Abstract
Retinal neuronal cell death underlies many incurable eye diseases such as retinitis pigmentosa (RP) and glaucoma, and causes adult blindness. We have shown that maintenance of ATP levels via inhibiting ATP consumption is a promising strategy for preventing neuronal cell death. Here, we show that branched chain amino acids (BCAAs) are able to increase ATP production by enhancing glycolysis. In cell culture, supplementation of the culture media with BCAAs, but not glucose alone, enhanced cellular ATP levels, which was canceled by a glycolysis inhibitor. Administration of BCAAs to RP mouse models, rd10 and rd12, significantly attenuated photoreceptor cell death morphologically and functionally, even when administration was started at later stages. Administration of BCAAs in a glaucoma mouse model also showed significant attenuation of retinal ganglion cell death. These results suggest that administration of BCAAs could contribute to a comprehensive therapeutic strategy for retinal neurodegenerative diseases such as RP and glaucoma.
Highlights
Retinitis pigmentosa (RP) is one of several incurable eye diseases; it leads to blindness, with approximately 1.5 million people affected worldwide, and its incidence is about 1 in 4,000 people (Hartong et al, 2006)
The ability of branched chain amino acids (BCAAs) to enhance ATP production was observed in the presence of 4.5 g/L of glucose, the effect did not achieve statistical significance at that concentration (Fig. 1A)
BCAAs improved the ATP levels and live cell numbers in a dose-dependent manner (ATP levels, p 1⁄4 0.001 and p < 0.0001; live cell numbers, p < 0.01 and p < 0.01, for the addition of 4.0 and 40 mM BCAA, respectively, vs. controls with tunicamycin and no BCAAs) (Fig. 1D and E). These results indicate that the addition of BCAAs, but not supplementary glucose alone, enhances the production of ATP and promotes cell survival in cultured cells under endoplasmic reticulum (ER) stress
Summary
Retinitis pigmentosa (RP) is one of several incurable eye diseases; it leads to blindness, with approximately 1.5 million people affected worldwide, and its incidence is about 1 in 4,000 people (Hartong et al, 2006). A much more common disease, glaucoma, is one of the leading causes of blindness worldwide, accounting for 4.0e15.5% of adult blindness (Bourne et al, 2013), and it ranks in the top third of causes of incurable visual impairment in Western countries (Klaver et al, 1998); the number of patients is increasing worldwide (Quigley and Broman, 2006). Strategies to reduce intraocular pressure are used in glaucoma treatment (Collaborative Normal-Tension Glaucoma Study Group, 1998; Leske et al, 2004). There remain considerable numbers of patients, up to 33% of the total, whose visual field impairment progresses despite intraocular pressure within the normal limit (Collaborative Normal-Tension Glaucoma Study Group, 1998; Hitchings, 1992). New therapeutic strategies that prevent cell death and prevent or retard disease progression are eagerly awaited
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