Dysfunctional Plasma Lipid Metabolism Contributes to Chronic Migraine Pathology
Authors: Fonteh Alfred Nji , Castor Katherine , Kershaw Kassie , Im Eun Jung , Dawlaty Jessica , Gross Noah , Arakaki Xianghong , Woldeamanuel Yohannes , Harrington Michael , Cowan Robert 
Published: December 2020

BackgroundLipids are a major storage form of energy, and the source of inflammatory and pain signaling molecules, yet their contribution to chronic migraine (CM) is not fully known. Our aim is to determine if plasma lipid metabolism contributes to CM pathology.MethodsWe obtained plasma from healthy controls (CT, n=10) or CM subjects (n=17) diagnosed using the International Headache Society criteria, and measured unesterified (UFA), and esterified fatty acids (EFA) using gas chromatography‐mass spectrometry. Plasma glycerophospholipids (GP) and sphingolipids (SP) were determined using LC‐MS/MS and phospholipase A2 (PLA2) activity was determined using fluorescent substrates.ResultsAge, gender distribution, and BMI were similar, but while 48 % and 35 % of CM participants were on NSAIDs or taking anti‐oxidants, respectively, no CT subjects were on medications. Unesterified levels of three even chain saturated fatty acids (SAFA), two odd chain SAFAs, the sum of even chain SAFAs, sum of SAFAs, six even chain monounsaturated fatty acids (MUFA), 2 odd chain MUFAs, five omega‐3 (n−3) polyunsaturated fatty acids (PUFA), and five omega‐6 (n−6) PUFAs are higher in CM. The sum of all UFAs is significantly elevated in CM plasma. Esterified levels of two even chain SAFAs, the sum of even chain SAFAs, one odd chain SAFAs, the sum of all SAFAs, five even chain MUFAs, three odd chain MUFAs, five n−3 PUFAs, the sum of n−3 PUFAs, and three n−6 PUFAs, are higher in CM plasma. For both UFA and EFA, only the C16:1 composition was significantly higher in CM plasma. The ratios C16:1/C16:0 and C20:4n−6/homo‐γ‐C20:3n−6 representative of delta‐9 and delta‐5 desaturases, respectively, are higher in CM. While PLA2 activity was similar, the UFA to EFA ratio of even chain MUFA and the sum of MUFAs is higher in CM. Elongase indices < C18:0 were lower and indices >C20:0 were higher in CM. Of all GP/SPs detected, only ceramide composition is lower (p=0.0003) in CM (0.26 ± 0.07) compared to CT (0.48 ± 0.06). The ceramide to dihydroceramide and ceramide to sphingomyelin ratios are also significantly lower in CM.ConclusionSince plasma UFAs are known to correspond to adipose tissue levels, higher plasma fatty acids and UFA/EFA ratios suggest enhanced mobilization from adipose storage sites in CM. Higher C16:1 composition concomitant with an increase in the C16:1/C16:0 ratio suggests increased delta‐9 desaturase activity in CM. Lower ceramide ratios suggest reduced de novo synthesis and/or hydrolysis of sphingomyelin. Together, these studies show dysfunctional lipid metabolism in CM. We propose that controlling plasma lipid metabolism may relieve CM symptoms.Support or Funding InformationRecruitment and sample collection at Stanford University School of Medicine was supported by generous gifts from the Higgins Family Trusts. Lipid analyses was supported by NIH 5R01NSO72497 and HMRI.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.