Background-Statins have anti-inflammatory properties that are independent of their lipid-lowering abilities. We hypothesized that statin therapy before the onset of an acute bacterial infection may have a protective effect against severe sepsis.

Lithium is a unique drug with therapeutic as well as prophylactic value for both manic and depressive phases of manic-depressive illness. The precise mechanisms of its clinical efficacy remain unknown, but there are two main theories of its biochemical action. One proposes that lithium inhibits adrenergically activated adenylate cyclase function whereas the other suggests that it inhibits phosphatidyl inositol turnover, which is known to be activated by cholinergic agonists. Neither mechanism alone, however, can explain both the antimanic and antidepressant effects of lithium. Because of the pivotal role of G proteins in post-receptor information transduction, we have investigated the interaction of lithium with G protein function. Lithium at therapeutically efficacious concentrations completely blocked both adrenergic and cholinergic agonist-induced increases in [3H]GTP binding to membranes from rat cerebral cortex, in both in vitro and ex vivo experiments. The same lithium treatments also abolished guanine nucleotide modulation of agonist binding. Our findings suggest G proteins (Gs and Gi or Go) as the molecular site of action for both the antimanic and antidepressant effects of lithium.

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Ethyl arachidonate was administered orally to 4 healthy male volunteers in a dose of 6 gm daily for a 2 to 3 wk period after a JO-day control period. The increased intake of this precursor of the dienoic prostaglandins resulted in significant increases in the relative and absolute amount of arachidonate in plasma triglycerides, phospholipids, and cholesteryl esters. Similar changes in lipid composition were noted in platelets. The excretion of 7 a-hydroxy-5, ll-diketotetranorprostane-1 ,16-dioic acid, the major urinary metabolite of E prostaglandins in man, was increased by an average of 47% in 3 of the 4 volunteers. Platelet reactivity was assessed by determining the threshold concentration of adenosine diphosphate (ADP) necessary to induce secondary, irreversible aggregation of platelet-rich plasma. This threshold concentration dropped significantly in all volunteers (10% to 60% of control values). It is concluded that the biosynthesis and function of prostaglandins can be augmented in man by oral administration of an esterified precursor fatty acid.Free arachidonic acid is the precursor of the dienoic prostaglandins, including prostaglandins E2 and F 2a . In tissue and plasma, arachidonic acid is found in the ester linkage of phospholipids, cholesteryl esters, and triglycerides. Before arachidonic acid becomes available to prostaglandin synthetase, it must be released by either phospholipases or tri-

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The circulating renin-angiotensin system (RAS), including the biologically active angiotensin II, is a fundamental regulatory mechanism of blood pressure conserved through evolution. Angiotensin II components of the RAS have also been identified in the brain. In addition to pro-inflammatory cytokines, neuromodulators, such as angiotensin II can induce (through angiotensin type 1 receptor (AT1R)) some of the inflammatory actions of brain glial cells and influence brain inflammation. Moreover, in Alzheimer’s disease (AD) models, where neuroinflammation occurs, increased levels of cortical AT1Rs have been shown. Still, the precise role of RAS in neuroinflammation is not completely clear. The overall aim of the present study was to elucidate the role of RAS in the modulation of glial functions and AD pathology. To reach this goal, the specific aims of the present study were a. to investigate the long term effect of telmisartan (AT1R blocker) on tumor necrosis factor-α (TNF-α), interleukin 1-β (IL1-β) and nitric oxide (NO) release from glial cells. b. to examine the effect of intranasally administered telmisartan on amyloid burden and microglial activation in 5X familial AD (5XFAD) mice. Telmisartan effects in vivo were compared to those of perindopril (angiotensin converting enzyme inhibitor). Long-term-exposure of BV2 microglia to telmisartan significantly decreased lipopolysaccharide (LPS) -induced NO, inducible NO synthase, TNF-α and IL1-β synthesis. The effect of Telmisartan on NO production in BV2 cells was confirmed also in primary neonatal rat glial cells. Intranasal administration of telmisartan (1 mg/kg/day) for up to two months significantly reduced amyloid burden and CD11b expression (a marker for microglia) both in the cortex and hipoccampus of 5XFAD. Based on the current view of RAS and our data, showing reduced amyloid burden and glial activation in the brains of 5XFAD transgenic mice, one may envision potential intervention with the progression of glial activation and AD by using AT1R blockers.

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