Ethyl-eicosapentaenoate modulates changes in neurochemistry and brain lipids induced by parkinsonian neurotoxin 1-methyl-4-phenylpyridinium in mouse brain slices

Abstract

Evidence suggests a link between Parkinson's disease and the dietary intake of omega (n)−3a n dn −6 polyunsaturated fatty acids (PUFAs). Presently, we investigated whether an acute dose of parkinsonian neurotoxin 1-methyl-4-phenylpyridinium (MPP + ) affects brain n−3andn−6 PUFA content and expression of fatty acid metabolic enzymes cytosolic phospholipase A2 (cPLA2) and cyclooxygenase-2 (COX-2) in brain slices from C57Bl/6 mice. Furthermore, we investigated whether feeding a diet of n−3 PUFA ethyl-eicosapentaenoate (E-EPA) to these mice can attenuate the MPP + induced changes in brain PUFA content and expression of cPLA2and COX-2, and attenuate MPP + induced changes in neurotransmitters and metabolites and apoptotic markers, bax, bcl-2 and caspase-3. MPP + increased brain content of n−6 PUFAs linoleic acid and arachidonic acid, and increased the mRNA expression of cPLA2. MPP + also depleted striatal dopamine levels and increased dopamine turnover, and depleted noradrenaline levels in the frontal cortex. The neurotoxin induced increases in bax, bcl-2 and caspase-3 mRNA expression that approached significance. E-EPA by itself increased brain n−3c o n t e n t , including EPA and docosapentaenoic acid (C22:5, n−3), and increased cortical dopamine. More importantly, E-EPA attenuated the MPP + induced increase in n−6 fatty acids content, partially attenuated the striatal dopaminergic turnover, and prevented the increases of pro-apoptotic bax and caspase-3 mRNAs.In conclusion, increases in n−6P U F A si nt h ea c u t es t a g eo fe x p o s u r et op a r k i n s o n i a nn e u r o t o x i n sm a y promote pro-inflammatory conditions. EPA may provide modest beneficial effects in Parkinson's disease, but further investigation is warranted.

Cognitive enhancement by omega-3 fatty acids from child-hood to old age: Findings from animal and clinical studies

“…For instance, increased intake of EPA over the course of 6e8 weeks can significantly increase brain content of EPA and metabolite DPA (C22:5, n-3) in mice, even though these are trace components of neuronal membranes (Luchtman et al, 2012;Meng et al, 2010). Prolonged intake of DHA will modestly increase brain DHA content, with a reciprocal decrease in brain n-6 content, in particular DPA (C22:5, n-6) (Bousquet et al, 2008).…”

“…Furthermore, supplementation with n-3 PUFA, including EPA, has substantial effects on monoamine and metabolite levels in the brain of adult rodents (e.g. Luchtman et al, 2012;Meng et al, 2010).…”

N-3 polyunsaturated fatty acids in animal models with neuroinflammation: An update

“…injection of 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of MPTP. Both studies achieved increases in brain EPA, but not brain DHA with s.c. ethyl- EPA (Luchtman et al, 2012;Meng et al, 2010). In a third study, fat-1 transgenic mice with raised cortical DHA, have lower levels of the astrocytic marker GFAP compared to their wildtype littermates after MPTP-induced injury (Bousquet et al, 2011b).…”

Identification of disease-distinct complex biomarker patterns by means of unsupervised machine-learning using an interactive R toolbox (Umatrix)

“…Its pathophysiology involves, e.g., accumulation and spreading of misfolded proteins [48], neuro-inflammation including persistent microglial activity [49], neuro-inflammation including persistent microglial activity [49] and dysfunctions of mitochondrial biogenesis and quality control systems [50]. The latter processes are essentially regulated by bioactive lipids including ceramides, sphingolipids, lysophospholipids, eicosanoids, endocannabinoids, HETEs, omega-3 and omega-6 lipids and EETs [17,[51][52][53][54][55][56][57][58][59]. The relevance of subtle changes in complex regulatory circuits has been taken into account by modern omics-based analysis tools using "gene set enrichment analyses" for the detection of pattern changes [60,61].…”