Caloric restriction promotes cell survival in a mouse model of normal tension glaucoma

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.

Edaravone suppresses retinal ganglion cell death in a mouse model of normal tension glaucoma

“…The retinas of EAAC1 KO mice show normal organization at 5 W, but RGC loss and the thinning in the inner retina was clear at 8 and 12 W ( Figure 1b ). 7 , 19 , 20 , 21 The cell number in the ganglion cell layer (GCL) at 8 and 12 W was significantly lower in EAAC1 KO mice compared with WT mice ( Figure 1c ). In addition, the thickness of the inner retinal layer (IRL) was significantly decreased at 8 and 12 W in EAAC1 KO mice ( Figure 1d ).…”

Topical Ripasudil Suppresses Retinal Ganglion Cell Death in a Mouse Model of Normal Tension Glaucoma

“…In addition, every other day fasting, a form of caloric restriction, suppressed RGC death in EAAC1 KO mice under normal IOP. 66 These findings raise intriguing possibilities for the management of glaucoma by caloric restriction and/or utilizing existing drugs for neuroprotection in combination with conventional treatments to lower IOP. 2,50,67,68 Further studies will be required to determine the long-term effect of ripasudil on p38 activation and ocular blood flow in EAAC1 KO mice and other animal models of glaucoma.…”

Caloric Restriction Mimetics against Age-Associated Disease: Targets, Mechanisms, and Therapeutic Potential

“…Both in mice and in humans, acute starvation causes a reduction of the acetylation of cytoplasmic proteins in peripheral blood mononuclear cells (Pietrocola et al, 2017). However, every-other-day fasting increases histone acetylation in the mouse retina (Guo et al, 2016), and acetylation is reduced in aged mouse livers, a phenomenon that is reversed by CR, which causes hepatic protein hyperacetylation (Sato et al, 2017). This is at odds with chronic alcohol abuse, which leads to NAD + depletion and SIRT inhibition, resulting in hyperacetylation of multiple proteins in the liver (such as AMPK, b-catenin, histone H3, and the transcription factors SREBB2, PPARa, FOX01, NFkB, and NFAT) (French, 2016).…”