Comment; Ketogenic diets have great health benefits. Decreased seizure activity due to less rapidly released energy by glucose metabolism sounds rational. There’s a lot more involved than that however as the excerpt shows. Very detailed, great article!
Mechanism of Action
The understanding of the mechanisms of action of KD is incomplete; however, some theories have been advanced about how it modifies the neuronal metabolism and excitability in order to reduce the seizure frequency. Possibly, the real mechanism of reduction of cortical hyperexcitability involves multiple factors. Some of the systems involved in seizure reduction are related to metabolic changes in the blood and cerebrospinal fluid (CSF), including a decrease in glucose levels and an increase in KB. The mitochondria function and energy reserve may also play a role in the KD mechanisms, resulting in synapse stabilization and excitatory decrease.
Ketone Bodies: Anticonvulsant Effects
Ketone bodies, acetoacetate, and β-hydroxybutyrate (βOHB), are byproducts of fatty acid oxidation in the mitochondrial matrix of the hepatocytes. There are many theories about the role of KB, but the existence of an anticonvulsant effect is controversial. Some authors have found no relationship between KB and synaptic transmission and seizure control.
Experimental studies in an animal model showed that in rats exposed to KD there was no change in synaptic plasticity, using paired-pulse modulation and long-term potentiation (Thio et al., 2010). Similarly, Likhodii et al. (2003) did not detect any anticonvulsant effects in either ketone body (Likhodii et al., 2003). In spontaneously epileptic Kcna1-null mice, KB supplementation resulted in attenuation of electrographic seizure-like events (Kim et al., 2015). These authors also observed an inhibitory effect of KB on mitochondrial permeability transition related to apoptotic and necrotic death. Moreover, in experimental models, acetoacetate exerted a broad-spectrum anticonvulsant effect (Rho et al., 2002). In another study, Rho (2017) described a relationship among KB, neurotransmitter release and ATP-sensitive potassium channels (Rho, 2017). Similarly, to these studies, injection of KB led to the reduction of seizure susceptibility (Gasior et al., 2008). Ma et al. (2007) found a decrease of the spontaneous firing rate in sections of mouse tissue, which was eliminated in the absence of ATP-sensitive potassium channels (KATP). In addition, KB can exert a direct inhibitory effect on the vesicular glutamate transport (Juge et al., 2010). It is possible that these divergent results are related to the different concentrations of KB used in these studies and the diverse seizure thresholds of the animal models. These conflicting results can be also explained by differences in diet composition.
Neuronal Metabolism and Synaptic Function
Another hypothesis regarding the function of the KD is related to changes in neuronal metabolism, mitochondrial function and energy reserve, and the environment. In normal conditions, the usual substrate for the neurons is glucose. To facilitate its diffusion through the brain-blood barrier, glucose transports are present in the brain capillary endothelial layer (Greene et al., 2003). The glucose metabolism produces the rapidly available energy that is necessary for seizure activity. Therefore, in patients on the KD, the blood glucose energy levels are low, and the brain begins to use KB for energy. This anaerobic metabolism slows the energy availability, which reduces seizures. The anticonvulsant propriety of a decrease in glucose metabolism has been shown in experimental models in which the administration of 2-Deoxy-D-glucose elevates the seizure threshold (Garriga-Canut et al., 2006). The anticonvulsant effect of the KD can be quickly reversed after glucose infusion (Huttenlocher, 1976). Based on these data, we can postulate the influences not only of the KB, as discussed above, but also the reduction in glucose levels as a mechanism of action of the KD.
Chronic ketosis may play a role in the KD anticonvulsant properties, since it has been shown that chronic ketosis elevates the brain energy reserve via stabilization and reduction of excitability of synapses (Devivo et al., 1978). The energy reserve is directly associated with mitochondria, which is an important element to consider in the antiepileptic effect of KD. Bough et al. (2006) demonstrated an increase in mitochondria biogenesis in an experimental model of rats fed with KD, indicating an increase in the energy stores (Bough et al., 2006). The increase in mitochondrial metabolism leads to an increase in ATP production, which activates KATP, in turn attenuating neuronal excitability. This activation may be associated with adenosine A1 receptors (Li et al., 2010) and GABAB receptors (Mironov and Richter, 2000).
In this process, we can postulate that modifications of the metabolism are associated with an increase of ATP, and improve mitochondrial capacity and cell energy, with an increase in metabolic resilience.
Neurotransmitter Function
The KD-induced synaptic stabilization is additionally related to changes in critical amino acids as a result of ketone metabolism. It has been proposed that KD interferes with the concentration of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter. There is evidence in clinical practice of increased GABA levels in the CSF of patients on the KD diet (Wang et al., 2003). The decrease in aspartate levels promoted by KB lead to the synthesis of GABA. This occurs because of the inhibitory effect of aspartate on glutamate decarboxylase and the facilitation of the conversation of glutamate to glutamine in the astrocytes (Yudkoff et al., 2008). Not only can GABA be increased, but also other neurotransmitters such as adenosine A1 can be implicated in the anti-seizure effect of the KD (Szot et al., 2001). However, more evidence is needed.
Gut Microbiota, Inflammation, and Genetic
The role of gut microbiota has recently been studied for its effect on several diseases, especially those with some inflammatory involvement. Several metabolic pathways are known to be modulated by the gut microbiota. Olson et al. (2018) demonstrated the impact of gut microbiota on the anti-seizure effect of KD. She found that KD modifies the gut microbiota, with a decrease in alpha-diversity and increases in the putatively beneficial bacteria Akkermansia muciniphila and Parabacteroides spp. This microbiota transformation leads to changes in the colonic luminal metabolome, with a decrease in gamma-glutamyl amino acids. This increases the GABA/glutamate content in the brain by decreasing gamma-glutamyl amino acids in the blood (Olson et al., 2018). In an acute electroshock model, it is reported that KD confers protection against seizures. Moreover, KD decreases the frequency of spontaneous seizures in Kcna1 knockout mice (Kim et al., 2015). In summary, changes in the gut microbiota seem to be important for the KD-mediated seizure protection.
The role of inflammatory cytokines in epilepsy is well known, and there is evidence that KD also interferes with pro-inflammatory cytokines. Dupuis et al. (2015) showed a peripheral and brain reduction of interleukin 1β and other pro-inflammatory cytokines in rats treated with KD in the LPS model.
Notably, there is a relationship between metabolic and epigenetic modifications. Shimazu et al. (2013)observed that βOHB inhibits class I histone deacetylases. During the KD, the elevation of βOHB causes changes in large-scale gene transcription but particularly those linked to oxidative-stress resistance factors. This result emphasizes that the KD has a potential role as a disease-modifying treatment in epilepsy.
In conclusion, all the mechanisms described above lead to systemic modifications and a dynamic metabolic homeostasis, in which the interplay among KB, glucose levels, mitochondrial function, synaptic neurotransmitters, and channel modifications can lead to changes in the seizure threshold and hyperexcitability. These changes contribute to the final antiseizure mechanism of KD.
Multiple mechanisms of action may explain why the modification of the KD can be effective even without ketosis. Importantly, the KD systemic action can have a broad spectrum of effects that may be beneficial in the treatment of different types of epilepsy and associated comorbidities such as cognition impairment, psychiatric disturbance, and sudden unexplained death.
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