Lipid Mediator Profiles Predict Response to Therapy with an Oral Frankincense Extract in Relapsing-Remitting Multiple Sclerosis

Klarissa Hanja Stürner,Oliver Werz,Frank Leypoldt,Andreas Koeberle,Ole Pless,Christoph Heesen,Markus Otto,Friedemann Paul

doi:10.1038/s41598-020-65215-6

Abstract

Lipid mediators (LMs) are a unique class of immunoregulatory signalling molecules and known to be affected by frankincense extracts. We performed LM profiling by metabololipidomics in plasma samples from 28 relapsing-remitting multiple sclerosis (RR-MS) patients who took a standardised frankincense extract (SFE) daily for eight months in a clinical phase IIa trial (NCT01450124) and in 28 age- and gender-matched healthy controls. Magnetic resonance imaging, immunological outcomes and serum neurofilament light chain levels were correlated to changes in the LM profiles of the RR-MS cohort. Eight out of 44 analysed LMs were significantly reduced during an eight-month treatment period by the SFE and seven of these eight significant LM derive from the 5-lipoxygenase (5-LO) pathway. Baseline levels of 12- and 15-LO products were elevated in patients who exhibited disease activity (EDA) during SFE treatment compared to no-evidence-of-disease-activity (NEDA) patients and could predict treatment response to the SFE in a prediction model at baseline. Oral treatment with an SFE significantly reduces 5-LO-derived LMs in RR-MS patients during an eight-month treatment period. Treatment response to an SFE, however, seems to be related to 12-,15-LO and cyclooxygenase product levels before SFE exposure. Further studies should confirm their biomarker potential in RR-MS and SFE treatment.

Highlights

The Lipid mediators (LMs) profile in relapsing-remitting multiple sclerosis (RR-MS) patients before and after oral BA-treatment with an standardised frankincense extract (SFE) for eight months in a clinical phase IIa trial
12-HHT, measured LMs were significantly higher in RR-MS patients compared to healthy age- and gender-matched controls with the topmost fold-increase (>1000-fold) in five LMs being: the three 5-LO-derived LM lipoxin A4 and/or isomers, 5,12-di-hydroxyeicosatetraenoic acid (5,12-diHETE), leukotriene B4 (LTB4), and the two 12- or 15-LO-derived LM protectin D1 (PD1) and protectin DX (PDX)
These were: 9-HETE, lipoxin A4 and/or isomers, lipoxin B4 and/or isomers, 5,15-diHETE, LTB4, 5-HETE and its metabolites 5-oxo-eicosatetraenoic acid (5-oxo-ETE), and 5S-hydroxy-6E,8Z,11Z-eicosatrienoic acid, (5-HETrE). Seven of these eight LMs are generated www.nature.com/scientificreports by the 5-LO pathway, while 9-HETE is predominantly produced by non-enzymatic oxidation of arachidonic acid. For seven of these LMs the reduction was more pronounced in exhibited disease activity (EDA) patients when compared to MS patients fulfilling NEDA criteria during SFE treatment (Figs. 2, 3b and Supplemental Table S2) thereby triggering further analyses of the NEDA and EDA subgroups

Summary

Methods

The study was approved by the German Federal Institute for Drugs and Medical Devices (BfArM, Approval No 4036771), and by the local ethics committees (Ethik-Kommission der Ärztekammer Hamburg, Approval No PVN3389 and PVN2758 and Ethikkommission der Charité – Universitätsmedizin Berlin, Approval No ZS EK 13572/09). All participants gave their written informed consent at screening and the study and all experiments were conducted in accordance with the Declaration of Helsinki and with good clinical practice. Signal intensities (peak areas) were normalized to the internal standard PGB1 to correct for differences in sample preparation

Results

Discussion

Conclusion