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.
Highlights
Electroretinography to evaluate functional effects of EODF5–10,21,23,24
To investigate whether caloric restriction is capable of ameliorating the NTGlike pathology in EAAC1−/− mice, we performed EODF on EAAC1−/− mice between 5 weeks old (5 W) and 12 W (Fig. 1A)
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)
Summary
Electroretinography (mfERG) to evaluate functional effects of EODF5–10,21,23,24. We explored possible mechanisms associated with EODF-mediated neuroprotection in EAAC1−/− mice. The concentration of β-HB in EAAC1−/− mice was significantly increased on the fasting days (Fig. 1B). EODF significantly increased the number of surviving neurons in the GCL and IRL thickness compared with those in control mice (Fig. 2A–C).
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