br Ketone body metabolism and neuronal excitability One of t

Ketone body metabolism and neuronal excitability One of the best examples of the close connection between metabolism and neuronal excitability is illustrated by the effect of ketone bodies on epileptic seizures. One third of patients suffering from epileptic seizures do not respond to conventional pharmacological treatments. In these cases of pharmacoresistant epilepsy, the use of so-called "ketogenic diets" has proven successful. These diets have an elevated content in fat and a reduced content in carbohydrates, thus mimicking fasting and forcing the body to produce high levels of ketone bodies [5]. Ketone bodies are by-products of fatty the original source catabolism. They can cross the blood-brain barrier and temporarily replace glucose as the main fuel to meet the energy requirements of the brain in face of glucose shortage or low availability. These situations include starvation or pathological situations in which glucose sensing and uptake are limited, such as diabetes [6]. There are several proposed mechanisms through which ketone bodies may confer resistance against epileptic seizures. Some of these mechanisms, which are not mutually exclusive, include their effect on modulation of ionic channels such the potassium ATP-sensitive (KATP) channels, the Acid Sensing Ion Channel 1a (ASIC-1a) or the A1 purinergic receptor [7], [8], [9], [10]. Other studies have suggested changes in gene expression that involve chromatine remodeling and subsequent decreased expression of BDNF and its receptor TrkB through the assembly of a transcriptional repression complex derived from reduced glycolytic flux [11] or by the direct inhibitory effects of the ketone body β-hydroxybutyrate on Histone Deacetylases (HDAC) [12], which could lead to upregulation of the transcription factor Nrf2 and increased levels of glutathione that can protect against seizure-induced oxidative damage [13], [14]. It has also been shown that ketogenic diets lead to alterations in amino acid metabolism with concomitant changes in the balance of excitatory vs. inhibitory neurotransmitters [15], [16], thus affecting neuronal firing rates. The precise mechanisms through which ketone bodies regulate neuronal excitability constitute a highly active and fascinating field of research. Given the limited length of this manuscript, we refer the readers to other review articles that have discussed this topic extensively [17], [18], [19]. Interestingly, it has also been proposed that it might not only be the increase in ketone body utilization, but the attendant decrease in glycolytic flux, which could ultimately be responsible for the protective effect of the ketogenic diet on neuronal excitability and seizure control [11], [20]. However, whether reduction in glycolytic flux attenuates or elevates the threshold for epileptic seizures remains still under debate, as its efficiency depends on the nature of the seizure trigger [21]. Ketogenic diets not only alters the ketone body:glucose ratio, but they also increase the presence of other metabolites in circulation. Ketogenic diets contain both long-chain fatty acids (LCFA) and medium-chain fatty acids (MCFA) to feed ketogenesis in the liver. Both LCFA and MCFA are abundant in plasma of patients fed a ketogenic a diet. Unlike LCFAs, MCFAs can cross the blood-brain barrier and become available to brain cells [22]. In fact, MCFAs have the ability to reduce excessive firing both in vitro and in vivo[23], [24], and further studies showed that the MCFA decanoic acid has a strong inhibitory effect on seizures through a mechanism that involves direct inhibition of AMPA receptor, probably through physical interaction with its transmembrane domain [25]. Altogether, these results strongly suggest that the anticonvulsant effects derived from the ketogenic diet are not only derived from the biological effects of ketone bodies, but rather from the complexity of systemic metabolic adaptations.