Abstract
An increasing amount of evidence suggests that migraines are a response to a cerebral energy deficiency or oxidative stress levels that exceed antioxidant capacity. The ketogenic diet (KD), a diet mimicking fasting that leads to the elevation of ketone bodies (KBs), is a therapeutic intervention targeting cerebral metabolism that has recently shown great promise in the prevention of migraines. KBs are an alternative fuel source for the brain, and are thus likely able to circumvent some of the abnormalities in glucose metabolism and transport found in migraines. Recent research has shown that KBs—D-β-hydroxybutyrate in particular—are more than metabolites. As signalling molecules, they have the potential to positively influence other pathways commonly believed to be part of migraine pathophysiology, namely: mitochondrial functioning, oxidative stress, cerebral excitability, inflammation and the gut microbiome. This review will describe the mechanisms by which the presence of KBs, D-BHB in particular, could influence those migraine pathophysiological mechanisms. To this end, common abnormalities in migraines are summarised with a particular focus on clinical data, including phenotypic, biochemical, genetic and therapeutic studies. Experimental animal data will be discussed to elaborate on the potential therapeutic mechanisms of elevated KBs in migraine pathophysiology, with a particular focus on the actions of D-BHB. In complex diseases such as migraines, a therapy that can target multiple possible pathogenic pathways seems advantageous. Further research is needed to establish whether the absence/restriction of dietary carbohydrates, the presence of KBs, or both, are of primary importance for the migraine protective effects of the KD.
Highlights
Migraine is a complex, common and debilitating neurological disorder [1]
Despite migraine’s primary pathogenic mechanisms being still largely unknown [8], accumulating evidence suggests that migraines could be—at least partially—an energy deficit syndrome of the brain, and the migraine attack a response to increased oxidative stress and/or hypometabolism [9]
Out of the three physiological ketone bodies (KBs), D-BHB constitutes up to 70% of KBs produced during ketosis [15] and is of particular interest, since it is a glucose transporter protein, i.e., a (GLUT)-independent alternative metabolite, and a vital signalling molecule [16]
Summary
Common and debilitating neurological disorder [1]. Its episodic form is characterized by recurrent moderate to severe, typically throbbing and unilateral headache attacks that last between 4–72 h, which are aggravated by any kind of physical activity and accompanied by either photo-, phono-, or osmophobia, nausea, or a combination of these. This review will describe the mechanisms by which the presence of ketone bodies, D-BHB in particular, could influence migraine pathophysiology (see Figure 1) To this end, common abnormalities in migraine (such as abnormalities in glucose metabolism and transport, mitochondrial functioning, oxidative stress, cerebral excitability, inflammation and the gut microbiome) are summarised with a particular focus on clinical data, including phenotypic, biochemical, genetic and therapeutic studies. (b) D-β-hydroxybutyrate (D-BHB; with or without the context of a ketogenic diet) has been shown to positively influence each of these mechanisms: increasing cerebral metabolism, increasing glucose transport (including glucose transporter 1 (GLUT1) deficiency), increasing mitochondrial functioning, reducing cerebral excitability, decreasing cortical spreading depressions (CSD) incidence, reducing oxidative stress (reactive oxygen species (ROS)), decreasing inflammation, improving the microbiome and increasing digestive health.
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