Neuroketotherapeutics: A modern review of a century-old therapy

Abstract

Neuroketotherapeutics represent a class of bioenergetic medicine therapies that feature the induction of ketosis. These therapies include medium-chain triglyceride supplements, ketone esters, fasting, strenuous exercise, the modified Atkins diet, and the classic ketogenic diet. Extended experience reveals persons with epilepsy, especially pediatric epilepsy, benefit from ketogenic diets although the mechanisms that underlie its effects remain unclear. Data indicate ketotherapeutics enhance mitochondrial respiration, promote neuronal long-term potentiation, increase BDNF expression, increase GPR signaling, attenuate oxidative stress, reduce inflammation, and alter protein post-translational modifications via lysine acetylation and β-hydroxybutyrylation. These properties have further downstream implications involving Akt, PLCγ, CREB, Sirtuin, and mTORC pathways. Further studies of neuroketotherapeutics will enhance our understanding of ketone body molecular biology, and reveal novel central nervous system therapeutic applications.

Keywords: Alzheimer's disease; Bioenergetics; Ketogenic diet; Ketone bodies; Mitochondria; β-hydroxybutyrate.

Figure 1. Ketogenesis and Ketolysis

Hepatic mitochondria serve as the primary site for the production of serum ketone bodies. Acetyl-CoA generated from acyl-CoA β-oxidation is converted to HMG-CoA by the rate-limiting enzyme HMGCS2. HMG-CoA is further processed to the primary ketone bodies acetoacetate and β-hydroxybutyrate, which are released into the circulation via the monocarboxylate transporters (MCTs) 1 and 2. Ketone bodies enter the CNS via MCTs and are oxidized to acetyl-CoA through a series of reactions that require SCOT. Acetyl-CoA undergoes terminal oxidation through the TCA cycle to generate the high-energy electron carriers NADH and FADH₂. Electrons enter the respiratory chain, leading to the generation of ATP through ATP synthase.

Figure 2. Chemical Structures of Biologically Relevant Ketone Bodies

The physiologically relevant ketone bodies in order of decreasing serum concentrations are β-hydroxybutyrate (A), acetoacetate (B), and acetone (C). Acetone is highly volatile and is readily excreted via the pulmonary system or converted to lactate by the liver.

Figure 3. Pleiotropic Effects and Hypothesized Benefits of Ketotherapeutics

Multiple ketotherapeutics produce an increase in serum ketone bodies. Ketone bodies increase oxidative metabolism, reduce oxidative stress, alter epigenetic protein post-translational modifications, increase BDNF signaling, and signal through GPRs in various model systems. Many of these effects require further study to determine the underlying mechanism of action and ultimate therapeutic value. Observed and predicted effects are indicated with solid and dashed lines respectively.