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S. Narayan, N. Tsivkovskaia, T. V. Bui, N. L. Mata; N-(4-hydroxyphenyl)Retinamide Mediates Preservation of Retinal Ganglion Cells Through Induction of Ceramide Biosynthesis. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5465.
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N-(4-hydroxyphenyl)retinamide (HPR) is a synthetic retinoid that halts the production of toxic fluorophores in the retina by reducing serum retinol. Previously, we have shown that HPR inhibits angiogenesis and reduces inflammatory biomarker expression in retinas of Ins2Akita mice. Significantly, HPR treatment results in a preservation of retinal ganglion cells (RGCs) indicating a protective effect. HPR is known to increase ceramide, an important cellular metabolite involved in sphingolipid (SL) metabolism. Dysregulated SL metabolism has been implicated in apoptosis and insulin resistance. Moreover, ceramide levels are reduced in animal models of diabetes. We hypothesized that the therapeutic effect of HPR is a consequence of HPR-mediated changes in SL metabolism within the retina.
The retinas of mice heterozygous for the insulin 2 gene (Ins2Akita) exhibit vascular, neural, and glial abnormalities generally consistent with clinical observations and other animal models of diabetes. Ins2Akita mice were fed HPR-supplemented chow for 2 months. At the end of the treatment period, mice were euthanized and eyecups were prepared for biochemical and immunohistochemical analyses.
Serum RBP-retinol was significantly reduced in HPR-fed mice (~ 70%, compared to the control group). However, this had no effect on the glycemic status. HPLC analysis showed ~ 20 pmoles HPR/eye in the treated group. Immunohistochemical and biochemical analyses indicated that ceramide levels are reduced in untreated Ins2Akita mice relative to wild type mice. Importantly, we found that levels of VEGF were reduced, and ceramide levels were increased to wild-type levels, in HPR-treated Ins2Akita mice.
HPR-mediated amelioration of Ins2Akita pathology is highly reminiscent of the reported therapeutic effect observed following treatment with pentazocine, a Sigma 1 receptor (S1R) ligand. While we find that HPR is not a S1R agonist, it is possible that it exerts a protective effect through induction of ceramide biosynthesis. We propose that in diabetes where ceramide levels are reduced, HPR-mediated restoration of ceramide homeostasis may be therapeutic for preservation of RGCs.
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