LIPOPOLYSACCHARIDE INDUCED NEUROINFLAMMATION ANTI-INFLAMMATORY EFFECT OF ASPIRIN ON BRAIN ARACHIDONIC ACID METABOLITES. Pro-inflammatory and anti-inflammatory mediators derived from arachidonic acid (AA) modulate peripheral inflammation and its resolution. Aspirin (ASA) is a non-steroidal anti-inflammatory drug (NSAID) that switches AA metabolism from prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) to lipoxin A (LXA) and 15-epi-LXA. It is unknown whether chronic therapeutic doses of ASA are anti-inflammatory in the brain. To test this, we measured brain concentrations of AA metabolites in a rat model of neuroinflammation, produced by a 6-day intracerebroventricular infusion of bacterial lipopolysaccharide (LPS). In rats infused with LPS (0.5 ng/h) and given ASA-free water to drink, concentrations in high-energy microwaved brain of PGE2, TXB2 and leukotriene B (LTB) were elevated. In rats infused with artificial cerebrospinal fluid, 6 weeks of treatment with a low (10 mg/kg/day) or high (100 mg/kg/day) ASA dose decreased brain PGE2, but increased LTB, LXA and 15-epi-LXA concentrations. Both doses attenuated the LPS effects on PGE2 and TXB2. The increments in LXA and 15-epi-LXA caused by high-dose ASA were significantly greater in LPS-infused rats. The ability of ASA to increase anti-inflammatory LXA and 15-epi-LXA and reduce pro-inflammatory PGE2 and TXB2 suggests considering aspirin for treating clinical neuroinflammation (1). DOSE-DEPENDENT CHANGES IN NEUROINFLAMMATORY AND ARACHIDONIC ACID CASCADE AND SYNAPTIC MARKERS IN LIPOPOLYSACCHARIDE MODEL OF NEUROINFLAMMATION. We examined effects of a six-day infusion of low-dose (0.5 ng/h) or high-dose (250 ng/h) LPS, compared with artificial cerebrospinal fluid, on neuroinflammatory, arachidonic acid (AA) cascade, and synaptic markers in rat brain. Infusion of either LPS dose increased brain protein levels of TNFalpha and iNOS. 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. Both 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 (2). HIV-1 NEUROINFLAMMATION MODEL IMAGING NEUROINFLAMMATION WITH LABELED ARACHIDONIC ACID IN HIV-1 TRANSGENIC RAT. Human immunodeficiency virus (HIV)-1 infection is being successfully treated with antiretroviral drugs, but with prolongation of life, about 50% of patients develop HIV-1 associated neurocognitive dysfunction (HAND), particularly with aging. Infection is associated with entry of virus-bearing monocytes into brain, followed by microglial activation, neuroinflammation, and upregulated AA metabolic enzymes. The HIV-1 transgenic (Tg) rat, a noninfectious HIV-1 model, shows neurologic and behavioral abnormalities after 5 months of age. We used our in vivo imaging method with 1-14CAA and quantitative autoradiography to demonstrate that brain AA metabolism was elevated in 6-7 month old unanesthetized HIV-1 Tg rats. Brain activities of cytosolic cPLA2-IV, secretory sPLA2, and calcium independent iPLA2-VI, which release AA and docosahexaenoic acid from membrane phospholipids, and concentrations of proinflammatory PGE2 and LTB4, also were elevated, consistent with increased AA metabolism. We are writing a clinical protocol with NIAID to use positron emission tomography with 1-11CAA, to test whether brain AA metabolism is upregulated in HIV-1-infected patients as a biomarker of neuroinflammation and cognitive dysfunction(2). INCREASED INFLAMMATORY AND ARACHIDONIC ACID CASCADE MARKERS, AND REDUCED SYNAPTIC PROTEINS, IN BRAIN OF HIV-1 TRANSGENIC RAT. Cognitive impairment has been reported in human immune deficiency virus-1 (HIV-1) infected patients and in the HIV-1 transgenic (Tg) rat. To further test whether impairment in the rat is linked to neuroinflammation, we measured molecular markers of neuroinflammation, the AA cascade, and synaptic integrity in brain from 7- to 9-month-old HIV-1 Tg and control rats. Compared with control, HIV-1 Tg rat brain showed immunoreactivity to glycoprotein 120 and tat HIV-1 viral proteins, and higher protein and mRNA levels of (1) inflammatory cytokines interleukin-1βand tumor necrosis factor alpha, (2) activated microglial/macrophage marker CD11b, (3) AA cascade enzymes: AA-selective cPLA2-IVA, secretory sPLA2-IIA, cyclooxygenase (COX)-2, membrane prostaglandin E2 synthase, 5-lipoxygenase (LOX), 15-LOX, cytochrome p450 epoxygenase, and (4) transcription factor NF-κBp50 DNA binding activity. HIV-1 Tg rat brain also exhibited decreased levels of brain-derived neurotrophic factor (BDNF) and drebrin, a marker of post-synaptic excitatory dendritic spines. Thus, the HIV-1 Tg rat may be a useful model for understanding progression and treatment of cognitive impairment in HIV-1 patients (5) . ALTERED TISSUE LIPID COMPOSITION IN HIV-1 TRANSGENIC RAT. Disturbed lipid metabolism has been reported in antiretroviral-naive HIV-1-infected patients. We confirmed marked disturbances in the 7-9 month old HIV-1 Tg model of this infection, testing high energy microwaved tissue. Plasma triglycerides and liver cholesteryl ester and total cholesterol concentrations were significantly higher in HIV-1 Tg rats than controls. Heart and plasma fatty acid concentrations reflected concentration differences in liver, which showed higher n-3 and n-6 polyunsaturated fatty acid (PUFA) concentrations. Fatty acid concentrations were increased or decreased in heart and liver phospholipid subfractions. Brain fatty acid concentrations differed between the groups for minor fatty acids. The profound changes in the different tissues suggest a direct effect of chronic exposure to the HIV-1 virus on peripheral lipid (including PUFA) metabolism (6). CHRONIC LITHIUM FEEDING REDUCES UPREGULATED BRAIN ARACHIDONIC ACID METABOLISM IN HIV-1 TRANSGENIC RAT. (see AG000150-04) CHRONIC CEREBRAL ISCHEMIA. Brain lipid metabolism was studied in rats following permanent bilateral common carotid artery ligation (BCCL), a model for cerebral hypoperfusion that can be associated with hypertension and atherosclerosis and contribute to mortality in the elderly. We measured brain lipids after 6 h, 24 h, and 7 days of BCCL or sham surgery in rats. 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 6 h. At 24 h, immunoreactivity for secretory phospholipase sPLA2, was increased near blood vessels. There was no evidence of neuroinflammation. BCCL affected brain lipid metabolism transiently, possibly because of compensatory sPLA2-mediated vasodilation, without producing evidence of neuroinflammation, but may increase vulnerability to further brain stress (3).

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000151-05
Application #
8552323
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2012
Total Cost
$876,974
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
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
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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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