Adenosine and Ketogenic Treatments

Abstract

It is well known that the neuromodulator adenosine, acting through the adenosine A 1 receptor subtype, can limit or stop seizures. In 2008, adenosine was proposed as a key component of the anticonvulsant mechanism of the ketogenic diet (KD), a very low carbohydrate diet that can be highly effective in drug-refractory epilepsy. In this study, we review the accumulated data on the intersection among adenosine, ketosis, and anticonvulsant/antiepileptogenic effects. In several rodent models of epilepsy and seizures, antiseizure effects of ketogenic treatments (the KD itself, exogenous ketone bodies, medium-chain triglycerides or fatty acids) are reversed by administration of an adenosine A 1 receptor antagonist. In addition, KD treatment elevates extracellular adenosine and tissue adenosine content in brain. Efforts to maintain or mimic a ketogenic milieu in brain slices reveal a state of reduced excitability produced by pre-and postsynaptic adenosine A 1 receptor-based effects. Long-lasting seizure reduction may be due to adenosinebased epigenetic effects. In conclusion, there is accumulating evidence for an adenosinergic anticonvulsant action in the ketogenic state. In some cases, the main trigger is mildly but consistently lowered glucose in the brain. More research is needed to investigate the importance of adenosine in the antiepileptogenic and neuroprotective effects of these treatments. Future research may begin to investigate alternative adenosinepromoting strategies to enhance the KD or to find use as treatments themselves.

Enhancement of Ketone Supplements-Evoked Effect on Absence Epileptic Activity by Co-Administration of Uridine in Wistar Albino Glaxo Rijswijk Rats

“…Thus, these results above suggest that effect of both uridine and KSMCT on absence epileptic activity may be modulated (at least partly) by A 1 Rs. According to this hypothesis, it was demonstrated that A 1 Rs can inhibit epileptic activity [ 1 , 4 , 45 , 58 , 62 ], brain areas, such as somatosensory cortex, which may have a role in absence epilepsy genesis contain A 1 Rs [ 1 , 44 , 45 , 63 ] and activity (expression) of A 1 Rs was decreased in the somatosensory cortex (cortical focus) in presymptomatic WAG/Rij rats [ 1 , 4 , 45 ]. By synaptic inhibition, A 1 Rs, among others, may reduce Ca 2+ influx and inhibits excitatory synaptic transmission (e.g., decreases the release of glutamate) as well as increase the activity of ATP-sensitive potassium channels [ 4 , 60 , 64 ].…”

Pharmacological and non-pharmacological therapeutic interventions for the treatment of spinal cord injury-induced pain

“…Additionally, a ketogenic diet causes the body to utilize ketones instead of glucose for cellular energy, and ketone metabolism produces fewer reactive oxygen species and free radicals than glucose metabolism ( 154 ). Finally, ketone metabolism elevates adenosine ( 155 ), which is known to be anti-inflammatory ( 156 ).…”

Supplementation of Regular Diet With Medium-Chain Triglycerides for Procognitive Effects: A Narrative Review

“…One of the mechanisms of the C8 anticonvulsant properties seems to be mediated through adenosine receptors. It is well established that elevated extracellular adenosine reduces seizure activity in several seizure models, and the anticonvulsant action is mediated through A 1 R adenosine receptors (104,105). One of the main factors controlling the amount of extracellular adenosine is the adenosine kinase (ADK) (105).…”

“…It is well established that elevated extracellular adenosine reduces seizure activity in several seizure models, and the anticonvulsant action is mediated through A 1 R adenosine receptors (104,105). One of the main factors controlling the amount of extracellular adenosine is the adenosine kinase (ADK) (105). KD reduces ADK activity which results in increased extracellular adenosine and suppressed seizure activity (106).…”

“…Therefore, both KD and ketogenic supplementation of regular diet seem to have neuroprotective effects mediated by A 1 R and possibly also A 2 R receptors (Figure 2). It is possible that increased ATP synthesis due to influx of KB or MCFAs in the brain results in elevated extracellular adenosine concentrations, which act upon AR (105,113), although the exact mechanism is unknown.…”