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Akito Shimouchi, Harumasa Yokota, Taiji Nagaoka, Shinji Ono, Hiroko Takumi, S.Priya Narayanan, Ruth Caldwell, Akitoshi Yoshida; Water-dispersible hesperetin prevents ganglion cell loss in the retina after retinal ischemia reperfusion injury. Invest. Ophthalmol. Vis. Sci. 2013;54(15):6351.
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© ARVO (1962-2015); The Authors (2016-present)
The citrus flavonoid hesperetin (Hpt) has been shown to improve retinal blood flow and enhance recovery of retinal function after ischemic injury in rats. The aim of this study was to determine whether water-dispersible Hpt could prevent degeneration of ganglion cell neurons in a mouse model of retinal ischemia reperfusion (I/R) injury and to examine the mechanisms of its actions.
Retinal I/R injury was induced in C57BL/6 mice by increasing the intraocular pressure (IOP) to 110 mmHg for 40 minutes followed by reperfusion. The contralateral eyes served as controls. The mice received daily intraperitoneal injection with either normal saline (NS, 0.3ml/) or Hpt (200mg/kg/) until sacrifice. The mice were sacrificed at 6h, 24h and 7 days after I/R. The whole mount retinas were immunostained with NeuN antibody to detect surviving neurons in the ganglion cell layer at 7 days after I/R. Western blotting was performed to examine the expression of molecules that initiate or promote apoptosis at 6h after I/R.
I/R resulted in a 37% reduction in the number of ganglion cells compared to the fellow eyes in the mice treated with NS, whereas the number of NeuN positive cells in the mice treated with Hpt was reduced by only 5% (p<0.01). At 6 hours after I/R the expression of heme oxygenase-1 (HO-1) and phosphorylation of ERK and p38 MAP kinase were significantly increased in the retina treated with NS, whereas bcl-2 was decreased. In contrast, I/R-induced alteration of those molecules at 6 hours after I/R was markedly attenuated in the mice treated with Hpt.
Our data demonstrate that Hpt protects ganglion cell layer neurons from I/R injury. A marker of oxidative stress, HO-1, and apoptosis signaling pathway indicators, p-ERK, p-p38 MAP kinase, were suppressed by the administration of Hpt whereas a survival pathway indicator, bcl-2, was increased. Thus, water-dispersible hesperetin may provide a promising treatment for ischemic retinopathy.
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