Abstract
BackgroundRetinal ischemia-related eye diseases result in visual dysfunction. This study investigates the protective effects and mechanisms of Xue-Fu-Zhu-Yu decoction (XFZYD) with respect to retinal ischemia.MethodsRetinal ischemia (I) was induced in Wistar rats by a high intraocular pressure (HIOP) of 120 mmHg for 1 h, which was followed by reperfusion of the ischemic eye; the fellow untreated eye acted as a control. Electroretinogram (ERG), biochemistry and histopathology investigations were performed.ResultsSignificant ischemic changes occurred after ischemia including decreased ERG b-wave ratios, less numerous retinal ganglion cells (RGCs), reduced inner retinal thickness, fewer choline acetyltransferase (ChAT) labeled amacrine cell bodies, increased glial fibrillary acidic protein (GFAP) immunoreactivity and increased vimentin Müller immunolabeling. These were accompanied by significant increases in the mRNA/protein concentrations of vascular endothelium growth factor, hypoxia-inducible factor-1α, pyruvate kinase M2 and retinoblastoma-binding protein 2. The ischemic changes were concentration-dependently and significantly altered when XFZYD was given for seven consecutive days before or after retina ischemia, compared to vehicle. These alterations included enhanced ERG b-wave amplitudes, more numerous RGCs, enhanced inner retinal thickness, a greater number of ChAT immunolabeled amacrine cell bodies and decreased GFAP/vimentin immunoreactivity. Furthermore, decreased mRNA levels of VEGF, HIF-1α, PKM2, and RBP2 were also found. Reduced protein concentrations of VEGF, HIF-1α, PKM2, and RBP2 were also demonstrated. Furthermore, there was an inhibition of the ischemia-associated increased ratios (target protein/β-actin) in the protein levels of VEGF, HIF-1α, PKM2, and RBP2, which were induced by Shikonin, JIB-04 or Avastin.ConclusionXFZYD would seem to protect against well-known retinal ischemic changes via a synergistic inhibition of RBP2 and PKM2, as well as down-regulation of HIF-1α and a reduction in VEGF secretion.
Highlights
Retinal ischemia-related eye diseases result in visual dysfunction
Our findings reveal that preischemia or postischemia administration of Xue-Fu-Zhu-Yu decoction (XFZYD) is able to bring about a significant counteraction of these ischemic features, namely an attenuation of the ischemia-induced decrease in the number of the retinal ganglion cells (RGCs) (Fig. 2c~f ), an alleviation of the ischemia-associated decrease in the inner/whole retina thickness (Fig. 3c~f ), as well as mitigation of the ischemia-related reduction in amacrine cell bodies (Fig. 4d~g)
Significant upregulation of the mRNA/protein levels of vascular endothelium growth factor (VEGF), hypoxia-inducible factor-1α (HIF-1α), PKM2 and RBP2 were found in the ischemic retina
Summary
Retinal ischemia-related eye diseases result in visual dysfunction. This study investigates the protective effects and mechanisms of Xue-Fu-Zhu-Yu decoction (XFZYD) with respect to retinal ischemia. Retinal ischemia related diseases include central retinal artery occlusion (CRAO), central retinal vein occlusion (CRVO), branch retinal artery occlusion (BRAO), branch retinal vein occlusion (BRVO), glaucoma, and age-related macular degeneration (AMD) [1,2,3]. All of these disorders can result in serious complications and the treatment of retinal ischemia is vital to patient outcomes. JIB-04, a paninhibitor of the Jumonji demethylase superfamily, was selected to observe the inhibition of RBP2 upregulation in retinal ischemia. An investigation as to whether an overexpression of VEGF, HIF-1α, PKM2 and RBP2 coexists in the ischemic retina has been included in the present investigation
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