Ketogenic Diet Attenuates NMDA-Induced Damage to Rat's Retinal Ganglion Cells in an Age-Dependent Manner

Żarnowski, Tomasz; Chorągiewicz, Tomasz; Schuettauf, Frank; Zrenner, Eberhart; Ręjdak, Robert; Gąsior, Maciej; Żarnowska, Iwona; Thaler, Sebastian

doi:10.1159/000379753

Cited by 11 publications

(11 citation statements)

References 31 publications

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“…Changes in the beneficial effect of CR (Li et al., 2003) or ketogenic diet (Zarnowski et al., 2015) have been reported based on the age at onset of these diets. In addition, ketone oxidation declines in an age‐dependent manner due to decrease in metabolic enzyme activity (Bregere, Rebrin, Gallaher, & Sohal, 2010).…”

Section: Resultsmentioning

confidence: 99%

“…CR attenuates the decrease in RGC activity caused by intraocular pressure elevation (Kong et al., 2012) and protects against ischemia/reperfusion stress‐induced RGC reduction (Kawai et al., 2001). A ketogenic diet and high‐fat/low‐carbohydrate and protein diet cause the elevation of endogenous 3HB and attenuate age‐related damage to RGC in rats (Zarnowski et al., 2015). …”

Section: Introductionmentioning

confidence: 99%

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Ketone body 3‐hydroxybutyrate mimics calorie restriction via the Nrf2 activator, fumarate, in the retina

et al. 2017

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SummaryCalorie restriction (CR) being the most robust dietary intervention provides various health benefits. D‐3‐hydroxybutyrate (3HB), a major physiological ketone, has been proposed as an important endogenous molecule for CR. To investigate the role of 3HB in CR, we investigated potential shared mechanisms underlying increased retinal 3HB induced by CR and exogenously applied 3HB without CR to protect against ischemic retinal degeneration. The repeated elevation of retinal 3HB, with or without CR, suppressed retinal degeneration. Metabolomic analysis showed that the antioxidant pentose phosphate pathway and its limiting enzyme, glucose‐6‐phosphate dehydrogenase (G6PD), were concomitantly preserved. Importantly, the upregulation of nuclear factor erythroid 2 p45‐related factor 2 (Nrf2), a regulator of G6PD, and elevation of the tricarboxylic acid cycle's Nrf2 activator, fumarate, were also shared. Together, our findings suggest that CR provides retinal antioxidative defense by 3HB through the antioxidant Nrf2 pathway via modification of a tricarboxylic acid cycle intermediate during 3HB metabolism.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ketone body 3‐hydroxybutyrate mimics calorie restriction via the Nrf2 activator, fumarate, in the retina

et al. 2017

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“…However, KD effects on mitochondria were not analyzed in any of these patients. On the other hand, KD has not been used in LHON patients, but LHON patients suffer from RGC loss and, in rodent models of RGC damage, it was shown that KD have a RGC neuroprotective effect, preserving its structure and function, increasing mitochondrial respiration and up-regulating mitochondrial biogenesis [39, 40].…”

Section: Discussionmentioning

confidence: 99%

Ketogenic treatment reduces the percentage of a LHON heteroplasmic mutation and increases mtDNA amount of a LHON homoplasmic mutation

Emperador

López‐Gallardo

Hernández-Ainsa

et al. 2019

Orphanet J Rare Dis

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Background The vision loss in Leber hereditary optic neuropathy patients is due to mitochondrial DNA mutations. No treatment has shown a clear-cut benefit on a clinically meaningful end-point. However, clinical evidences suggest two therapeutic approaches: the reduction of the mutation load in heteroplasmic patients or the elevation of mitochondrial DNA amount in homoplasmic patients. Results Here we show that ketogenic treatment, in cybrid cell lines, reduces the percentage of the m.13094 T > C heteroplasmic mutation and also increases the mitochondrial DNA levels of the m.11778G > A mitochondrial genotype. Conclusions These results suggest that ketogenic diet could be a therapeutic strategy for Leber hereditary optic neuropathy.

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“…There is a precedent to suggest that ketone metabolism plays an important role in retinal homeostasis. [13][14][15] In the retinal pigment epithelium (RPE), degraded lipids from the shed photoreceptor outer segments are metabolized via β-oxidation to generate acetyl CoA, an important source of energy. 14,15 Furthermore, the RPE converts acetyl CoA into the ketone, β-hydroxybutyrate (BHB), which can be shuttled back to the photoreceptors and used as an additional energy source.…”

Section: Introductionmentioning

confidence: 99%

“…Previous work has shown that a ketogenic diet with approximately 80% fats, 8% proteins, and <1% carbohydrates protected retinal ganglion cells from N-methyl D-aspartate-induced damage. 13 We hypothesized that inducing ketosis through ketogenic diet administration would elicit neuroprotection of photoreceptors. To test this hypothesis, we evaluated two different ketogenic diets in rd10 mice, a relevant and well-characterized genetic model of RP.…”

Section: Introductionmentioning

confidence: 99%

A Ketogenic & Low-Protein Diet Slows Retinal Degeneration in rd10 Mice

Ryals

Huang

Wafai

et al. 2020

Trans. Vis. Sci. Tech.

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Treatments that delay retinal cell death regardless of genetic causation are needed for inherited retinal degeneration (IRD) patients. The ketogenic diet is a high-fat, low-carbohydrate diet, used to treat epilepsy, and has beneficial effects for neurodegenerative diseases. This study aimed to determine whether the ketogenic diet could slow retinal degeneration. Methods: Early weaned, rd10 and wild-type (WT) mice were placed on either standard chow, a ketogenic diet, or a ketogenic & low-protein diet. From postnatal day (PD) 23 to PD50, weight and blood β-hydroxybutyrate levels were recorded. Retinal thickness, retinal function, and visual performance were measured via optical coherence tomography, electroretinography (ERG), and optokinetic tracking (OKT). At PD40, serum albumin, rhodopsin protein, and phototransduction gene expression were measured. Results: Both ketogenic diets elicited a systemic induction of ketosis. However, rd10 mice on the ketogenic & low-protein diet had significant increases in photoreceptor thickness, ERG amplitudes, and OKT thresholds, whereas rd10 mice on the ketogenic diet showed no photoreceptor preservation. In both rd10 and WT mice, the ketogenic & low-protein diet was associated with abnormal weight gain and decreases in serum albumin levels, 27% and 56%, respectively. In WT mice, the ketogenic & low-protein diet was also associated with an ∼20% to 30% reduction in ERG amplitudes. Conclusions: The ketogenic & low-protein diet slowed retinal degeneration in a clinically relevant IRD model. In WT mice, the ketogenic & low-protein diet was associated with a decrease in phototransduction and serum albumin, which could serve as a protective mechanism in the rd10 model. Although ketosis was associated with protection, its role remains unclear. Translational Relevance: Neuroprotective mechanisms associated with the ketogenic & low-protein diet have potential to slow retinal degeneration.

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Ketogenic Diet Attenuates NMDA-Induced Damage to Rat's Retinal Ganglion Cells in an Age-Dependent Manner

Cited by 11 publications

References 31 publications

Ketone body 3‐hydroxybutyrate mimics calorie restriction via the Nrf2 activator, fumarate, in the retina

Ketone body 3‐hydroxybutyrate mimics calorie restriction via the Nrf2 activator, fumarate, in the retina

Ketogenic treatment reduces the percentage of a LHON heteroplasmic mutation and increases mtDNA amount of a LHON homoplasmic mutation

A Ketogenic & Low-Protein Diet Slows Retinal Degeneration in rd10 Mice

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