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

Abstract

Cardiovascular diseases lead to retinal ischemia, one of the leading causes of blindness. Retinal ischemia triggers pathological retinal glial responses and functional deficits. Therefore, maintaining retinal neuronal activities and modulating pathological gliosis may prevent loss of vision. Previously, pemafibrate, a selective peroxisome proliferator-activated receptor alpha modulator, was nominated as a promising drug in retinal ischemia. However, a protective role of pemafibrate remains untouched in cardiovascular diseases-mediated retinal ischemia. Therefore, we aimed to unravel systemic and retinal alterations by treating pemafibrate in a new murine model of retinal ischemia caused by cardiovascular diseases. Adult C57BL/6 mice were orally administered pemafibrate (0.5 mg/kg) for 4 days, followed by unilateral common carotid artery occlusion (UCCAO). After UCCAO, pemafibrate was continuously supplied to mice until the end of experiments. Retinal function (a-and b-waves and the oscillatory potentials) was measured using electroretinography on day 5 and 12 after UCCAO. Moreover, the retina, liver, and serum were subjected to qPCR, immunohistochemistry, or ELISA analysis. We found that pemafibrate enhanced liver function, elevated serum levels of fibroblast growth factor 21 (FGF21), one of the neuroprotective molecules in the eye, and protected against UCCAO-induced retinal dysfunction, observed with modulation of retinal gliosis and preservation of oscillatory potentials. Our current data suggest a promising pemafibrate therapy for the suppression of retinal dysfunction in cardiovascular diseases.

Clinically Relevant Dose of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα), Lowers Serum Triglyceride Levels by Targeting Hepatic PPARα in Mice

“…We found that PEM at the relatively high dose (0.3 mg/kg/day) caused serum ALT increase and histological alterations, such as sinusoidal narrowing, increased binuclear hepatocytes, and bizarre eosinophilic hepatocytes. There were no obvious data regarding hepatotoxicity in the previous studies of mice treated with more than 0.3 mg/kg/day of PEM [22][23][24]38,61], while apparent hepatotoxicity was not reported in the previous mouse studies at 0.1 mg/kg/day or less of PEM [55,56], which is consistent with the results in the current study. Therefore, the clinically relevant dose of PEM (0.1 mg/kg/day) used in the present study is likely appropriate to evaluate the action of PEM using mice, from the viewpoint of not only pharmacodynamic similarity to humans but also hepatotoxicity.…”

Retinal degeneration induced in a mouse model of ischemia–reperfusion injury and its management by pemafibrate treatment

“…Serum levels of triglycerides (TG), total cholesterol (TC), and fibroblast growth factor 21 (FGF21) were measured, as previously described. 23,28,32 An FGF21 enzyme linked immunosorbent assay (ELISA) kit (Cat #RD291108200R, BioVendor Laboratory Medicine, Brno, Czech Republic), TC kit (Cat #STA-384, Cell Biolabs, Inc., San Diego, CA, USA), and TG kit (Cat #STA-396, Cell Biolabs, Inc.) were used by following the manufacturer's instructions.…”

PPARα Modulation-Based Therapy in Central Nervous System Diseases

“…In the disease state of an ocular ischemic syndrome (OIS), little is known about the therapeutic roles of PPARα activation. Nonetheless, based on our recent studies, fenofibrate and pemafibrate showed neuroprotective effects (analyzed by electroretinography) via boosting liver PPARα function with systemic induction of FGF21, which is one of the neuroprotective molecules in the CNS [101,102]. Furthermore, pemafibrate treatment exerted the modulation of pathological gliosis in the ischemic retina to reduce ischemic damages in the inner retina [102].…”

“…Nonetheless, based on our recent studies, fenofibrate and pemafibrate showed neuroprotective effects (analyzed by electroretinography) via boosting liver PPARα function with systemic induction of FGF21, which is one of the neuroprotective molecules in the CNS [101,102]. Furthermore, pemafibrate treatment exerted the modulation of pathological gliosis in the ischemic retina to reduce ischemic damages in the inner retina [102]. Although the functions of PPARα were only examined in the liver and retina, we suspect that PPARα activation by pemafibrate/fenofibrate may not be limited to the liver.…”