LIPOPOLYSACCHARIDE INDUCED NEUROINFLAMMATION SELECTIVE INVOLVEMENT OF ARACHIDONIC ACID IN NEUROINFLAMMATION In a rat model of neuroinflammation, produced by a 6-day intracerebral ventricular infusion of bacterial lipopolysaccharide (LPS), we reported marked disturbances in brain arachidonic acid (AA, 20:4n-6) metabolism. In the present study, we demonstrated that parameters of brain docosahexaenoic acid (DHA, 22:6n-3) metabolism were unaffected in this model. Selective targeting of brain AA metabolism with non-steroidal antiinflammatory or other drugs should be considered for treating human brain diseases associated with neuroinflammation (Rosenberger et al., 2010). 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 E (PGE) and thromboxane B (TXB) to lipoxin A (LXA) and 15-epi-LXA. It is unknown whether chronic therapeutic doses of ASA are anti-inflammatory in the brain. We hypothesized that ASA would dampen increases in 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 PGE, TXB 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 in drinking water decreased brain PGE, but increased LTB, LXA and 15-epi-LXA concentrations. Both doses attenuated the LPS effects on PGE, and TXB. 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 PGE and TXB suggests considering aspirin further for treating clinical neuroinflammation (Basselin et al., 2011a). LITHIUM MODIFIES BRAIN ARACHIDONIC AND DOCOSAHEXAENOIC METABOLISM IN RAT LIPOPOLYSACCHARIDE MODEL OF NEUROINFLAMMATION. Neuroinflammation, caused by 6 days of intracerebroventricular infusion of a low dose of lipopolysaccharide (LPS;0.5 ng/h), stimulates brain arachidonic acid (AA) metabolism in rats, but 6 weeks of lithium pretreatment reduces this effect. To further understand this action of lithium, we measured concentrations metabolites generated from AA and docosahexaenoic acid (DHA), in high-energy microwaved rat brain using LC/MS/MS and two doses of LPS. In rats fed a lithium-free diet, low (0.5 ng/h)- or high (250 ng/h)-dose LPS compared with artificial cerebrospinal fluid increased brain unesterified AA and prostaglandin E2 concentrations and activities of AA-selective Ca2+-dependent cytosolic phospholipase A2 (cPLA2)-IV and secretory sPLA2. LiCl feeding prevented these increments. Lithium increased brain concentrations of lipoxygenase-derived AA metabolites, 5- hydroxyeicosatetraenoic acid (HETE), 5-oxo-eicosatetranoic acid, and 17-hydroxy-DHA by 1.8-, 4.3- and 1.9-fold compared with control diet. Lithium also increased 15-HETE in high-dose LPS-infused rats. This study demonstrated, for the first time, that lithium can increase brain 17-hydroxy-DHA formation, a precursor of antiinflammatory resolvins, indicating a new antiinflammatory therapeutic action of lithium (Basselin et al., 2010). PARKINSON DISEASE MODEL UPREGULATED BRAIN ARACHIDONIC ACID ENZYMES IN RAT MODEL OF UNILATERAL PARKINSON DISEASE We had reported that arachidonic acid (AA) signaling is upregulated in the caudate-putamen and frontal cortex of unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats, a model for asymmetrical Parkinson disease. In the present study, we demonstrated that this upregulation was associated with increased expression of two enzymes involved in AA metabolism, cytosolic phospholipase A2 (cPLA2) and cyclooxygenase (COX)-2, ipsilateral to the lesion in the caudate putamen and frontal cortex. This confirms that the tonically increased ipsilateral AA signal in the lesioned rat corresponds to upregulated cPLA2 and COX-2 expression within the AA metabolic cascade;such changes, if present in Parkinson disease, may contribute to symptoms and pathology of this disorder (Lee et al., 2010). HIV-1 DEMENTIA MODEL IMAGING NEUROINFLAMMATION WITH ARACHIDONIC ACID IN HIV-1 TRANSGENIC RAT Human immunodeficiency virus (HIV)-1 associated infection involves entry of virus-bearing monocytes into brain, followed by microglial activation, neuroinflammation, and upregulated arachidonic acid (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 quantitative autoradiography to demonstrate that brain AA metabolism was elevated in 6-7 month old unanesthetized HIV-1 Tg rats. Brain activities of cytosolic phospholipase A2 (cPLA2-IV), secretory sPLA2, and calcium independent iPLA2-VI, which release AA and docosahexaenoic acid from membrane phospholipids, and concentrations of proinflammatory prostaglandin E2 and leukotriene B4, also were elevated, consistent with neuroinflammation and increased AA metabolism (Basselin et al., 2011b). We now plan to use our clinical method of positron emission tomography with 1-11CAA, to test whether brain AA metabolism is upregulated in HIV-1-infected patients as a marker of neuroinflammation (AG000148). 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. We hypothesized that this impairment in the rat could be linked to neuroinflammation, disturbed brain arachidonic acid (AA) metabolism, and synapto-dendritic injury. To test this, we measured protein and mRNA levels of markers of neuroinflammation and the AA cascade, as well as pro-apoptotic factors and synaptic proteins, in brain from 7- to 9-month-old HIV-1 Tg and control rats. Compared with control brain, HIV-1 Tg rat brain showed immunoreactivity to glycoprotein 120 and tat HIV-1 viral proteins, and significantly higher protein and mRNA levels of (1) the inflammatory cytokines interleukin-1and tumor necrosis factor alpha, (2) the activated microglial/macrophage marker CD11b, (3) AA cascade enzymes: AA-selective Ca2+-dependent cytosolic phospholipase A2 (cPLA2)-IVA, secretory sPLA2-IIA, cyclooxygenase (COX)-2, membrane prostaglandin E2 synthase, 5-lipoxygenase (LOX) and 15-LOX, cytochrome p450 epoxygenase, and (4) transcription factor NF-Bp50 DNA binding activity. HIV-1 Tg rat brain also exhibited decreased levels of brain-derived neurotrophic factor and drebrin, a marker of post-synaptic excitatory dendritic spines. In summary, HIV-1 Tg rats show elevated brain markers of neuroinflammation and AA metabolism, with a deficit in several synaptic proteins. These changes are associated with viral proteins and may contribute to cognitive impairment. The HIV-1 Tg rat may be a useful model for understanding progression and treatment of cognitive impairment in HIV-1 patients (Rao et al., In press).
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