2), 484.
[http://dx.doi.org/10.3390/ijms21020484] [PMID: 31940911]
[23]
Avcı, B.; Günaydın, C.; Güvenç, T.; Yavuz, C.K.; Kuruca, N.; Bilge, S.S. Idebenone Ameliorates Rotenone-induced Parkinson's disease in rats through decreasing lipid peroxidation. Neurochem. Res., 2021, 46(3), 513-522.
[24]
Yan, A.; Liu, Z.; Song, L.; Wang, X.; Zhang, Y.; Wu, N.; Lin, J.; Liu, Y.; Liu, Z. Idebenone alleviates neuroinflammation and modulates microglial polarization in LPS-stimulated BV2 cells and MPTP-induced Parkinson’s disease mice. Front. Cell. Neurosci., 2019, 12, 529.
[http://dx.doi.org/10.3389/fncel.2018.00529] [PMID: 30687016]
[25]
Linenberg, I.; Fornes, D.; Higa, R.; Jawerbaum, A.; Capobianco, E. Intergenerational effects of the antioxidant Idebenone on the placentas of rats with gestational diabetes mellitus. Reprod. Toxicol., 2021, 104, 16-26.
[http://dx.doi.org/10.1016/j.reprotox.2021.06.013] [PMID: 34175429]
[26]
Klionsky, D.J.; Petroni, G.; Amaravadi, R.K.; Baehrecke, E.H.; Ballabio, A.; Boya, P.; Bravo-San Pedro, J.M.; Cadwell, K.; Cecconi, F.; Choi, A.M.K.; Choi, M.E.; Chu, C.T.; Codogno, P.; Colombo, M.I.; Cuervo, A.M.; Deretic, V.; Dikic, I.; Elazar, Z.; Eskelinen, E.L.; Fimia, G.M.; Gewirtz, D.A.; Green, D.R.; Hansen, M.; Jäättelä, M.; Johansen, T.; Juhász, G.; Karantza, V.; Kraft, C.; Kroemer, G.; Ktistakis, N.T.; Kumar, S.; Lopez-Otin, C.; Macleod, K.F.; Madeo, F.; Martinez, J.; Meléndez, A.; Mizushima, N.; Münz, C.; Penninger, J.M.; Perera, R.M.; Piacentini, M.; Reggiori, F.; Rubinsztein, D.C.; Ryan, K.M.; Sadoshima, J.; Santambrogio, L.; Scorrano, L.; Simon, H.U.; Simon, A.K.; Simonsen, A.; Stolz, A.; Tavernarakis, N.; Tooze, S.A.; Yoshimori, T.; Yuan, J.; Yue, Z.; Zhong, Q.; Galluzzi, L.; Pietrocola, F. Autophagy in major human diseases. EMBO J., 2021, 40(19), e108863.
[http://dx.doi.org/10.15252/embj.2021108863] [PMID: 34459017]
[27]
Mizushima, N.; Levine, B. Autophagy in human diseases. N. Engl. J. Med., 2020, 383(16), 1564-1576.
[http://dx.doi.org/10.1056/NEJMra2022774] [PMID: 33053285]
[28]
Allaire, M.; Rautou, P.E.; Codogno, P.; Lotersztajn, S. Autophagy in liver diseases: Time for translation? J. Hepatol., 2019, 70(5), 985-998.
[http://dx.doi.org/10.1016/j.jhep.2019.01.026] [PMID: 30711404]
[29]
Su, L.; Zhang, J.; Gomez, H.; Kellum, J.A.; Peng, Z. Mitochondria ROS and mitophagy in acute kidney injury. Autophagy, 2023, 19(2), 401-414.
[http://dx.doi.org/10.1080/15548627.2022.2084862] [PMID: 35678504]
[30]
Yun, H.R.; Jo, Y.H.; Kim, J.; Shin, Y.; Kim, S.S.; Choi, T.G. Roles of autophagy in oxidative stress. Int. J. Mol. Sci., 2020, 21(9), 3289.
[http://dx.doi.org/10.3390/ijms21093289] [PMID: 32384691]
[31]
Li, X.; He, S.; Ma, B. Autophagy and autophagy-related proteins in cancer. Mol. Cancer, 2020, 19(1), 12.
[http://dx.doi.org/10.1186/s12943-020-1138-4] [PMID: 31969156]
[32]
Yang, J.; Pi, C.; Wang, G. Inhibition of PI3K/Akt/mTOR pathway by apigenin induces apoptosis and autophagy in hepatocellular carcinoma cells. Biomed. Pharmacother., 2018, 103, 699-707.
[http://dx.doi.org/10.1016/j.biopha.2018.04.072] [PMID: 29680738]
[33]
Kma, L.; Baruah, T.J. The interplay of ROS and the PI3K/Akt pathway in autophagy regulation. Biotechnol. Appl. Biochem., 2022, 69(1), 248-264.
[http://dx.doi.org/10.1002/bab.2104] [PMID: 33442914]
[34]
Tong, C.; Wu, Y.; Zhang, L.; Yu, Y. Insulin resistance, autophagy and apoptosis in patients with polycystic ovary syndrome: Association with PI3K signaling pathway. Front. Endocrinol. (Lausanne), 2022, 13, 1091147.
[http://dx.doi.org/10.3389/fendo.2022.1091147] [PMID: 36589825]
[35]
Rong, L.; Li, Z.; Leng, X.; Li, H.; Ma, Y.; Chen, Y.; Song, F. Salidroside induces apoptosis and protective autophagy in human gastric cancer AGS cells through the PI3K/Akt/mTOR pathway. Biomed. Pharmacother., 2020, 122, 109726.
[http://dx.doi.org/10.1016/j.biopha.2019.109726] [PMID: 31918283]
[36]
Tang, L.; Zhang, C.; Lu, L.; Tian, H.; Liu, K.; Luo, D.; Qiu, Q.; Xu, G.T.; Zhang, J. Melatonin maintains inner blood–retinal barrier by regulating Microglia via inhibition of PI3K/Akt/Stat3/NF-κB signaling pathways in experimental diabetic retinopathy. Front. Immunol., 2022, 13, 831660.
[http://dx.doi.org/10.3389/fimmu.2022.831660] [PMID: 35371022]
[37]
Daley, R.; Maddipatla, V.; Ghosh, S.; Chowdhury, O.; Hose, S.; Zigler, J.S., Jr; Sinha, D.; Liu, H. Aberrant Akt2 signaling in the RPE may contribute to retinal fibrosis process in diabetic retinopathy. Cell Death Discov., 2023, 9(1), 243.
[http://dx.doi.org/10.1038/s41420-023-01545-4] [PMID: 37443129]

Rights & Permissions Print Cite
Article Metrics
Pdf icon 31
Html icon 2
Find your institution