Ketogenic Diet and Ketone Bodies against Ischemic Injury: Targets, Mechanisms, and Therapeutic Potential

Abstract

The ketogenic diet (KD) has been used as a treatment for epilepsy since the 1920s, and its role in the prevention of many other diseases is now being considered. In recent years, there has been an intensive investigation on using the KD as a therapeutic approach to treat acute pathologies, including ischemic ones. However, contradictory data are observed for the effects of the KD on various organs after ischemic injury. In this review, we provide the first systematic analysis of studies conducted from 1980 to 2022 investigating the effects and main mechanisms of the KD and its mimetics on ischemia–reperfusion injury of the brain, heart, kidneys, liver, gut, and eyes. Our analysis demonstrated a high diversity of both the composition of the used KD and the protocols for the treatment of animals, which could be the reason for contradictory effects in different studies. It can be concluded that a true KD or its mimetics, such as β-hydroxybutyrate, can be considered as positive exposure, protecting the organ from ischemia and its negative consequences, whereas the shift to a rather similar high-calorie or high-fat diet leads to the opposite effect.

Investigation of neural functional connectivity in thick acute mouse brain slices with novel multi-region 3D neural probe arrays

“…The preparation follows most of the "protective recovery" methods established in the last decade (13), to both reduce excitotoxicity during decapitation and slicing, as well as supply neuroprotective compounds throughout the entire procedure. The addition of a ketone metabolite is based on literature suggesting the brain preferentially uses ketones (25) during an ischemic state and they may provide a protective effect (26). Carbogenation refers to ultra-fine bubbling of mixed gas (95% O2/5% CO2) into the solutions.…”

The interplay between glucose and ketone bodies in neural stem cell metabolism

“…The administration of β‐OHB before or after an ischemic injury was found to improve both permanent and transient middle cerebral artery occlusion (MCAO), as well as recovery from spinal cord injury. β‐OHB administration was also found to protect against neuronal cell damage in oxygen and glucose deprivation, in addition to mitochondrial fragmentation (Makievskaya et al., 2023). Metabolomic profiling of blood plasma following ischemic injury, displayed decreased glycolytic intermediates and an increase in plasma ketone bodies, thereby mimicking a state of ketosis induced by the ischemic event.…”

“…Elevated β‐OHB levels in blood plasma may also indicate the neuroprotective effects of ketone bodies post‐ischemic injury (Baranovicova et al., 2022). These benefits may be attributed to their anti‐inflammatory effects, a reduction in oxidative stress, epigenetic regulation, restoration of energy supply, or the prevention of fragmentation and damage to mitochondria (Makievskaya et al., 2023). In rat models of ischemic stroke induced by MCAO, the transplantation of rat NSCs into the ventricular space increased glucose uptake within the ischemic region.…”

Is there a role for ketones as alternative fuel in critical illness?

“…The rate-determining step is the reconstitution of acetoacetyl-CoA from acetoacetate by the enzyme succinyl CoA-oxoacid transferase, which, unlike pyruvate dehydrogenase kinase, is not regulated by hypoxia or inflammation [18]. In contrast to glycolysis or lipolysis (via beta-oxidation), the intermediary stages of this metabolic pathway do not require ATP and yield two guanosine triphosphate (GTP) and 22 ATP molecules per AcAc/ 3HB molecule [19], making ketones more energy-efficient than glucose. In addition to their role as a metabolic substrate, ketone bodies have been shown to exert signalling functions both at the cell surface and intracellularly, influencing gene expression, lipid metabolism, metabolic rate and neuronal function [17].…”