Abstract
The ketogenic diet (KD) is a high-fat low-carbohydrate diet that has been used for decades as a non-pharmacologic approach to treat metabolic disorders and refractory pediatric epilepsy. In recent years, enthusiasm for the KD has increased in the scientific community due to evidence that the diet reduces pathology and improves various outcome measures in animal models of neurodegenerative disorders, including multiple sclerosis, stroke, glaucoma, spinal cord injury, retinal degenerations, Parkinson's disease and Alzheimer's disease. Clinical trials also suggest that the KD improved quality of life in patients with multiple sclerosis and Alzheimer's disease. Furthermore, the major ketone bodies BHB and ACA have potential neuroprotective properties and are now known to have direct effects on specific inflammatory proteins, transcription factors, reactive oxygen species, mitochondria, epigenetic modifications and the composition of the gut microbiome. Neuroprotective benefits of the KD are likely due to a combination of these cellular processes and other potential mechanisms that are yet to be confirmed experimentally. This review provides a comprehensive summary of current evidence for the effectiveness of the KD in humans and preclinical models of various neurological disorders, describes molecular mechanisms that may contribute to its beneficial effects, and highlights key controversies and current gaps in knowledge.
Highlights
The ketogenic diet (KD) and related diets have been used for many decades for weight loss, managing metabolic disorders and reducing seizures in pediatric epilepsy
It is important to consider that molecular mechanisms that lead to reduced inflammation and lower oxidative stress may change with longer durations of the diet, and the reported short-term mechanisms of neuroprotection may not necessarily contribute to its longterm effects
The KD has been used for many years to reduce seizures in treatment-intractable pediatric epilepsy and was confirmed to be effective in a randomized control clinical trial [11]
Summary
The ketogenic diet (KD) and related diets have been used for many decades for weight loss, managing metabolic disorders and reducing seizures in pediatric epilepsy. In a study using the DBA/2J mouse model of elevated intraocular pressure and secondary glaucoma, mice fed the KD for 8 weeks showed significantly increased retinal ganglion cell (RGC) survival and axon number compared to mice fed the control diet [14] This neuroprotection was associated with increased mitochondria and reduced expression of pro-inflammatory molecules in the retina and optic nerves. The neuroprotective effects of the KD in animal models are often correlated with reduced proinflammatory signaling and are characterized by lower microglia numbers, decreased expression of the inflammation inducer NF-κB p65 protein and reduced levels of pro-inflammatory molecules such as TNFα Until recently, it was unknown whether these inflammatory changes are directly induced by ketones or secondary to other processes. Over 1,300 other proteins in addition to histones were identified as targets of ketone-related modifications, suggesting that this is a major regulatory pathway that is potentially altered by the KD [66]
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