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Diabetic retinopathy (DR) is a common neurovascular complication of type 1 diabetes. Current therapeutics target neovascularization characteristic of end-stage disease, but are associated with significant adverse effects. Targeting early events of DR such as neurodegeneration may lead to safer and more effective approaches to treatment. Two indepen...
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... found that at 28 weeks diabetic, retinal levels of antioxi- dant enzymes Gsm1, Prdx6 and Txnrd1 were increased in WT STZ mice, and further increased in Pparα -/-STZ mice (p � 0.05) (Fig 7). Full gene names are shown in Table 1. Cat was signifi- cantly increased in Pparα -/-diabetic mice relative to wild-type diabetic mice (p � 0.05). ...
Citations
... Moreover, some studies indicate that fenofibrate is an independent protective factor for the development of diabetic retinopathy and neuropathy. [9][10][11] Data on the effects of fenofibrate in subjects with T1D are very limited. However, preliminary reports are promising. ...
Introduction
Sphingolipids regulate proinsulin folding, insulin secretion and control beta cells apoptosis. Recent evidence has demonstrated that, among other factors, reduced amounts of sulfatide may be relevant in the development of type 1 diabetes (T1D). Thus, fenofibrate, which activates sulfatide biosynthesis, may prolong remission in subjects with T1D. The aim of the study is to evaluate clinical efficacy of fenofibrate on the maintenance of residual beta-cell function in children with newly diagnosed T1D.
Methods and analysis
A total of 102 children aged 10–17 years with newly diagnosed T1D will be enrolled in a double-blind, two-centre randomised, non-commercial, placebo-controlled trial. Subjects who will meet all inclusion criteria will be randomly assigned to receive fenofibrate at a dose of 160 mg or an identically appearing placebo, orally, once daily, for 12 months. The primary endpoint will be the area under the curve of the C-peptide level during 2-hour responses to a mixed-meal tolerance test (MMTT). Secondary endpoints include fasting and maximum C-peptide concentration in the MMTT, parameters of diabetes control and glucose fluctuations, daily insulin requirement, inflammation markers, genetic analysis, safety and tolerance of the fenofibrate
Ethics and dissemination
The study protocol was approved by the Bioethics Committee. The results of this study will be submitted to a peer-reviewed diabetic journal. Abstracts will be submitted to international and national conferences.
Trial registration number
EnduraCT 2020-003916-28.
... Endogenous neuroprotective agents, including insulin-like growth factor 1 [5], pigment epithelium-derived factor (PEDF) [101], somatostatin (SST), pituitary adenylate-cyclaseactivating polypeptide (PACAP), glucagon-like peptide-1 (GLP-1), and neurotrophins such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), are potential neuroprotective factors for DR [39,102]. Peroxisome proliferator-activator receptor alpha (PPARα) has been identified as a putative therapeutic target for retinopathy in type 1 and 2 diabetes [103,104]. Fenofibrate, a PPARα agonist, manifests unprecedented neuroprotective effects in DR with type 1 diabetes [103]. Further studies are needed to examine the protection and maintenance of RGC morphology and physiology. ...
... Peroxisome proliferator-activator receptor alpha (PPARα) has been identified as a putative therapeutic target for retinopathy in type 1 and 2 diabetes [103,104]. Fenofibrate, a PPARα agonist, manifests unprecedented neuroprotective effects in DR with type 1 diabetes [103]. Further studies are needed to examine the protection and maintenance of RGC morphology and physiology. ...
Diabetic retinopathy (DR), the most common microvascular complication that occurs in diabetes mellitus (DM), is the leading cause of vision loss in working-age adults. The prevalence of diabetic retinopathy is approximately 30% of the diabetic population and untreated DR can eventually cause blindness. For decades, diabetic retinopathy was considered a microvascular complication and clinically staged by its vascular manifestations. In recent years, emerging evidence has shown that diabetic retinopathy causes early neuronal dysfunction and neurodegeneration that may precede vascular pathology and affect retinal neurons as well as glial cells. This knowledge leads to new therapeutic strategies aiming to prevent dysfunction of retinal neurons at the early stage of DR. Early detection and timely treatment to protect retinal neurons are critical to preventing visual loss in DR. This review provides an overview of DR and the structural and functional changes associated with DR, and discusses neuronal degeneration during diabetic retinopathy, the mechanisms underlying retinal neurodegeneration and microvascular complications, and perspectives on current and future clinic therapies.
... PPARα activation by fenofibrate in animal and cell models showed protective anti-inflammatory and antiapoptotic effects in endothelial cells, pericytes and RPE cells, which seem to be independent of the lipidreducing effect. PPARα overexpression in the retina of diabetic rats markedly attenuated retinal leakage and retinitis induced by diabetes, was neuroprotective and prevented the atrophy of pericytes [71,76,77]. Moreover, the overexpression of PPARα was found to inhibit the migration and proliferation of endothelial cells [40]. ...
Diabetes mellitus is a very important social issue, and its retinal complications continue to be one of the major causes of blindness worldwide. The effect of glucose level on the development of retinal retinopathy has been the subject of numerous studies and is well understood. Hypertension and hyperlipidemia have been known to be important risk factors in the development of diabetes complications. However, the mechanisms of this effect have not been fully explained and raise a good deal of controversy. The latest research results suggest that some lipoproteins are closely correlated with the incidence of diabetic retinopathy and that by exerting an impact on their level the disease course can be modulated. Moreover, pharmacotherapy which reduces the level of lipids, particularly by means of statins and fibrate, has been shown to alleviate diabetic retinopathy. Therefore, we have decided to review the latest literature on diabetic retinopathy with respect to the impact of hyperlipidemia and possible preventive measures
... Two landmark clinical trials have brought fenofibrate back to the forefront of attention: The Fenofibrate Intervention and Event Lowing in Diabetes (FIELD) [1] and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) [2] previously reported that oral administration of fenofibrate could delay the progression of DR and reduce retinal laser intervention in patients with DR. In addition, many animal model studies have also reported the beneficial effects of the oral administration of fenofibrate on DR [3,4]. Despite these benefits shown, careful attention should be paid to skeletal muscle injury if hypolipidemic drugs, including fenofibrate, are administered systemically. ...
We investigated the effect of fenofibrate nano-eyedrops (FenoNano) on impaired retinal blood flow regulation in type 2 diabetic mice. Six-week-old db/db mice were randomly divided into an untreated group (n = 6) and treated group, which received FenoNano (n = 6). The longitudinal changes in retinal neuronal function and blood flow responses to systemic hyperoxia and flicker stimulation were evaluated every 2 weeks in diabetic db/db mice treated with FenoNano (n = 6) or the vehicle (n = 6) from ages 8–14 weeks. The retinal blood flow was assessed using laser speckle flowgraphy. We also evaluated the expressions of vascular endothelial growth factor (VEGF), glial fibrillary acidic protein (GFAP), and aquaporin 4 (AQP4) and the phosphorylation of peroxisome proliferator-activated receptor alpha (PPAR-α) by immunofluorescence. In db/db mice treated with FenoNano, both responses were restored from 8 to 14 weeks of age compared with the diabetic mice treated with the vehicle. At 14 weeks of age, the impaired regulation of retinal blood flow during systemic hyperoxia and flicker stimulation improved to about half of that in the db/db mice treated with FenoNano compared with the db/m control group (n = 5). FenoNano prevented the activation of VEGF and GFAP expression and increased the AQP4 expression and the phosphorylation of PPAR-α detected by immunofluorescence compared with the diabetic mice treated with the vehicle eyedrop. Our results suggested that the fenofibrate nano-eyedrops prevent retinal glial dysfunction via the phosphorylation of PPAR-α and improves the retinal blood flow dysregulation in type 2 diabetic mice.
... Other pathogenic mechanism of hyperglycemia is the alteration of superoxide-generating enzyme system, which was also corrected with the treatment of Fenofibrate. They also suggested that Fenofibrate could prevent the retinal vascular leakage in diabetic C57BL/6J-Ins2 Akita mice, which is one of the hallmark complications of DR. Pearsall et al. (2019) found that long term treatment with Fenofibrate could boost the visual acuity which was lost once and verified using optokinetic tracking in streptozocin (STZ)-induced brown norway (BN) rats. A reduction in the retinal apoptosis was also demonstrated in STZ induced BN rats through deoxyribonucleic acid (DNA) fragmentation and ELISA. ...
... They also are suggesting that Fenofibrate inhibit the Wnt/β-catenin cascade in a PPARα -dependent manner. Similarly, Pearsall et al. (2019) found that this medication could also improve the mitochondrial functioning, thereby adding a neuroprotective effect in type 1 DR. The imbalance between increased superoxide generation and decreased antioxidant properties would result in ROS production and it is found to be detrimental to the retinal neuronal cells. ...
Fenofibrate is a peroxisome-proliferator-activator α agonist and it is a widely used drug for hyperlipidemia since its approval in 2004. So, in this review we are focusing on the effect of fenofibric acid’s mechanism to alleviate type 1 diabetic micro vascular complications like diabetic retinopathy, diabetic cardiomyopathy in animal models, since the drug is safe, efficacious and more economical when compared with the currently available treatment strategies for juvenile diabetic complications and also a profound observation is needed due to the rarity of research in these therapeutic areas. Important preclinical animal studies published from January 2001 to June 2020 were recognised from databases like PubMed and Cochrane central register of controlled trials. Reviewers screened the articles based on the selection criteria and risk of bias was determined using Systematic Review Centre for Laboratory animal Experimentation risk of bias tool for animal studies. Our literature search yielded a total of 5 studies and after pooling up the data from the 5 preclinical studies, we found that Fenofibrate have the efficacy to prevent type 1 diabetic complications, chiefly diabetic retinopathy and those mechanisms are dependent on peroxisome-proliferator-activator and fibroblast growth factor-21 pathways. Fenofibrate is a well safe and moreover, cost effective medication in preventing type 1 diabetic micro vascular complications especially diabetic retinopathy and also in maintaining the glucose homeostasis in apart from its anti-dyslipidemic effect.
... Furthermore, PPARα-dependent therapeutic effects of fenofibrate on DR were confirmed using Pparα knockout animals [69]. The same group further demonstrated the neuroprotective effects of PPARα activation in the retinopathy of type 1 diabetes mellitus [70]. The oral administration of fenofibrate protected against visual dysfunction (analyzed by spatial frequency threshold), and intraperitoneal injection of fenofibric acid (a PPARα activator) reduced retinal apoptosis (analyzed by DNA fragmentation assay) [70]. ...
... The same group further demonstrated the neuroprotective effects of PPARα activation in the retinopathy of type 1 diabetes mellitus [70]. The oral administration of fenofibrate protected against visual dysfunction (analyzed by spatial frequency threshold), and intraperitoneal injection of fenofibric acid (a PPARα activator) reduced retinal apoptosis (analyzed by DNA fragmentation assay) [70]. Furthermore, using in vitro R28 cells (immortalized rat retinal precursor cells), the restoration of mitochondrial respiration by PPARα activation was confirmed under 4-hydroxynonenal (4-HNE)-induced oxidative stress condition [70]. ...
... The oral administration of fenofibrate protected against visual dysfunction (analyzed by spatial frequency threshold), and intraperitoneal injection of fenofibric acid (a PPARα activator) reduced retinal apoptosis (analyzed by DNA fragmentation assay) [70]. Furthermore, using in vitro R28 cells (immortalized rat retinal precursor cells), the restoration of mitochondrial respiration by PPARα activation was confirmed under 4-hydroxynonenal (4-HNE)-induced oxidative stress condition [70]. As pericyte loss has been reported to occur in the early stage of DR and plays a critical role in its progression [71][72][73], the protective roles of PPARα were also examined in capillary pericytes in the diabetic retina by the same group [74]. ...
The burden of neurodegenerative diseases in the central nervous system (CNS) is increasing globally. There are various risk factors for the development and progression of CNS diseases, such as inflammatory responses and metabolic derangements. Thus, curing CNS diseases requires the modulation of damaging signaling pathways through a multitude of mechanisms. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors (PPARα, PPARβ/δ, and PPARγ), and they work as master sensors and modulators of cellular metabolism. In this regard, PPARs have recently been suggested as promising therapeutic targets for suppressing the development of CNS diseases and their progressions. While the therapeutic role of PPARγ modulation in CNS diseases has been well reviewed, the role of PPARα modulation in these diseases has not been comprehensively summarized. The current review focuses on the therapeutic roles of PPARα modulation in CNS diseases, including those affecting the brain, spinal cord, and eye, with recent advances. Our review will enable more comprehensive therapeutic approaches to modulate PPARα for the prevention of and protection from various CNS diseases.
... In diabetic Müller cell culture, high glucose levels and oxidative stress induced GFAP expression [47] . Muller cell expression increased in the DR in response to retinal inflammation [48] and toxic ROS release [49] . Müller cells produced and secreted cytokines that induced retinal neuronal and vascular cell dysfunction [48] . ...
... MSCs, according to Gaddam et al. [67] , may be a highly effective treatment for diabetic retinopathy. The therapeutic benefit of MSCs could be due to their ability to differentiate into various types of retinal cells, including Ganglion cells [8] , improved integrity of the blood-retinal barrier [68] , and the secretion of anti-inflammatory and neuroprotective mediators [49] . MSCs have the ability to differentiate into pericytes and incorporate into the retinal blood vessels [69] . ...
... Furthermore, our findings revealed that CMS inhibited oxidative stress and inflammatory response in rats with DR by activating SIRT1, as indicated by the decreased levels of ROS, MDA, iNOS, NO, and other inflammatory factors as well as an increased activity of SOD. Induction of ROS production a resultant mitochondrial dysfunction is a major causative factor of retinal cell death in DR [20]. DR has also been regarded as a stimulator for the release of pro-inflammatory cytokines including IL-1β, IL-6 and TNF-α [21,22]. ...
Diabetes-induced oxidative stress is vital in initiating neuronal damage in the diabetic retina, leading to diabetic retinopathy (DR). This study investigates the possible effects of coumestrol (CMS) on streptozotocin (STZ)-induced DR. First, we established a rat model of DR by STZ injection and a cell model involving high-glucose (HG) exposure of human retinal microvascular endothelial cells (hRMECs). We characterized the expression patterns of oxidative stress indicators, pro-inflammatory cytokines, and pro-apoptotic proteins in hRMECs. Polymerase chain reaction showed sirtuin 1 (SIRT1) to be poorly expressed in the retinal tissues of STZ-treated rats and HG-exposed hRMECs, but its expression was upregulated upon treatment with CMS treatment. Furthermore, CMS treatment attenuated the STZ-induced pathologies such as oxidative stress, inflammation, and cell apoptosis. Consistent with the in vivo results, CMS activated the expression of SIRT1, thereby inhibiting oxidative stress, inflammation, and apoptosis of HG-treated hRMECs. From these findings, we concluded that CMS ameliorated DR by inhibiting inflammation, apoptosis and oxidative stress through activation of SIRT1.
... For example, fenofibrate was shown to inhibit palmitate-induced myocardial apoptosis in mice [39]. Moreover, a recent study showed that daily intraperitoneal injection of fenofibric acid significantly decreased retinal apoptosis in STZ-induced diabetes [40]. Hence, long-term studies will be needed to support the idea that pemafibrate has potential for treatment of diabetic retinopathy since apoptosis is involved in the pathophysiology of this disease [41]. ...
Excitotoxicity is involved in the retinal neuronal cell death in diabetic retinopathy. Although fenofibrate has been shown to ameliorate the progression of diabetic retinopathy, the effect of pemafibrate, which is highly selective for peroxisome proliferator-activated receptor α on retinal neuronal cell death has not been documented. Here, we investigated whether pemafibrate exerts a beneficial effect against retinal ganglion cell (RGC) death induced by N-methyl-D-aspartate (NMDA) in rats. Experiments were performed on adult male Wistar rats that received an intravitreal injection of 20 nmol NMDA. Fluoro-Gold labeled RGC morphometry showed that oral intake of pemafibrate once a day for 7 days resulted in significant protection on RGC death induced by NMDA. Phosphorylated c-Jun protein, which is involved in apoptosis, was upregulated after NMDA exposure, and this increase was significantly lessened by the systemic pemafibrate treatment. Phosphorylated c-Jun immunopositive cells were colocalized with Thy-1 immunopositive cells, and the increased these cells were ameliorated by the pemafibrate treatment. An increase in TUNEL-positive cells was significantly suppressed by the pemafibrate treatment. Phosphorylated c-Jun immunopositive cells were colocalized with TUNEL-positive cells, and they were decreased by pemafibrate treatment. These results suggest that the RGC protection achieved with pemafibrate appears to be associated with inhibition of phosphorylated c-Jun and its anti-apoptotic effect.
... Functional data suggest that fenofibrate plays a protective role in mouse and rat models of DR. Electroretinography (ERG) studies of db/db mice (a model of type 2 diabetes) at two and five months of age demonstrated reductions in b-wave amplitudes that improved with fenofibrate treatment, and fenofibrate partially rescued a decline in visual function as assessed by optokinetic (OKN) drum in rats treated with streptozotocin (STZ, a model of type 1 diabetes) [8][9][10]. These functional data support the use of animal models in studying the molecular pathways underlying the protective effect of fenofibrate in DR. ...
... Further, PPARα appears to be essential for normal retinal function, with PPARα knockout (KO) mice showing reduced b-wave amplitudes, capillary dropout and leakage, increased leukocyte adhesion and increased levels of vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF) and intracellular adhesion molecule (ICAM) [11,12]. These features are worsened in the setting of STZ-induced diabetes [8]. Several protective effects of fenofibrate appear to be dependent on PPARα. ...
... Our results confirm that oral fenofibrate alters metabolism in a mouse model of type 2 diabetes by altering circulating lipids, modulating gliosis and improving ERG abnormalities. Our findings are consistent with changes reported in other models of type 1 and type 2 diabetes, and models of retinopathy of prematurity [8][9][10]15,17,34,35]. These data lend further support to pursuing fenofibrate as a treatment for DR in patients. ...
Fenofibrate slows the progression of clinical diabetic retinopathy (DR), but its mechanism of action in the retina remains unclear. Fenofibrate is a known agonist of peroxisome proliferator-activated receptor alpha (PPARα), a transcription factor critical for regulating metabolism, inflammation and oxidative stress. Using a DR mouse model, db/db, we tested the hypothesis that fenofibrate slows early DR progression by activating PPARα in the retina. Relative to healthy littermates, six-month-old db/db mice exhibited elevated serum triglycerides and cholesterol, retinal gliosis, and electroretinography (ERG) changes including reduced b-wave amplitudes and delayed oscillatory potentials. These pathologic changes in the retina were improved by oral fenofibrate. However, fenofibrate did not induce PPARα target gene expression in whole retina or isolated Müller glia. The capacity of the retina to respond to PPARα was further tested by delivering the PPARα agonist GW590735 to the intraperitoneal or intravitreous space in mice carrying the peroxisome proliferator response element (PPRE)-luciferase reporter. We observed strong induction of the reporter in the liver, but no induction in the retina. In summary, fenofibrate treatment of db/db mice prevents the development of early DR but is not associated with induction of PPARα in the retina.
