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Caloric restriction promotes cell survival in a mouse model of normal tension glaucoma

View Article: PubMed Central - PubMed

ABSTRACT

Glaucoma is characterized by progressive degeneration of retinal ganglion cells (RGCs) and their axons. We previously reported that loss of glutamate transporters (EAAC1 or GLAST) in mice leads to RGC degeneration that is similar to normal tension glaucoma and these animal models are useful in examining potential therapeutic strategies. Caloric restriction has been reported to increase longevity and has potential benefits in injury and disease. Here we investigated the effects of every-other-day fasting (EODF), a form of caloric restriction, on glaucomatous pathology in EAAC1−/− mice. EODF suppressed RGC death and retinal degeneration without altering intraocular pressure. Moreover, visual impairment was ameliorated with EODF, indicating the functional significance of the neuroprotective effect of EODF. Several mechanisms associated with this neuroprotection were explored. We found that EODF upregulated blood β-hydroxybutyrate levels and increased histone acetylation in the retina. Furthermore, it elevated retinal mRNA expression levels of neurotrophic factors and catalase, whereas it decreased oxidative stress levels in the retina. Our findings suggest that EODF, a safe, non-invasive, and low-cost treatment, may be available for glaucoma therapy.

No MeSH data available.


Effects of EODF on oxidative stress levels in the EAAC1−/− mouse retina.(A) Representative images of the 4-HNE expression in the retina of mice at 12 W. Scale bar: 100 μm. (B) Quantitative analyses of (A). Data are normalized to the 4-HNE intensity at the GCL in control WT mice (100%). The data are presented as means ± SEM of six samples for each experiment. **P < 0.01, *P < 0.05.
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f6: Effects of EODF on oxidative stress levels in the EAAC1−/− mouse retina.(A) Representative images of the 4-HNE expression in the retina of mice at 12 W. Scale bar: 100 μm. (B) Quantitative analyses of (A). Data are normalized to the 4-HNE intensity at the GCL in control WT mice (100%). The data are presented as means ± SEM of six samples for each experiment. **P < 0.01, *P < 0.05.

Mentions: Quantitative PCR analysis demonstrated that both BDNF and basic fibroblast growth factor (bFGF) expressions were significantly upregulated by EODF treatment although expressions of glial cell-derived neurotrophic factor (GDNF) and nerve growth factor (NGF) were unchanged (Fig. 5B). These data suggest that neuroprotection of EODF might be partially due to the upregulated neurotrophic factors. Moreover, catalase, a well-defined oxidative stress resistance gene, was found to be upregulated by EODF (Fig. 5B), indicating that oxidative stress in the retina might be suppressed by EODF. To confirm this point, we carried out immunohistochemical analyses of 4-hydroxy-2-nonenal (4-HNE), which represents oxidative stress levels, in the retinas of WT and EAAC1−/− mice treated with or without EODF. As previously reported10, a significant increase of 4-HNE intensity was observed in EAAC1−/− mice, but EODF treatment partially suppressed its expression levels (Fig. 6). Taken together, these results suggest that EODF prevents retinal degeneration in EAAC1−/− mice by upregulating expressions of neurotrophic factors and reducing oxidative stress levels in the retina.


Caloric restriction promotes cell survival in a mouse model of normal tension glaucoma
Effects of EODF on oxidative stress levels in the EAAC1−/− mouse retina.(A) Representative images of the 4-HNE expression in the retina of mice at 12 W. Scale bar: 100 μm. (B) Quantitative analyses of (A). Data are normalized to the 4-HNE intensity at the GCL in control WT mice (100%). The data are presented as means ± SEM of six samples for each experiment. **P < 0.01, *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5037377&req=5

f6: Effects of EODF on oxidative stress levels in the EAAC1−/− mouse retina.(A) Representative images of the 4-HNE expression in the retina of mice at 12 W. Scale bar: 100 μm. (B) Quantitative analyses of (A). Data are normalized to the 4-HNE intensity at the GCL in control WT mice (100%). The data are presented as means ± SEM of six samples for each experiment. **P < 0.01, *P < 0.05.
Mentions: Quantitative PCR analysis demonstrated that both BDNF and basic fibroblast growth factor (bFGF) expressions were significantly upregulated by EODF treatment although expressions of glial cell-derived neurotrophic factor (GDNF) and nerve growth factor (NGF) were unchanged (Fig. 5B). These data suggest that neuroprotection of EODF might be partially due to the upregulated neurotrophic factors. Moreover, catalase, a well-defined oxidative stress resistance gene, was found to be upregulated by EODF (Fig. 5B), indicating that oxidative stress in the retina might be suppressed by EODF. To confirm this point, we carried out immunohistochemical analyses of 4-hydroxy-2-nonenal (4-HNE), which represents oxidative stress levels, in the retinas of WT and EAAC1−/− mice treated with or without EODF. As previously reported10, a significant increase of 4-HNE intensity was observed in EAAC1−/− mice, but EODF treatment partially suppressed its expression levels (Fig. 6). Taken together, these results suggest that EODF prevents retinal degeneration in EAAC1−/− mice by upregulating expressions of neurotrophic factors and reducing oxidative stress levels in the retina.

View Article: PubMed Central - PubMed

ABSTRACT

Glaucoma is characterized by progressive degeneration of retinal ganglion cells (RGCs) and their axons. We previously reported that loss of glutamate transporters (EAAC1 or GLAST) in mice leads to RGC degeneration that is similar to normal tension glaucoma and these animal models are useful in examining potential therapeutic strategies. Caloric restriction has been reported to increase longevity and has potential benefits in injury and disease. Here we investigated the effects of every-other-day fasting (EODF), a form of caloric restriction, on glaucomatous pathology in EAAC1&minus;/&minus; mice. EODF suppressed RGC death and retinal degeneration without altering intraocular pressure. Moreover, visual impairment was ameliorated with EODF, indicating the functional significance of the neuroprotective effect of EODF. Several mechanisms associated with this neuroprotection were explored. We found that EODF upregulated blood &beta;-hydroxybutyrate levels and increased histone acetylation in the retina. Furthermore, it elevated retinal mRNA expression levels of neurotrophic factors and catalase, whereas it decreased oxidative stress levels in the retina. Our findings suggest that EODF, a safe, non-invasive, and low-cost treatment, may be available for glaucoma therapy.

No MeSH data available.