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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.


Experimental timeline and effects of EODF on blood β-HB levels in EAAC1−/− mice.(A) Experimental protocols. EODF was started in EAAC1−/− mice from 5 W and continued for 7 weeks. OCT, mfERG and IOP of mice were measured before sampling at 12 W. β-HB levels in the blood of mice were measured every 24 h in the first week of the experiment. The control group (EODF−) had continual access to food, while the EODF group (EODF+) had access to food on alternate days. Both groups were given ad libitum access to water. (B) Increased β-HB levels in the blood of EODF mice on fasting days. The data are presented as means ± SEM of six samples for each experiment. **P < 0.001.
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f1: Experimental timeline and effects of EODF on blood β-HB levels in EAAC1−/− mice.(A) Experimental protocols. EODF was started in EAAC1−/− mice from 5 W and continued for 7 weeks. OCT, mfERG and IOP of mice were measured before sampling at 12 W. β-HB levels in the blood of mice were measured every 24 h in the first week of the experiment. The control group (EODF−) had continual access to food, while the EODF group (EODF+) had access to food on alternate days. Both groups were given ad libitum access to water. (B) Increased β-HB levels in the blood of EODF mice on fasting days. The data are presented as means ± SEM of six samples for each experiment. **P < 0.001.

Mentions: The retinas of EAAC1−/− mice show normal organization at 5 weeks old (5 W) and NTG-like retinal degeneration starts thereafter, as we previously reported57810. To investigate whether caloric restriction is capable of ameliorating the NTG-like pathology in EAAC1−/− mice, we performed EODF on EAAC1−/− mice between 5 W and 12 W (Fig. 1A). Since caloric restriction has been reported to increase the β-HB concentration12, we first examined its concentration in the blood during EODF. The concentration of β-HB in EAAC1−/− mice was significantly increased on the fasting days (Fig. 1B).


Caloric restriction promotes cell survival in a mouse model of normal tension glaucoma
Experimental timeline and effects of EODF on blood β-HB levels in EAAC1−/− mice.(A) Experimental protocols. EODF was started in EAAC1−/− mice from 5 W and continued for 7 weeks. OCT, mfERG and IOP of mice were measured before sampling at 12 W. β-HB levels in the blood of mice were measured every 24 h in the first week of the experiment. The control group (EODF−) had continual access to food, while the EODF group (EODF+) had access to food on alternate days. Both groups were given ad libitum access to water. (B) Increased β-HB levels in the blood of EODF mice on fasting days. The data are presented as means ± SEM of six samples for each experiment. **P < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Experimental timeline and effects of EODF on blood β-HB levels in EAAC1−/− mice.(A) Experimental protocols. EODF was started in EAAC1−/− mice from 5 W and continued for 7 weeks. OCT, mfERG and IOP of mice were measured before sampling at 12 W. β-HB levels in the blood of mice were measured every 24 h in the first week of the experiment. The control group (EODF−) had continual access to food, while the EODF group (EODF+) had access to food on alternate days. Both groups were given ad libitum access to water. (B) Increased β-HB levels in the blood of EODF mice on fasting days. The data are presented as means ± SEM of six samples for each experiment. **P < 0.001.
Mentions: The retinas of EAAC1−/− mice show normal organization at 5 weeks old (5 W) and NTG-like retinal degeneration starts thereafter, as we previously reported57810. To investigate whether caloric restriction is capable of ameliorating the NTG-like pathology in EAAC1−/− mice, we performed EODF on EAAC1−/− mice between 5 W and 12 W (Fig. 1A). Since caloric restriction has been reported to increase the β-HB concentration12, we first examined its concentration in the blood during EODF. The concentration of β-HB in EAAC1−/− mice was significantly increased on the fasting days (Fig. 1B).

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.