Caffeic Acid Alkyl Amide Derivatives Ameliorate Oxidative Stress and Modulate ERK1/2 and AKT Signaling Pathways in a Rat Model of Diabetic Retinopathy

Abstract

The purpose of this study was to examine the neuroprotective effects of caffeic acid hexyl (CAF6) and dodecyl (CAF12) amide derivatives on the early stage of retinopathy in streptozotocin-induced diabetic rats. Animals were divided in five groups (n = 8/group); one group consisted of non-diabetic rats as control, while the other four were diabetic animals either non-treated or treated with CAF6, CAF12 or resveratrol intravitreally for four weeks. Retinal superoxide dismutase (SOD) activity and 8-iso-prostaglandin F 2α (iPF 2α ) levels were evaluated by an ELISA assay. Phosphorylation of ERK1/2 and AKT was determined by immunoblotting in retinal homogenates. Retinal morphology was also examined using light microscopy. Treatment with CAF6 and CAF12 increased retinal SOD activity, while it decreased iPF 2α levels in diabetic rats. Phosphorylation of ERK1/2 was increased, while AKT phosphorylation was decreased in diabetic rats compared to normal control and these alterations were significantly reversed in diabetic rats treated with CAF6 and CAF12. Furthermore, thickness of the whole retinal layer, outer nuclear layer, and ganglion cell count were decreased in diabetic rats compared to control and CAF6 and CAF12 treatments prevented these changes. CAF6 and CAF12 seem to be effective agents for treatment of diabetic retinopathy via attenuation of retinal oxidative stress and improvement of neuronal survival signaling.

Resveratrol Improves Bnip3-Related Mitophagy and Attenuates High-Fat-Induced Endothelial Dysfunction

“…At the molecular level, two mechanisms involved in how resveratrol attenuates hyperlipemia-related cardiomyocyte injury have been reported: one is driven by upregulation of antioxidative factors and the other involves downregulation of pro-inflammation cytokines. For example, resveratrol attenuates lipid peroxidation (Jalili et al, 2019) through modulation of several antioxidative signaling pathways such as Nrf2 (Zhuang et al, 2019), Sirt1 (Liu et al, 2019a), Akt/mTOR (Radwan and Karam, 2020), and ERK1/2 (Fathalipour et al, 2019). In addition, the mRNA expression of inflammatory cytokines in diabetic mice are largely inhibited by resveratrol (Xing et al, 2020).…”

Update on the Effects of Antioxidants on Diabetic Retinopathy: In Vitro Experiments, Animal Studies and Clinical Trials

“…There is an increasing body of evidence about the role of antioxidants in the control of diabetic retinopathy in animal models ( Table 2 ) [ 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , …”

“…Retinal expressions of TNFα, IL-1 β, MCP-1, ICAM-1 and IL-6 are also diminished [ 91 , 92 , 93 ]. Caffeic acid hexyl (CAF6) and Dodecyl (CAF12) amides also have a neuroprotective effect [ 57 , 60 ].…”

Efficacy of Caffeic Acid on Diabetes and Its Complications in the Mouse

“…The pathological effect of alloxan is based on the selective inhibition of glucose-stimulated insulin secretion and ROS formation through the alloxan redox cycle, leading to selective apoptosis and necrosis in pancreatic β-cells. Furthermore, impaired red blood cell (RBC) deformability due to oxidative stress plays a key role in the pathogenesis of the chronic vascular complications of DM and renal failure progression [ 2 , 11 , 12 , 13 , 14 , 15 , 16 ]. Oxidative DNA damage associated with ROS include apurinic/apyrimidinic (abasic) DNA sites, oxidized purines and pyrimidines, and single-strand breaks (SSBs) and double-strand breaks (DSBs) in different tissues, including lymphocytes, kidney, heart, eyes, nerves, liver, small and large vessels, and the gastrointestinal system [ 2 , 11 , 14 , 15 , 16 , 17 , 18 ].…”

“…Furthermore, impaired red blood cell (RBC) deformability due to oxidative stress plays a key role in the pathogenesis of the chronic vascular complications of DM and renal failure progression [ 2 , 11 , 12 , 13 , 14 , 15 , 16 ]. Oxidative DNA damage associated with ROS include apurinic/apyrimidinic (abasic) DNA sites, oxidized purines and pyrimidines, and single-strand breaks (SSBs) and double-strand breaks (DSBs) in different tissues, including lymphocytes, kidney, heart, eyes, nerves, liver, small and large vessels, and the gastrointestinal system [ 2 , 11 , 14 , 15 , 16 , 17 , 18 ]. ROS may also damage DNA indirectly, through a reaction with lipids, proteins and other cellular components that produces electrophilic species that can react with DNA, leading to the development of diseases such as aging, cancer, CVD, immune system diseases and degenerative diseases [ 14 , 15 , 16 , 17 , 18 ].…”