DOSE-DEPENDENT CHANGES IN NEUROINFLAMMATORY AND ARACHIDONIC ACID CASCADE AND SYNAPTIC MARKERS IN LIPOPOLYSACCHARIDE MODEL OF NEUROINFLAMMATION High-dose LPS infusion upregulated brain protein and mRNA levels of AA cascade markers (AA selective cytosolic cPLA2-IVA, secretory sPLA2-V, cyclooxygenase-2 and 5-lipoxygenase), and transcription factor NF-kappaB p50 DNA binding activity in rat brain. Both high and low doses increased cPLA2 and p38 mitogen-activated protein kinase levels, while reducing protein levels of pre-synaptic synaptophysin. Post-synaptic drebrin and PSD95 protein levels were decreased with high- but not low-dose LPS. Thus, chronic LPS infusion has differential effects, depending on dose, on inflammatory, AA and synaptic markers in rat brain. Neuroinflammation associated with upregulated brain AA metabolism can lead to synaptic dysfunction (1) . NMDA-INDUCED NEUROPATHOLOGY IN RATS IS WORSENED BY DIETARY N-3 PUFA DEPRIVATION BUT NOT DAMPENED BY FISH OIL SUPPLEMENTATION. Studies suggest that dietary long-chain n-3 polyunsaturated fatty acid (PUFAs) supplementation is beneficial for chronic illnesses, but the issue is not agreed on. We are examining effects of both dietary n-3 PUFA deprivation or supplementation compared with an n-3 PUFA adequate diet (containing alpha-linolenic but not docosahexaenoic acid) on brain markers of lipid metabolism and excitotoxicity, in rats treated chronically with saline or NMDA. Chronic NMDA compared with saline increased cPLA2 activity and protein in each of the three groups. cPLA2 activity in saline injected animals was increased by the diet deficient compared with adequate group, but there was no effect of fish oil supplementation. sPLA2 expression was unchanged in the different conditions, whereas iPLA2 expression was reduced by deprivation but not changed by supplementation. COX-1 was unchanged, while COX-2 was elevated significant by NMDA in the deficient rats. BDNF protein was reduced by NMDA in diet deficient rats, but protein levels of IL-1, NGF, and GFAP, markers of neuroinflammation, did not differ on between group comparisons Thus, a dietary n-3 PUFA deficiency compared with an adequate diet worsened brain changes produced by NMDA, whereas supplementation did not reduce them. UPREGULATED EXPRESSION OF BRAIN ENZYMATIC MARKERS OF ARACHIDONIC AND DOCOSAHEXAENOIC ACID METABOLISM IN A RAT MODEL OF THE METABOLIC SYNDROME. BACKGROUND: In animal models, the metabolic syndrome elicits a cerebral response characterized by altered phospholipid and unesterified fatty acid concentrations and increases in pro-apoptotic inflammatory mediators that may cause synaptic loss and cognitive impairment. We hypothesized that these changes are associated with disturbed metabolism of phospholipase (PLA2) enzymes that regulate arachidonic (AA, 20:4n-6) and docosahexaenoic (DHA, 22:6n-6) acid metabolism, in brain. Male Wistar rats were fed a control or high-sucrose diet for 8 weeks to produce the metabolic syndrome. Thus diet induced insulin resistance, and increased phosphorylated-cPLA2 protein, cPLA2 and iPLA2 activity and 12-lipoxygenase mRNA, but decreased BDNF mRNA and protein, and drebrin mRNA, concentrations of several n-6 fatty acids These findings show upregulated brain AA and DHA metabolism and reduced BDNF and drebrin, in an animal model of the metabolic syndrome, all of which may contribute to functional impairment. (2) CEREBRAL HYPOPERFUSION. Brain lipid metabolism was studied in rats following permanent bilateral common carotid artery ligation (BCCL), a model for cerebral hypoperfusion. We measured brain lipids after 6 h, 24 h, and 7 days of BCCL or sham surgery in rats. Six hours following BCCL compared to sham, AA-selective cPLA2 immunoreactivity, and concentrations of unesterified fatty acids and arachidonoyl-CoA, an intermediate for AA reincorporation into phospholipids, were increased. At 24 h, immunoreactivity for secretory phospholipase sPLA2, was increased near blood vessels. Thus BCCL affected brain lipid metabolism transiently, but may increase vulnerability to further stress (3) . BRAIN PATHOLOGY IN AGED IPLA2ΒKNOCKOUT MOUSE MODEL FOR PARKINSON DISEASE. Calcium-independent phospholipase A2 group VIa (iPLA2β) preferentially releases docosahexaenoic acid (DHA) from the sn-2 position of phospholipids in vitro. Mutations of its gene, PLA2G6, are found in patients with Parkinson disease and other motor disorders. At 4 months, PLA2G6 knockout mice (iPLA2β-/-) show minimal pathology but altered brain DHA kinetics, whereas after one year of age they show motor disturbances and neuropathological changes. In 15-20-month old male iPLA2β-/- mice compared with wildtype, phosphorylated cytosolic phospholipase A2-IVa (P-cPLA2α) protein and secretory PLA2 (sPLA2-V) mRNA levels were increased, and cyclooxygenase (COX)-2 mRNA was decreased in iPLA2β-/-. Inducible nitrite oxide synthase (iNOS), CD11b, glial fibrillary acid (GFAP) protein levels and α-synuclein mRNA also were increased, while brain-derived neurotrophic factor (BDNF) expression was reduced. Thus, a lifetime dysfunction of brain DHA metabolism in iPLA2β-/- mice is associated with slowly progressive neuropathological abnormalities like those in Parkinson disease. BRAIN ARACHIDONIC METABOLISM IN AN ANIMAL MODEL OF DEPRESSION: THE FLINDERS SENSITIVE LINE RATS. The Flinders Sensitive Line is a well-characterized model of depression. Previous publication showed higher AA concentration in brain phospholipids. We are using our validated infusion method in awake rat to determine the brain AA kinetics in this depression model.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000151-06
Application #
8736485
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2013
Total Cost
$1,355,078
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
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State
Country
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Taha, Ameer Y; Hennebelle, Marie; Yang, Jun et al. (2016) Regulation of rat plasma and cerebral cortex oxylipin concentrations with increasing levels of dietary linoleic acid. Prostaglandins Leukot Essent Fatty Acids :
Taha, Ameer Y; Chang, Lisa; Chen, Mei (2016) Threshold changes in rat brain docosahexaenoic acid incorporation and concentration following graded reductions in dietary alpha-linolenic acid. Prostaglandins Leukot Essent Fatty Acids 105:26-34
Blanchard, Helene C; Taha, Ameer Y; Rapoport, Stanley I et al. (2015) Low-dose aspirin (acetylsalicylate) prevents increases in brain PGE2, 15-epi-lipoxin A4 and 8-isoprostane concentrations in 9 month-old HIV-1 transgenic rats, a model for HIV-1 associated neurocognitive disorders. Prostaglandins Leukot Essent Fatty Acids 96:25-30
Primiani, Christopher T; Ryan, Veronica H; Rao, Jagadeesh S et al. (2014) Coordinated gene expression of neuroinflammatory and cell signaling markers in dorsolateral prefrontal cortex during human brain development and aging. PLoS One 9:e110972
Bondi, Corina O; Taha, Ameer Y; Tock, Jody L et al. (2014) Adolescent behavior and dopamine availability are uniquely sensitive to dietary omega-3 fatty acid deficiency. Biol Psychiatry 75:38-46
Bhattacharjee, Abesh Kumar; White, Laura; Chang, Lisa et al. (2012) Bilateral common carotid artery ligation transiently changes brain lipid metabolism in rats. Neurochem Res 37:1490-8
Kellom, Matthew; Basselin, Mireille; Keleshian, Vasken L et al. (2012) Dose-dependent changes in neuroinflammatory and arachidonic acid cascade markers with synaptic marker loss in rat lipopolysaccharide infusion model of neuroinflammation. BMC Neurosci 13:50
Kim, Hyung-Wook; Cheon, Yewon; Modi, Hiren R et al. (2012) Effects of chronic clozapine administration on markers of arachidonic acid cascade and synaptic integrity in rat brain. Psychopharmacology (Berl) 222:663-74
Taha, Ameer Y; Basselin, Mireille; Ramadan, Epolia et al. (2012) Altered lipid concentrations of liver, heart and plasma but not brain in HIV-1 transgenic rats. Prostaglandins Leukot Essent Fatty Acids 87:91-101
Cheon, Yewon; Kim, Hyung-Wook; Igarashi, Miki et al. (2012) Disturbed brain phospholipid and docosahexaenoic acid metabolism in calcium-independent phospholipase A(2)-VIA (iPLA(2)β)-knockout mice. Biochim Biophys Acta 1821:1278-86

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