Ketone Bodies in Neurological Diseases: Focus on Neuroprotection and Underlying Mechanisms

Abstract

There is growing evidence that ketone bodies, which are derived from fatty acid oxidation and usually produced in fasting state or on high-fat diets have broad neuroprotective effects. Although the mechanisms underlying the neuroprotective effects of ketone bodies have not yet been fully elucidated, studies in recent years provided abundant shreds of evidence that ketone bodies exert neuroprotective effects through possible mechanisms of anti-oxidative stress, maintaining energy supply, modulating the activity of deacetylation and inflammatory responses. Based on the neuroprotective effects, the ketogenic diet has been used in the treatment of several neurological diseases such as refractory epilepsy, Parkinson's disease, Alzheimer's disease, and traumatic brain injury. The ketogenic diet has great potential clinically, which should be further explored in future studies. It is necessary to specify the roles of components in ketone bodies and their therapeutic targets and related pathways to optimize the strategy and efficacy of ketogenic diet therapy in the future.

Synchronous nonmonotonic changes in functional connectivity and white matter integrity in a rat model of sporadic Alzheimer’s disease

“…Remarkably, we report "partial recovery" in terms of axonal integrity and functional hyperconnectivity at six weeks post-injection, in a context of marked FDG uptake differences at that timepoint. This observation follows the caveat that metabolism underlies structure and function, and supports the assumption that past the acute phase, the brain switches to other forms of energy, such as ketone bodies, as a means to maintain energy homeostasis and restore normal brain function (Yang et al, 2019). Interestingly, the same regions with reduced FDG uptake at 6 weeks after STZ injection eventually showed functional hypoconnectivity at 13 weeks (Figure 4 and Figure 5), supporting the manifestation of a chronic phase of disease.…”

Oxidative-Antioxidant Imbalance and Impaired Glucose Metabolism in Schizophrenia

“…According to the conception of de la Monte [259], neurodegeneration may be called type III diabetes or CNS metabolic disease, where it comes to an increase in oxygen, nitrogen, and sulfuric free radicals (ROS, RNS, RSS) [260] due to activation of inflammatory pathways (and increased release of proinflammatory cytokines, e.g., IL-6, IL-1B, TNF-α, by glial cells and astrocytes) [261]. It causes mitochondrial damage and activation of a number of kinase pathways, e.g., MAP, JNK, and p38MAPK, which may also result in inhibition of insulin signaling [262]. Disorders of glucose metabolism in the CNS increase the production of ketone bodies and the activation of additional pathways mediated by free radicals, including NF-kB [7].…”

Epigenetic Inactivation of Acetyl-Co A acetyltransferase 1 promotes the proliferation and metastasis of nasopharyngeal carcinoma via decreasing ketogenesis

“…Functioning as a kind of high-energy mitochondrial fuels, ketone bodies are normally generated in hepatocytes and used during starvation (20). Recent studies provide evidence that ketone bodies can be produced in cancer cells as well as in tumor stroma (19,21).…”