Changes in Plasma Lipid Levels Following Cortical Spreading Depolarization in a Transgenic Mouse Model of Familial Hemiplegic Migraine

Abstract

Metabolite levels in peripheral body fluids can correlate with attack features in migraine patients, which underscores the potential of plasma metabolites as possible disease biomarkers. Migraine headache can be preceded by an aura that is caused by cortical spreading depolarization (CSD), a transient wave of neuroglial depolarization. We previously identified plasma amino acid changes after CSD in familial hemiplegic migraine type 1 (FHM1) mutant mice that exhibit increased neuronal excitability and various migraine-related features. Here, we aimed to uncover lipid metabolic pathways affected by CSD, guided by findings on the involvement of lipids in hemiplegic migraine pathophysiology. Using targeted lipidomic analysis, we studied plasma lipid metabolite levels at different time points after CSD in wild-type and FHM1 mutant mice. Following CSD, the most prominent plasma lipid change concerned a transient increase in PGD2, which lasted longer in mutant mice. In wild-type mice only, levels of anti-inflammatory lipid mediators DPAn-3, EPA, ALA, and DHA were elevated 24 h following CSD compared to Sham-treated animals. Given the role of PGs and neuroinflammation in migraine pathophysiology, our findings underscore the potential of monitoring peripheral changes in lipids to gain insight in central brain mechanisms.

Alterations in metabolic flux in migraine and the translational relevance

“…and without aura, with associations with disease duration [37][38][39] • Hypoglycaemia reduced CSD threshold, increased duration and exhibited spontaneous CSD events [29][30][31] Repeated migraine attacks and activation of nociceptive regions may lead to abnormalities in glucose metabolism Lactate production • Serum and plasma measurements exhibit upregulated lactate in migraine patients both with and without aura [44][45][46] • 1 H-MRS studies demonstrated increased lactate in familial hemiplegic migraine and migraine with aura, but not in migraine without aura [48][49][50] • Rat 1 H-MRS studies exhibit increased lactate and reduced pH during CSD [41] Lactate excess may be produced as a result of tissue hypoxia during metabolically challenging events such as CSD. Lactate may be used as alternative energy substrate and could signify an impaired astrocytic-neuronal interaction Lipid metabolism • Alterations cholesterol and LDL were identified in migraine patients [58][59][60][61] • Higher lipid content in serum was associated with frequency and severity of migraine attacks [59,60,62] Following CSD in mice, blood metabolite measurements exhibit alterations in lipid metabolism including increased prostaglandin and anti-inflammatory lipid mediators [66] It is unknown if hyperlipemia is a cause or effect of migraine or related to comorbidities. Associations with cholesterol and LDL may provide an explanation for the increased cardiovascular and stroke risk in migraine with aura [63,64] Fatty acid oxidation • Chronic migraine patients demonstrated differentially metabolized fatty acids compared to controls, with levels correlating with depression [76] • PEA supplementation reduced headache attacks per month and pain intensity in migraine without aura, [78] and reduced pain intensity (in combination with non-steroidal anti-inflammatory analgesics) in migraine with aura [79].…”

“…It is not yet known if increased cholesterol in migraine is a cause, an effect or correlations are due to underlying common factors. However, metabolite measurements in blood from mice following CSD also demonstrate alterations in lipid metabolism including increased prostaglandin and anti-inflammatory lipid mediators [66]. Additional studies in murine model are needed to further elucidate links between migraine, aura subtypes and cholesterol metabolism as well as pathophysiology.…”