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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 histone acetylation, neurotrophic factors and antioxidant gene expressions in the retina.(A) Expression levels of AcH3K9 and AcH3K18 in the retina of WT mice. Histone H3 was used as an internal control. (B) mRNA expression levels of neurotrophic factors (BDNF, bFGF, GDNF and NGF) and an oxidative stress resistance gene (catalase) were determined using quantitative PCR analyses. GAPDH was used as an internal control. The data are presented as means ± SEM of six samples for each experiment. *P < 0.05.
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f5: Effects of EODF on histone acetylation, neurotrophic factors and antioxidant gene expressions in the retina.(A) Expression levels of AcH3K9 and AcH3K18 in the retina of WT mice. Histone H3 was used as an internal control. (B) mRNA expression levels of neurotrophic factors (BDNF, bFGF, GDNF and NGF) and an oxidative stress resistance gene (catalase) were determined using quantitative PCR analyses. GAPDH was used as an internal control. The data are presented as means ± SEM of six samples for each experiment. *P < 0.05.

Mentions: Next we investigated possible mechanisms associated with EODF-mediated neuroprotection. Since the concentration of β-HB, an endogenous HDAC inhibitor, was significantly increased upon EODF (Fig. 1B), we first investigated whether EODF could alter histone acetylation in the retina. To this aim, histones from retinas of WT mice undergone EODF for 7 days were purified. Acetylation of H3K9 and H3K18 was slightly detected in retinas of mice without EODF, and western blotting analysis revealed a significant upregulation of histone acetylation in retinas isolated from mice with EODF (Fig. 5A). Since acetylation of H3K9 influences various gene expressions13, EODF may alter gene expressions that result in neuroprotection. Therefore, we investigated the effects of EODF on expression levels of neurotrophic factors and antioxidants in the retina.


Caloric restriction promotes cell survival in a mouse model of normal tension glaucoma
Effects of EODF on histone acetylation, neurotrophic factors and antioxidant gene expressions in the retina.(A) Expression levels of AcH3K9 and AcH3K18 in the retina of WT mice. Histone H3 was used as an internal control. (B) mRNA expression levels of neurotrophic factors (BDNF, bFGF, GDNF and NGF) and an oxidative stress resistance gene (catalase) were determined using quantitative PCR analyses. GAPDH was used as an internal control. The data are presented as means ± SEM of six samples for each experiment. *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5: Effects of EODF on histone acetylation, neurotrophic factors and antioxidant gene expressions in the retina.(A) Expression levels of AcH3K9 and AcH3K18 in the retina of WT mice. Histone H3 was used as an internal control. (B) mRNA expression levels of neurotrophic factors (BDNF, bFGF, GDNF and NGF) and an oxidative stress resistance gene (catalase) were determined using quantitative PCR analyses. GAPDH was used as an internal control. The data are presented as means ± SEM of six samples for each experiment. *P < 0.05.
Mentions: Next we investigated possible mechanisms associated with EODF-mediated neuroprotection. Since the concentration of β-HB, an endogenous HDAC inhibitor, was significantly increased upon EODF (Fig. 1B), we first investigated whether EODF could alter histone acetylation in the retina. To this aim, histones from retinas of WT mice undergone EODF for 7 days were purified. Acetylation of H3K9 and H3K18 was slightly detected in retinas of mice without EODF, and western blotting analysis revealed a significant upregulation of histone acetylation in retinas isolated from mice with EODF (Fig. 5A). Since acetylation of H3K9 influences various gene expressions13, EODF may alter gene expressions that result in neuroprotection. Therefore, we investigated the effects of EODF on expression levels of neurotrophic factors and antioxidants 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.