Abstract
The ketogenic diet (KD) is a broad-spectrum therapy for medically intractable epilepsy and is receiving growing attention as a potential treatment for neurological disorders arising in part from bioenergetic dysregulation. The high-fat/low-carbohydrate "classic KD", as well as dietary variations such as the medium-chain triglyceride diet, the modified Atkins diet, the low-glycemic index treatment, and caloric restriction, enhance cellular metabolic and mitochondrial function. Hence, the broad neuroprotective properties of such therapies may stem from improved cellular metabolism. Data from clinical and preclinical studies indicate that these diets restrict glycolysis and increase fatty acid oxidation, actions which result in ketosis, replenishment of the TCA cycle (i.e., anaplerosis), restoration of neurotransmitter and ion channel function, and enhanced mitochondrial respiration. Further, there is mounting evidence that the KD and its variants can impact key signaling pathways that evolved to sense the energetic state of the cell, and that help maintain cellular homeostasis. These pathways, which include PPARs, AMP-activated kinase, mammalian target of rapamycin, and the sirtuins, have all been recently implicated in the neuroprotective effects of the KD. Further research in this area may lead to future therapeutic strategies aimed at mimicking the pleiotropic neuroprotective effects of the KD.
Highlights
The ketogenic diet (KD) is a broad-spectrum therapy for medically intractable epilepsy and is receiving growing attention as a potential treatment for neurological disorders arising in part from bioenergetic dysregulation
medium-chain triglyceride (MCT) produce a higher level of ketosis compared with long-chain triglycerides, and this allows for a decrease in the intake of these fats and a greater consumption of carbohydrates and protein on this modified diet [28]
A decrease in substrate-driven mitochondrial H2O2 production was shown in rats after 3 weeks on the diet, and this was associated with increased mitochondrial GSH levels, depletion of which is known to occur with seizures [96]
Summary
Notwithstanding the documented efficacy of the KD against seizure disorders, implementation remains challenging (e.g., poor compliance due to lack of palatability and concerns regarding long-term health consequences such as increases in cholesterol and triglycerides, slow growth in pediatric patients, etc.) [37, 55, 56]. Clinical researchers have sought alternative therapies that retain anti-seizure effects yet are devoid of these limitations. There is CR, a dietary practice known to reduce the progression of many age-related diseases. This particular dietary strategy, which the KD was originally designed to mimic, has been an intense focus for researchers interested in the mechanisms underlying aging/longevity, neurological diseases, and a host of other conditions [58,59,60]
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