Mechanisms of Ketogenic Diet Action

Within the past two decades, interest in understanding the therapeutic mechanisms of ketogenic diet (KD) action has grown steadily. Expanded knowledge about underlying mechanisms has yielded insights into the biochemical basis of brain function, both normal and pathologic. Metabolic changes likely related to the KD’s anticonvulsant properties include – but are not limited to – ketosis, reduced glucose, elevated fatty acid levels, and enhanced bioenergetic reserves. Direct neuronal effects induced by the KD may involve ATP-sensitive potassium (KATP) channel modulation, enhanced purinergic (i.e., adenosine) and GABAergic neurotransmission, increased brain-derived neurotrophic factor (BDNF) expression consequent to glycolytic restriction, attenuation of neuroinflammation, as well as an expansion in bioenergetic reserves and stabilization of the neuronal membrane potential through improved mitochondrial function. Importantly, beyond its utility as an anticonvulsant treatment, the KD may also exert neuroprotective and anti-epileptogenic properties, heightening the clinical potential of the KD as a disease-modifying intervention. As dietary treatments are already known to evoke a wide array of complex metabolic changes, future research will undoubtedly reveal a more complex mechanistic framework for KD action, but one which should enable improved formulations offering comparable or superior efficacy with fewer side-effects, not only for epilepsy but perhaps a broader range of neurological disorders.