PPARα Agonist Oral Therapy in Diabetic Retinopathy

Abstract

Diabetic retinopathy (DR) is an eye condition that develops after chronically poorly-managed diabetes, and is presently the main cause for blindness on a global scale. Current treatments for DR such as laser photocoagulation, topical injection of corticosteroids, intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents and vitreoretinal surgery are only applicable at the late stages of DR and there are possibilities of significant adverse effects. Moreover, the forms of treatment available for DR are highly invasive to the eyes. Safer and more effective pharmacological treatments are required for DR treatment, in particular at an early stage. In this review, we cover recently investigated promising oral pharmacotherapies, the methods of which are safer, easier to use, patient-friendly and pain-free, in clinical studies. We especially focus on peroxisome proliferator-activator receptor alpha (PPARα) agonists in which experimental evidence suggests PPARα activation may be closely related to the attenuation of vascular damages, including lipid-induced toxicity, inflammation, an excess of free radical generation, endothelial dysfunction and angiogenesis. Furthermore, oral administration of selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) agonists may induce hepatic fibroblast growth factor 21 expression, indirectly resulting in retinal protection in animal studies. Our review will enable more comprehensive approaches for understanding protective roles of PPARα for the prevention of DR development.

Fenofibrate Protects against Retinal Dysfunction in a Murine Model of Common Carotid Artery Occlusion-Induced Ocular Ischemia

“…Then, we examined expressions of PPARα downstream genes in mice ( Figure A4 ). The retina and the liver were used as expected target sites, in that the retina is our region of interest and the liver has been widely known to be associated with fenofibrate-related PPARα activation [ 31 , 32 , 33 ]. PPARα downstream genes such as Fgf21 and Acox1 were significantly upregulated in the fenofibrate-administered liver, compared with those in the vehicle-administered liver ( Figure A4 ).…”

“…FGF21 exerts a therapeutic effect on glucose and lipid metabolism in mice [ 50 ]. Therefore, a phase 2B clinical trial has been investigated to examine whether pegbelfermin (a novel long-acting FGF21) has therapeutic effects on nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) [ 31 ]. A previous study demonstrated that FGF21 had a synergistic effect with insulin on glucose absorption that is in accordance with enhanced Glut1 expression [ 51 ].…”

Pemafibrate Prevents Retinal Dysfunction in a Mouse Model of Unilateral Common Carotid Artery Occlusion

“…Next, the liver was targeted as it has been known as a region for pemafibrate-induced PPARα activation [24,38,39]. The livers in pemafibrate-administered UCCAO-operated mice seemed larger than those in PBS-administered UCCAO-operated mice while we collected the samples.…”

“…Peroxisome proliferator-activated receptor alpha (PPARα) is a well-known drug against hyperlipidemia. This agent can potentially reduce triglyceride levels and increase high-density lipoprotein cholesterol (HDL-C) levels [24]. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and The Action to Control Cardiovascular Risk in Diabetes (ACCORD) eye studies showed that fenofibrate, a well-known PPARα agonist, reduced the need for laser therapy and progression of diabetic retinopathy [25,26].…”

Improved Survival and Retinal Function of Aging ZDF Rats in Long-Term, Uncontrolled Diabetes by BGP-15 Treatment

“…It is a remarkable novelty of our present study that BGP-15 is able to counteract the detrimental effect of long-term diabetes on the functioning of the retina of ZDF rats. Such retinal protection in diabetes is usually seen in case of neuropeptides, trophic factors, antioxidants, or in case of agents with anti-inflammatory action (Varga et al, 2011;Varga et al, 2013;Varga et al, 2017;Tomita et al, 2020). Although BGP is not a neuropeptide, nor a trophic factor, it might exert some antioxidant or anti-inflammatory properties on the retina as described before on non-retinal cell lines (Sumegi et al, 2017).…”