Protective Effects of Oroxylin A on Retinal Ganglion Cells in Experimental Model of Anterior Ischemic Optic Neuropathy

Abstract

Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common cause of acute vision loss in older people, and there is no effective therapy. The effect of the systemic or local application of steroids for NAION patients remains controversial. Oroxylin A (OA) (5,7-dihydroxy-6-methoxyflavone) is a bioactive flavonoid extracted from Scutellariae baicalensis Georgi. with various beneficial effects, including anti-inflammatory and neuroprotective effects. A previous study showed that OA promotes retinal ganglion cell (RGC) survival after optic nerve (ON) crush injury. The purpose of this research was to further explore the potential actions of OA in ischemic injury in an experimental anterior ischemic optic neuropathy (rAION) rat model induced by photothrombosis. Our results show that OA efficiently attenuated ischemic injury in rats by reducing optic disc edema, the apoptotic death of retinal ganglion cells, and the infiltration of inflammatory cells. Moreover, OA significantly ameliorated the pathologic changes of demyelination, modulated microglial polarization, and preserved visual function after rAION induction. OA activated nuclear factor E2 related factor (Nrf2) signaling and its downstream antioxidant enzymes NAD(P)H:quinone oxidoreductase (NQO-1) and heme oxygenase 1 (HO-1) in the retina. We demonstrated that OA activates Nrf2 signaling, protecting retinal ganglion cells from ischemic injury, in the rAION model and could potentially be used as a therapeutic approach in ischemic optic neuropathy.

The Effects of Two Nrf2 Activators, Bardoxolone Methyl and Omaveloxolone, on Retinal Ganglion Cell Survival during Ischemic Optic Neuropathy

“…ROS expression has been reported in retinal ischemia or hypoxia, causing the loss of visual function and irreversible neuronal and axonal damage [46]. A previous study confirmed that increasing Nrf2 protein expression maintained the viability of RGCs in an rAION model [19,34]. In addition, Nrf2 activators have been approved by the FDA as drugs to treat kidney disease and relapsing-remitting multiple sclerosis [47][48][49].…”

“…Previous research has documented that ED-1-positive cells are found during ischemic injury to the optic nerve [ 19 , 34 ], enhancing microglia/macrophage transfer to their activated forms in order to secrete inflammatory cytokines and activate inflammation [ 50 ]. However, overactivated microglia provide excessive amounts of the inflammatory ligands IL-6, IL-1β, and TNF-α, causing ROS, iNOS, NFκB, and NLRP3 inflammatory complex activation; additionally, disruption of neuronal homeostasis was observed in ischemic optic neuropathy [ 11 , 51 , 52 ].…”

“…The experimental procedure to acquire the FVEPs followed that of our previous reports [ 34 , 35 ]. In short, after anesthesia, electrodes were placed on the frontal area (bregma +1 mm) and occipital area (bregma 8 mm, lateral 3 mm) and reference electrodes were plated on the tail.…”

“…These procedures have been further explained in our previous studies [ 34 , 35 ]. At day 21 after rAION induction, rats were anesthetized and placed in a stereotactic apparatus (Stoelting, Wood Dale, IL, USA).…”

Oroxylin A: A Promising Flavonoid for Prevention and Treatment of Chronic Diseases

“…OA markedly decreased the apoptosis of RGCs and optic disc edema and upregulated the Nrf2 signaling pathway and its downstream antioxidant enzymes NAD(P)H: quinone oxidoreductase (NQO-1) and HO-1 in the retina. Hence, OA can be efficiently used as a therapeutic drug candidate in the NAION [ 179 ].…”