The Role Of PLA2-mediated Phospholipids And Fatty Acids Anabolic Immunoinflammatory Pathway In Major Depressive Disorder

Background The inflammatory changes and mechanisms of Major depressive disorder(MDD)remain unknown.Phospholipase A2(PLA2)is a relatively positive inflammatory enzyme closely related to depression.Studies have shown that PLA2 may participate in the inflammatory changes of depression by mediating the fatty acid anabolic pathway.Previous studies found that the upstream components of the pathway(PLA2 gene polymorphism)and the downstream components of the pathway(eg.PUFAs' level,n-6/n-3 PUFAs)had abnormal change in MDD.Research in this field limited.Niacin skin flush response,as a non-invasive test that can indirectly reflect the erythrocyte membrane fatty acid concentration and the body's oxidative stress level,may help us understand depression better from the perspective of immune inflammation.Objective In view of the above background,we will further explore(1)the role of PLA2-mediated phospholipids and fatty acid metabolism-related immune inflammatory pathways in patients with depression;(2)whether niacin skin flush response can become a biomarker of MDD.Methods(1)90 untreated MDD patients with episodic phase from the Shanghai Mental Health Center and 45 gender-matched health controls(HCs)were recruited.Blood samples from all subjects were used to investigate PLA2 gene polymorphism: c PLA2,i PLA2,PAFAH.Difference between each genotype and clinical symptoms were further analyzed.(2)A total of 21 untreated MDD patients with acute phase from the Shanghai Mental Health Center,and 28 age and gender-matched health controls(HCs)were recruited during the year of 2018.Subjects received the following tests:(1)Food frequency questionnaires(FFQ)to investigate the difference in the average intake levels of fatty acids(especially PUFAs)between patients and HCs as well as the correlation with clinical symptoms;(2)Niacin skin flush response to investigate the differences between the MDD and HCs,and its role in diagnosis of MDD.Also,correlation between fatty acid intake,niacin skin response was further analyzed;(3)ELISA test to investigate the concentration of plasma cenyme PLA2 level.Differences between the MDD and HCs were analyzed.Results(1)There was no difference in the gene frequencies of PAFAH-Mae II,i PLA2-Avr II and c PLA2-Ban I enzyme sites compared to HCs.The genotype of PAFAH-Mae II locus had a statistically significant decrease in G/T genotype after adjusting for age(P<0.05).Correlation analysis showed patients with i PLA2-Avr II site TT type,compared to CT type and CC type,the sleep depth(middle insomnia),muscle system symptoms were heavier,while the sensory system symptoms were lighter.Patients with PAFAH-Mae II locus GG type had a heavier sleep(middle insomnia)than the GT type.Patients with c PLA2-Ban I locus A1 had a higher degree of somatic anxiety and suspected symptoms than the A2 type(P<0.05).(2)(1)Compared to the control group,MDD had significant lower total fatty acids,total MUFA and MUFA(16:1,20:1,22:1),total PUFA and PUFA(18:3,18:4,20:4,20: 5,22:5,22:6)and no statistical difference was found in the other types of fatty acids.Correlation analysis showed the total score of IDS-30 in MDD patients was negatively correlated with PUFA(18:3)level(r=-0.672,P<0.05);SFA was positively correlated with mood change;the more AA was positively correlated with pain symptoms;the n-6/n-3 PUFA ratio was positively correlated with cliniacal symtoms including general interest,energy level,pleasure,sexual interest,insensitivity,and pain.(2)?BF value at the AMN concentration of(10-2.5,10-2,10-1.5,10-1)mol/L and MBF were signicantly higher than that of HCs while log EC50 showed no difference between groups but a negative correlation with the total score of HAMD-17 in patients.ROC curve analysis for MBF in detecting MDD showed a good effect(AUC=0.90,P<0.01).Correlation analysis showed MBF was negatively related with total fatty acids and SFA;Log EC50 was positively related with PUFA(18:3)level.(3)The plasma PLA2 level in the patient group and the control group were 56(24,85)and 117(49,280)ng/m L,respectively,and there was statistical difference between the two groups(Z=-2.26,P<0.05).Correlation analysis: There was no correlation between PLA2 and HAMD-17 total score,HAMA total score as well as IDS-30 total score in patients with depression.There was no correlation between plasma PLA2 level and niacin skin flush response in MDD;there was negative correlation between plasma PLA2 level and SFA(16:0)(r=-0.40,P<0.05)and MUFA(r=-0.42,P<0.05)in all subjects included.Conclusion There is a lack of sources of unsaturated fatty acids in depressed patients,especially the lack of n-3 PUFA,and the increased intake of n-6/n-3 PUFAs are closely related to the symptoms of patients.The niacin skin flush response increased in untreated MDD patients,and the sensitivity is related to the severity of depressive symptoms and long-term intake level and proportion of fatty acid.MDD patients have abnormality polymorphism of gene PLA2 and lower plasma level,which coding the key enzyme in fatty acid anabolic pathway.PLA2 may be involved in the pathophysiological mechanisms of MDD at the level of fatty acid metabolism pathways.This conclusion requires further validation.