Table 2.
Putative mechanisms of the antiseizure effects of the ketogenic diet
| Mediator/physiological change | Basis | Mechanism of antiseizure effects |
|---|---|---|
| Ketone bodies (acetone, acetoacetate, and β-hydroxybutyrate have antiseizure activity; further, acetoacetate, and β-hydroxybutyrate provide resistance to oxidative stress) | Chronic ketosis as a result of elevated FFAs | Unknown ? Inhibit presynaptic release of glutamate by competing with Cl− for allosteric activation of vesicular glutamate transporter ? Activate KATP and GABAB receptors (reduced ATP also activates KATP) ? Inhibit HDAC, leading to increased resistance to oxidative stress ? Inhibit mitochondrial permeability transition |
| Increased GABA synthesis (flux through GAD) | Brain converts ketone bodies to acetyl-CoA; increased flux through TCA cycle, consumes oxaloacetate, which is less available to the aspartate aminotransferase reaction; less glutamate is converted to aspartate and relatively more glutamate becomes available to the glutamine synthetase and GAD reactions | ? Enhanced GABA-mediated inhibition |
| Adenosine | Levels of ATP elevated leading to increased conversion to adenosine in neurons and astrocytes | Activation of adenosine A1 receptors on excitatory neurons |
| Increased mitochondrial function and biogenesis | Unknown | Increase ATP production and enhanced energy reserves |
| Nrf2 | Ketogenic diet initially produces mild oxidative and electrophilic stress, activating Nrf2 via redox signaling | Reversal of chronically low GSH in epilepsy Induction of genes encoding protective proteins; improvement of the mitochondrial redox state |
| Reduced mitochondrial ROS | Enhanced expression of UCPs by fatty acids acting on PPAR and FOX | Increased UCPs diminish ΔΨ leading to reduced ROS |
| Anaplerosis | In ketogenic diet, there is reduction in glycolysis and increase in oxidation of FA and ketone bodies (glycolytic restriction/diversion) | Correct glutamate and GABA deficiencies in brain Enhanced neuronal ATP production Reduce expression of proepileptic BDNF and TrkB through NRSF binding to NRSE; decrease in cytosolic and nuclear levels of NADH |
| PUFAs | Ketogenic diet enhances mobilization of PUFAs from adipose tissue to liver and brains | PUFAs directly affect ion channels Activation of PPARα and PGC-1α (coactivator) leads to changes in transcription of genes linked to energy, amino acid, and neurotransmitter metabolism Boost activity of UCPs |
| Medium-chain triglycerides | Exogenous administration of in the medium-chain triglyceride ketogenic diet | Unknown (similar action to valproate) |
| FFA3 | Activated by short-chain fatty acids and β-hydroxybutyrate | Inhibit N-type voltage-gated calcium channels, leading to reduced glutamate release at synapses |
FFAs, Free fatty acids; HDAC, histone deacetylase; GABA, γ-aminobutyric acid; GAD, glutamic acid decarboxylase; Nrf2, NF E2-related factor 2; TCA, tricarboxylic acid; GSH, glutathione; ROS, reactive oxygen species; UCPs, uncoupling proteins; PPAR, peroxisome proliferator-activated receptor; FOX, forkhead box; FA, fatty acid; NRSF, neural restrictive silencing factor; NRSE, neuron restrictive silencing element; PUFAs, polyunsaturated fatty acids; BDNF, brain-derived neurotrophic factor; TrkB, tropomyosin receptor; NADH, nicotinamide adenine dinucleotide (reduced).