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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.


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Effects of EODF on retinal degeneration in EAAC1−/− mice.(A) Retinal sections stained with hematoxylin and eosin at 12 W in mice treated with or without EODF. Scale bar: 50 μm. GCL, ganglion cell layer; INL, inner nuclear layer; ONL, outer nuclear layer; IRL, inner retinal layer. (B,C) Quantitative analyses of the cell number in the GCL per section (B) and IRL thickness (C). (D) Representative images of FG-labeled RGCs at 12 W. Scale bar: 55 μm. (E) Quantitative analyses of RGCs in (D). Data are presented as means ± SEM of six samples for each experiment. ***P < 0.001, **P < 0.01, *P < 0.05.
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f2: Effects of EODF on retinal degeneration in EAAC1−/− mice.(A) Retinal sections stained with hematoxylin and eosin at 12 W in mice treated with or without EODF. Scale bar: 50 μm. GCL, ganglion cell layer; INL, inner nuclear layer; ONL, outer nuclear layer; IRL, inner retinal layer. (B,C) Quantitative analyses of the cell number in the GCL per section (B) and IRL thickness (C). (D) Representative images of FG-labeled RGCs at 12 W. Scale bar: 55 μm. (E) Quantitative analyses of RGCs in (D). Data are presented as means ± SEM of six samples for each experiment. ***P < 0.001, **P < 0.01, *P < 0.05.

Mentions: We then examined the effects of EODF on retinal degeneration. The cell number in the ganglion cell layer (GCL) and the thickness of the inner retinal layer (IRL) were significantly decreased in EAAC1−/− mice compared with wild type (WT) mice at 12 W (Fig. 2A–C). EODF significantly increased the number of surviving neurons in the GCL and IRL thickness compared with those in control mice (Fig. 2A–C). Because GCL contains cell types other than RGCs including displaced amacrine cells25, we next performed retrograde labeling of RGCs with Fluoro-Gold (FG) and determined the effect of EODF on RGC survival. Consistent with the results of cell counting in the GCL (Fig. 2B), the RGC number in EODF EAAC1−/− mice was significantly increased compared with control EAAC1−/− mice without EODF (Fig. 2D,E). These data demonstrate that EODF prevents RGC death observed in EAAC1−/− mice.


Caloric restriction promotes cell survival in a mouse model of normal tension glaucoma
Effects of EODF on retinal degeneration in EAAC1−/− mice.(A) Retinal sections stained with hematoxylin and eosin at 12 W in mice treated with or without EODF. Scale bar: 50 μm. GCL, ganglion cell layer; INL, inner nuclear layer; ONL, outer nuclear layer; IRL, inner retinal layer. (B,C) Quantitative analyses of the cell number in the GCL per section (B) and IRL thickness (C). (D) Representative images of FG-labeled RGCs at 12 W. Scale bar: 55 μm. (E) Quantitative analyses of RGCs in (D). Data are presented as means ± SEM of six samples for each experiment. ***P < 0.001, **P < 0.01, *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: Effects of EODF on retinal degeneration in EAAC1−/− mice.(A) Retinal sections stained with hematoxylin and eosin at 12 W in mice treated with or without EODF. Scale bar: 50 μm. GCL, ganglion cell layer; INL, inner nuclear layer; ONL, outer nuclear layer; IRL, inner retinal layer. (B,C) Quantitative analyses of the cell number in the GCL per section (B) and IRL thickness (C). (D) Representative images of FG-labeled RGCs at 12 W. Scale bar: 55 μm. (E) Quantitative analyses of RGCs in (D). Data are presented as means ± SEM of six samples for each experiment. ***P < 0.001, **P < 0.01, *P < 0.05.
Mentions: We then examined the effects of EODF on retinal degeneration. The cell number in the ganglion cell layer (GCL) and the thickness of the inner retinal layer (IRL) were significantly decreased in EAAC1−/− mice compared with wild type (WT) mice at 12 W (Fig. 2A–C). EODF significantly increased the number of surviving neurons in the GCL and IRL thickness compared with those in control mice (Fig. 2A–C). Because GCL contains cell types other than RGCs including displaced amacrine cells25, we next performed retrograde labeling of RGCs with Fluoro-Gold (FG) and determined the effect of EODF on RGC survival. Consistent with the results of cell counting in the GCL (Fig. 2B), the RGC number in EODF EAAC1−/− mice was significantly increased compared with control EAAC1−/− mice without EODF (Fig. 2D,E). These data demonstrate that EODF prevents RGC death observed in EAAC1−/− mice.

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.


Related in: MedlinePlus