Adenosine, Ketogenic Diet and Epilepsy: The Emerging Therapeutic Relationship Between Metabolism and Brain Activity

Abstract

For many years the neuromodulator adenosine has been recognized as an endogenous anticonvulsant molecule and termed a “retaliatory metabolite.” As the core molecule of ATP, adenosine forms a unique link between cell energy and neuronal excitability. In parallel, a ketogenic (high-fat, low-carbohydrate) diet is a metabolic therapy that influences neuronal activity significantly, and ketogenic diets have been used successfully to treat medically-refractory epilepsy, particularly in children, for decades. To date the key neural mechanisms underlying the success of dietary therapy are unclear, hindering development of analogous pharmacological solutions. Similarly, adenosine receptor–based therapies for epilepsy and myriad other disorders remain elusive. In this review we explore the physiological regulation of adenosine as an anticonvulsant strategy and suggest a critical role for adenosine in the success of ketogenic diet therapy for epilepsy. While the current focus is on the regulation of adenosine, ketogenic metabolism and epilepsy, the therapeutic implications extend to acute and chronic neurological disorders as diverse as brain injury, inflammatory and neuropathic pain, autism and hyperdopaminergic disorders. Emerging evidence for broad clinical relevance of the metabolic regulation of adenosine will be discussed.

Adenosine Kinase: Exploitation for Therapeutic Gain

“…Mitochondrial bioenergetics. As a "retaliatory metabolite" adenosine is directly linked to mitochondrial bioenergetics and energy homeostasis (Newby et al, 1985;Sommerschild and Kirkeboen, 2000;Peart and Headrick, 2007;Masino et al, 2009). It needs to be stressed that under basal conditions, levels of adenosine (;100 nM in brain) are nearly 10,000-fold lower than ATP (Pazzagli et al, 1995;Delaney and Geiger, 1996).…”

“…A ketogenic diet forces the brain to use ketones instead of glucose as primary energy source, and it is those metabolic changes that are thought to underlie the therapeutic effects of this type of dietary intervention (Bough et al, 2006;Kalapos, 2007;Ma et al, 2007;Bough, 2008;Yellen, 2008). A large body of evidence supports the notion that a ketogenic diet leads to increased adenosine signaling in the brain Geiger, 2008, 2009;Masino et al, 2009Masino et al, , 2012. Indeed, it was recently shown that a ketogenic diet reduced the expression of ADK in mice (Masino et al, 2011).…”

Changes in Brain Cortex Sensitivity to Epileptogens under Conditions of Ketogenic Diet

“…The animals were fed KD including 80% lipids, 3.3% carbohydrates, and 16.7% proteins [3] for 4 weeks. Controls received common fodder under the same conditions during the same period.…”

“…The development of anticonvulsive effect is associated with activation of the cerebral GABAergic system, inhibition of production and release of proinflammatory cytokines, increase in purinergic mediation, and reduction of the stimulatory amino acid tone [3,4]. Excitability of the cerebral cortex for the epileptogenic effects of neurotoxins with different mechanisms of neurotropic activity in animals receiving KD attracted our attention.…”

The Genetics of Common Epilepsy Disorders: Lessons Learned from the Channelopathy Era

“…Metabolic pathways, particularly those involved in energy homeostasis, have been implicated in neuropsychological phenotypes including bipolar disorder, schizophrenia, and anxiety disorders [104][105][106]. The brain is the most energetically demanding organ in the body and glucose is its preferred fuel.…”