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

Abstract

Retinal ischemia-reperfusion (I/R) injury is a common cause of visual impairment. To date, no effective treatment is available for retinal I/R injury. In addition, the precise pathological mechanisms still need to be established. Recently, pemafibrate, a peroxisome proliferator-activated receptor α (PPARα) modulator, was shown to be a promising drug for retinal ischemia. However, the role of pemafibrate in preventing retinal I/R injury has not been documented. Here, we investigated how retinal degeneration occurs in a mouse model of retinal I/R injury by elevation of intraocular pressure and examined whether pemafibrate could be beneficial against retinal degeneration. Adult mice were orally administered pemafibrate (0.5 mg/kg/day) for 4 days, followed by retinal I/R injury.The mice were continuously administered pemafibrate once every day until the end of the experiments. Retinal functional changes were measured using electroretinography. Retina, liver, and serum samples were used for western blotting, quantitative PCR, immunohistochemistry, or enzyme linked immunosorbent assay. Retinal degeneration induced by retinal inflammation was prevented by pemafibrate administration. Pemafibrate administration increased the hepatic PPARα target gene expression and serum levels of fibroblast growth factor 21, a neuroprotective molecule in the eye. The expression of hypoxia-response and pro-and anti-apoptotic/inflammatory genes increased in the retina following retinal I/R injury; however, these changes were modulated by pemafibrate administration. In conclusion, pemafibrate is a promising preventive drug for ischemic retinopathies.

Nicotinamide Mononucleotide Prevents Retinal Dysfunction in a Mouse Model of Retinal Ischemia/Reperfusion Injury

“…Previously, we found pathologic increases in isolectin GS-IB4 (IB4)-positive inflammatory cells in the retina five days after retinal I/R injury [ 13 ]. Therefore, we examined whether the likelihood of its occurrence could be lessened by NMN treatment ( Figure 2 A,B).…”

“…Previous reports from us and others have suggested that reductions in pathologic retinal inflammatory cells could be beneficial for retinal neuronal protection in a murine model of retinal I/R injury [ 13 , 32 , 33 ]. The therapeutic strategy of modulating pathologic inflammatory cells for neuroprotection can be seen in brain injury, rather than just retinal I/R injury [ 34 , 35 , 36 ].…”

“…Adult male mice (C57BL/6, 6–8 weeks old) were bought from CLEA Japan (Tokyo, Japan). After mouse randomization, retinal I/R injury was induced in their eyes, as described in our previous paper [ 13 ]. Briefly, anterior chamber cannulation was performed using a 35-gauge needle, and high intraocular pressure was maintained by PBS solution for 40 min.…”

“…General scotopic ERG was performed as described in our previous retinal I/R injury study [ 13 ]. After 24 h of dark adaptation, the mice were placed on a Ganzfeld dome table under dimly lit conditions.…”

“…IHC was performed as described in our previous retinal I/R injury study [ 13 ]. Briefly, after paraformaldehyde (4% PFA) fixation for more than 3 h, the mouse eyeballs were moved to a Petri dish with cold PBS.…”