DIETARY LINOLEIC ACID LOWERING REDUCES LIPOPOLYSACCHARIDE-INDUCED INCREASE IN BRAIN ARACHIDONIC ACID METABOLISM. Linoleic acid (LA, 18:2n-6) is a precursor to arachidonic acid (AA, 20:4n-6), which can be converted by brain lipoxygenase and cyclooxygenase (COX) enzymes into various lipid mediators involved in the regulation of brain immunity. Brain AA metabolism is activated in rodents by the bacterial endotoxin, lipopolysaccharide (LPS). This study tested the hypothesis that dietary LA lowering, which limits plasma supply of AA to the brain, reduces LPS-induced upregulation in brain AA metabolism. Male Fischer CDF344 rats fed an adequate LA (5.2 % energy (en)) or low LA (0.4 % en) diet for 15 weeks were infused with LPS (250 ng/h) or vehicle into the fourth ventricle for 2 days using a mini-osmotic pump. The incorporation rate of intravenously infused unesterified 14C-AA into brain lipids, eicosanoids, and activities of phospholipase A2 and COX-1 and 2 enzymes were measured. Dietary LA lowering reduced the LPS-induced increase in prostaglandin E2 concentration and COX-2 activity (P < 0.05 by two-way ANOVA) without altering phospholipase activity. The 14C-AA incorporation rate into brain lipids was decreased by dietary LA lowering (P < 0.05 by two-way ANOVA). The present findings suggest that dietary LA lowering reduced LPS-induced increase in brain markers of AA metabolism. The clinical utility of LA lowering in brain disorders should be explored in future studies. (11) REGULATION OF RAT PLASMA AND CEREBRAL CORTEX OXYLIPIN CONCENTRATIONS WITH INCREASING LEVELS OF DIETARY LINOLEIC ACID. Linoleic acid (LA, 18:2n-6) is the most abundant polyunsaturated fatty acid in the North American diet and is a precursor to circulating bioactive fatty acid metabolites implicated in brain disorders. This exploratory study tested the effects of increasing dietary LA on plasma and cerebral cortex metabolites derived from LA, its elongation-desaturation products dihomo-gamma linolenic (DGLA, 20:3n-6) acid and arachidonic acid (AA, 20:4n-6), as well as omega-3 alpha-linolenic (alpha-LNA, 18:3n-3), eicosapentaenoic (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3). Plasma and cortex were obtained from rats fed a 0.4%, 5.2% or 10.5% energy LA diet for 15 weeks and subjected to liquid chromatography tandem mass spectrometry analysis. Total oxylipin concentrations, representing the esterified and unesterified pool, and unesterified oxylipins derived from LA and AA were significantly increased and EPA metabolites decreased in plasma at 5.2% or 10.5% energy LA compared to 0.4% energy LA. Unesterified plasma DHA metabolites also decreased at 10.5% energy LA. In cortex, total and unesterified LA and AA metabolites increased and unesterified EPA metabolites decreased at 5.2% or 10.5% LA. DGLA and alpha-LNA metabolites did not significantly change in plasma or cortex. Dietary LA lowering represents a feasible approach for targeting plasma and brain LA, AA, EPA or DHA-derived metabolite concentrations. LOW-DOSE ASPIRIN DAMPENS INFLAMMATION-INDUCED INCREMENTS IN BRAIN ARACHIDONIC ACID METABOLITES IN OLD HIV-1 TRANSGENIC RAT. HIV-1 transgenic rats develop behavioral changes with aging and show neuroinflammation, neuronal loss, and increased brain arachidonic acid (AA) metabolism. They may be a model for HIV-1 neurocognitive disorder (HAND). . We reported that chronic low-dose aspirin (equivalent to a human low dose) reduced upregulated brain AA metabolism in aged HIV-1 transgenic rats. Wildtype and HIV-1 transgenic rats, aged 7-9 months, were treated for 42 days with 10 mg/kg/day (equivalent to human low-dose) aspirin in drinking water, then were subjected to head-focused microwave fixation. Enzyme-linked immunosorbent assays showed that brain 15-epi-lipoxin A4 and 8-isoprostane concentrations were significantly higher in the HIV-1 transgenic rats. These differences were insignificant following aspirin. Aspirin also reduced brain prostaglandin E2 and leukotriene B4 concentrations in HIV-1 Tg but not wildtype rats. Thromboxane B2, 15-HETE, lipoxin A4 and resolvin D1 concentrations were unrelated to genotype or treatment. Thus, treatment with low-dose aspirin reduces AA-metabolite markers of inflammation and oxidative stress in HIV-1 Tg brain, and might be considered in clinical trials in HIV-1 patients with HAND. TREATING NEUROINFLAMMATION OF PTSD WITH IL-1R ANTAGONIST ANAKINRA. There is increasing evidence linking inflammatory signaling cascades to physiological and adaptive stress that likely facilitates the onset of PTSD. Interleukin (IL)-1 is a critical cytokine in local and systemic inflammation and blocking IL-1 activity results in a reduction of inflammation-triggered disease severity. A particularly therapeutically promising IL-1 receptor antagonist, anakinra (brand name Kineret), blocks the IL-1 receptor and shows beneficial effects in attenuating peripheral and CNS inflammation. The therapeutic potential of such drugs in the context of sleep disturbances with symptoms worsened by environmental factors remains to be explored. In general, there is a pressing need for preclinical studies on how environmental and psychological stressors interact to accentuate PTSD symptoms and to impair cognition abilities and subsequently impedes military operations in extreme conditions. There is growing evidence that hypobaric environments resulting in significant exposure to hypoxia increase the neuroinflammatory response to injury and stress15,16. Therefore, with Dr. Zygmunt Galdzicki at USUHS we shall examine inflammatory changes in brain of mice subjected sleep deprivation and environmental stress, and effects of anakinra in ameliorating these changes. Anakinra is being used to suppress neuroinflammation in our clinical trial in HIV-1 patients.
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