Studies on Bioactive Lipid Mediators Involved in Brain Function and Neurodegenerative Disorders. The effect of ¿-3PUFA supplementation and lithium treatment on rat brain sphingomyelin species and endocannabinoids formation; changes in oxysterol profiles in blood of ALS patients and animal models of ALS.

Abstract

Lipids are important for structural and physiological functions of neuronal cell membranes. They exhibit a range of biological effects many are bioactive lipid mediators derived from polyunsaturated fatty acids such as sphingolipids, fatty acid ethanolamides (FA-EA) and endocannabinoids (EC). These lipid mediators and oxysterols elicit potent bioactive functions in many physiological and pathological processes of the brain and neuronal tissues. They have been investigated for biomarker discovery of ageing, neuroinflammation and neurodegenerative disorders. The n-3 fatty acids EPA and DPA are thought to exhibit a range of neuroprotective effects many of which are mediated through production of such lipid mediators. The aims of this study were to evaluate the effects of n-3 EPA and n-3 DPA supplementation on RBC membranes and in this way assess dietary compliance and to investigate brain sphingomyelin species of adult and aged rats supplemented with n-3 EPA and n-3 DPA to evaluate the effects and benefits on age-related changes in the brain. Furthermore, to study the effects of lithium on the brain FA-EAs and ECs to further understand the neuroprotective effects of lithium neuroprotective action on neuroinflammation as induced by LPS. Finally to examine if circulating oxysterols are linked to the prevalence of ALS and whether RBC fatty acids are markers of this action in relation to age and disease stages. These analytes were extracted from tissue samples and analysed with GC, LC/ESI-MS/MS and GC-MS. It was found that aged rats exhibited a significant increase in brain AA and decrease in ¿n-3 and ¿n-6 PUFAs when compared to adult animals. The observed increase of brain AA was reversed following n-3 EPA and n-3 DPA supplementation. Sphingomyelin was significantly increased when aged animals were supplemented with n-3 DPA. LPS treatment following lithium supplementation increased LA-EA and ALA-EA, while it decreased DHA-EA. Both oxysterols 24-OH and 27-OH increased in ALS patients and SOD1-mice. Eicosadienoic acid was different in ASL-patients compared to aged SOD1-mice. These studies demonstrated that dietary intake of n-3 EPA and n-3DPA significantly altered RBC fatty acids and sphingolipids in rat brain. They suggest that n-3 DPA can be a potential storage form for EPA, as shown by retro-conversion of n-3 DPA into EPA in erythrocyte membranes, ensuring supply of n-3 EPA. Also, n-3 EPA and n-3 DPA supplementation can contribute to an increase in brain sphingomyelin species with implications for age effects and regulation of brain development. Effects of lithium highlight novel anti-neuroinflammatory treatment pathways. Both 24-hydroxycholesterol and eicosadienoic acid may be used as biomarkers in ALS thereby possibly helping to manage the progressive stages of disease.