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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 visual responses and IOP in EAAC1−/− mice.(A) Averaged visual responses of the 2 K component demonstrated using three-dimensional plots. (B) Quantitative analysis of the visual response amplitude in (A). (C) Effects of EODF on IOP in EAAC1−/− mice at 12 W. The data are presented as means ± SEM of six samples for each experiment. **P < 0.01, *P < 0.05.
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f4: Effects of EODF on visual responses and IOP in EAAC1−/− mice.(A) Averaged visual responses of the 2 K component demonstrated using three-dimensional plots. (B) Quantitative analysis of the visual response amplitude in (A). (C) Effects of EODF on IOP in EAAC1−/− mice at 12 W. The data are presented as means ± SEM of six samples for each experiment. **P < 0.01, *P < 0.05.

Mentions: In order to determine if the histological observation of EODF-mediated neuroprotection in EAAC1−/− mice reflects functional aspects, we examined visual function using mfERG. We analyzed the second-order kernel (2 K) component, which appears to be a sensitive indicator of inner retinal dysfunction5678910212324 and is impaired in glaucoma patients26. The response topography demonstrating the 2 K component revealed that the average visual responses were impaired in all visual fields in EAAC1−/− mice, but EODF treatment ameliorated the deterioration in visual function (Fig. 4A,B). These results verify that the neuroprotective effects of EODF on glaucomatous retinal degeneration in EAAC1−/− mice are functionally significant.


Caloric restriction promotes cell survival in a mouse model of normal tension glaucoma
Effects of EODF on visual responses and IOP in EAAC1−/− mice.(A) Averaged visual responses of the 2 K component demonstrated using three-dimensional plots. (B) Quantitative analysis of the visual response amplitude in (A). (C) Effects of EODF on IOP in EAAC1−/− mice at 12 W. 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

f4: Effects of EODF on visual responses and IOP in EAAC1−/− mice.(A) Averaged visual responses of the 2 K component demonstrated using three-dimensional plots. (B) Quantitative analysis of the visual response amplitude in (A). (C) Effects of EODF on IOP in EAAC1−/− mice at 12 W. The data are presented as means ± SEM of six samples for each experiment. **P < 0.01, *P < 0.05.
Mentions: In order to determine if the histological observation of EODF-mediated neuroprotection in EAAC1−/− mice reflects functional aspects, we examined visual function using mfERG. We analyzed the second-order kernel (2 K) component, which appears to be a sensitive indicator of inner retinal dysfunction5678910212324 and is impaired in glaucoma patients26. The response topography demonstrating the 2 K component revealed that the average visual responses were impaired in all visual fields in EAAC1−/− mice, but EODF treatment ameliorated the deterioration in visual function (Fig. 4A,B). These results verify that the neuroprotective effects of EODF on glaucomatous retinal degeneration in EAAC1−/− mice are functionally significant.

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.