Plasma Lipolysis and Changes in Plasma and Cerebrospinal Fluid Signaling Lipids Reveal Abnormal Lipid Metabolism in Chronic Migraine

Abstract

BackgroundLipids are a primary storage form of energy and the source of inflammatory and pain signaling molecules, yet knowledge of their importance in chronic migraine (CM) pathology is incomplete. We aim to determine if plasma and cerebrospinal fluid (CSF) lipid metabolism are associated with CM pathology.MethodsWe obtained plasma and CSF from healthy controls (CT, n = 10) or CM subjects (n = 15) diagnosed using the International Headache Society criteria. We measured unesterified fatty acid (UFA) and esterified fatty acids (EFAs) using gas chromatography-mass spectrometry. Glycerophospholipids (GP) and sphingolipid (SP) levels were determined using LC-MS/MS, and phospholipase A2 (PLA2) activity was determined using fluorescent substrates.ResultsUnesterified fatty acid levels were significantly higher in CM plasma but not in CSF. Unesterified levels of five saturated fatty acids (SAFAs), eight monounsaturated fatty acids (MUFAs), five ω-3 polyunsaturated fatty acids (PUFAs), and five ω-6 PUFAs are higher in CM plasma. Esterified levels of three SAFAs, eight MUFAs, five ω-3 PUFAs, and three ω-6 PUFAs, are higher in CM plasma. The ratios C20:4n-6/homo-γ-C20:3n-6 representative of delta-5-desaturases (D5D) and the elongase ratio are lower in esterified and unesterified CM plasma, respectively. In the CSF, the esterified D5D index is lower in CM. While PLA2 activity was similar, the plasma UFA to EFA ratio is higher in CM. Of all plasma GP/SPs detected, only ceramide levels are lower (p = 0.0003) in CM (0.26 ± 0.07%) compared to CT (0.48 ± 0.06%). The GP/SP proportion of platelet-activating factor (PAF) is significantly lower in CM CSF.ConclusionsPlasma and CSF lipid changes are consistent with abnormal lipid metabolism in CM. Since plasma UFAs correspond to diet or adipose tissue levels, higher plasma fatty acids and UFA/EFA ratios suggest enhanced adipose lipolysis in CM. Differences in plasma and CSF desaturases and elongases suggest altered lipid metabolism in CM. A lower plasma ceramide level suggests reduced de novo synthesis or reduced sphingomyelin hydrolysis. Changes in CSF PAF suggest differences in brain lipid signaling pathways in CM. Together, this pilot study shows lipid metabolic abnormality in CM corresponding to altered energy homeostasis. We propose that controlling plasma lipolysis, desaturases, elongases, and lipid signaling pathways may relieve CM symptoms.

Identifying causal genes for migraine by integrating the proteome and transcriptome

“…Enriched pathways related to lipid transport and regulation, particularly cholesterol transport and efflux, suggest a key role for lipid balance in migraine development. This aligns with recent research linking lipid metabolism to migraines, indicating potential for lipid-lowering treatments [45]. We observed enrichment in the STING-mediated immune response pathway, suggesting the genes could regulate immune responses, potentially controlling inflammation-related migraine symptoms.…”

The Microbiota-Dependent Treatment of Wuzhuyu Decoction for Chronic Migraine Model Rat Associated with Anxiety-Depression Like Behavior

“…Subtle changes in sphingolipid balance might be associated to neurological disorders and involved in pain-related neuronal function and signaling pathways. By detecting the concentration of sphingolipids in serum and cerebrospinal fluid of patients with migraine attacks, it was used to judge migraine attacks of the decreased total ceramide and dihydroceramide [ 30 ]. The metabolic pathways regulated by WZYD treatment, such as PWY-7347 and SUCSYN-PWY, were reversed in the WZYD+ABX group, which were related to sucrose biosynthesis, which were reported of analgesia in newborn infants undergoing painful procedure [ 31 ].…”

Dysregulation of Amino Acid, Lipid, and Acylpyruvate Metabolism in Idiopathic Intracranial Hypertension: A Non-targeted Case Control and Longitudinal Metabolomic Study

“…Obesity and recent weight gain are known major risk factors for IIH, and significant weight loss through surgical or dietary interventions has been shown to be a disease-modifying treatment of IIH. − Changes in the relative concentrations of lipids including acyl carnitines, diacylglycerides, fatty acids, glycerophospholipids, and lysoglycerophospholipids have previously been associated with obesity compared to non-obese populations. − Changes in acyl carnitines, fatty acids, and oxidized fatty acids are associated with obesity including changes linked to mitochondrial dysfunction and increased oxidative stress in the mitochondria. − The BMIs of the IIH patients and control subjects were matched, so observed changes suggest differences in lipid metabolism in IIH patients independent of obesity. Changes in lipid species in these classes were also observed in response to surgical interventions and differentiated disease remission subjects from those with ongoing active disease in serum (but not CSF).…”