Abed N. Azab

Effects of lithium on inflammation.

Lithium is an effective medication for the treatment of bipolar affective disorder. Accumulating evidence suggests that inflammation plays a role in the pathogenesis of bipolar disorder and that lithium has anti-inflammatory effects that may contribute to its therapeutic efficacy. This article summarizes the studies which examined the effects of lithium on pro- and anti-inflammatory mediators. Some of the summarized data suggest that lithium exerts anti-inflammatory effects (e.g., suppression of cyclooxygenase-2 expression, inhibition of interleukin (IL)-1β and tumor necrosis factor-α production, and enhancement of IL-2 and IL-10 synthesis). Nevertheless, there is a large body of data which indicates that under certain experimental conditions lithium also exhibits pro-inflammatory properties (e.g., induction of IL-4, IL-6 and other pro-inflammatory cytokines synthesis). The reviewed studies utilized various experimental model systems, and it is thus difficult to draw an unequivocal conclusion regarding the effect of lithium on specific inflammatory mediators.

Effects of lithium on lipopolysaccharide-induced inflammation in rat primary glia cells

Lithium is the gold-standard treatment for bipolar disorder, a severe mental illness. A large body of evidence suggests that inflammation plays a role in the pathogenesis of bipolar disorder and that mood stabilizers exhibit anti-inflammatory properties. However, contradicting findings have also been reported. In this study, we examined the effects of lithium on LPS-induced inflammation in rat primary glia cells. Cells were pre-treated with lithium (1 or 10 mM) for 6 or 24 h, after which, inflammation was induced by the addition of LPS (for another 18 h) to the culture medium. Thereafter, medium was collected and cells were harvested for further analyses. Levels of TNF-α, IL1-β and PGE2 were determined by ELISA and NO levels by the Griess reaction assay. Expression levels of cyclooxygenase-2 (COX-2) and inducible NO synthase (iNOS) were examined by Western blot analysis. We found that pre-treatment with lithium 10 mM (but not 1 mM) significantly reduced LPS-induced secretion of TNF-α, IL1-β, PGE2 and NO. In addition, lithium significantly reduced the expression of COX-2 and iNOS. These findings indicate that lithium exhibits a potent anti-inflammatory effect. However, it’s important to emphasize that this effect was obtained mainly under treatment with an extra-therapeutic concentration of the drug.

Effects of estrogen against LPS-induced inflammation and toxicity in primary rat glial and neuronal cultures

Several lines of evidence link inflammation with neurodegenerative diseases, which are aggravated by the age-related decline in estrogen levels in postmenopausal women. Lipopolysaccharide (LPS) is used widely to stimulate glial cells to produce pro-inflammatory mediators such as NO, PGE2, and TNF-α, and was found to be toxic in high doses. We examined the effects of a physiological dose of 17β-estradiol (E2) against LPS-induced inflammation and toxicity (cell death) in rat primary glial and neuronal cultures. Cultures were treated with 0.1 nM E2 for 24 h and then exposed to LPS 0.5—200 µg/ml for another 24 h. Levels of NO, PGE2, and TNF-α in the culture medium were determined by the Griess reaction assay, radio-immunoassay, and enzyme-linked immunoassay, respectively. Cell death was quantified by measuring the leakage of lactate dehydrogenase (LDH) into the medium from dead or dying cells using the non-radioactive cytotoxicity assay. E2 significantly reduced the LPS-induced increase in NO and TNF-α (but not PGE2) production in glial cells. PGE 2 and TNF-α were undetectable in neuronal cultures, while only basal levels of NO were detected, even after stimulation with LPS. Moreover, pretreatment with E2 significantly reduced LPS-induced cell death, as measured by the release of LDH, in both glial and neuronal cultures. These results suggest that the neuroprotective effects attributed to E2 are derived, at least in part, from its anti-inflammatory and cytoprotective effects in both glial and neuronal cells.

Inositol phosphates and phosphoinositides in health and disease.

In the past two decades, considerable progress has been made toward understanding inositol phosphates and PI metabolism. However, there is still much to learn. The present challenge is to understand how inositol phosphates and PIs are compartmentalized, identify new targets of inositol phosphates and PIs, and elucidate the mechanisms underlying spatial and temporal regulation of the enzymes that metabolize inositol phosphates and PIs. Answers to these questions will help clarify the mechanisms of the diseases associated with these molecules and identify new possibilities for drug design.

Glycogen synthase kinase‐3 is required for optimal de novo synthesis of inositol

Studies have shown that the inositol biosynthetic pathway and the enzyme glycogen synthase kinase‐3 (GSK‐3) are targets of the mood‐stabilizing drugs lithium and valproate. However, a relationship between these targets has not been previously described. We hypothesized that GSK‐3 may play a role in inositol synthesis, and that loss of GSK‐3 may lead to inositol depletion, thus providing a mechanistic link between the two drug targets. Utilizing a yeast Saccharomyces cerevisiae gsk‐3Δ quadruple‐null mutant, in which all four genes encoding homologues of mammalian GSK‐3 are disrupted, we tested the hypothesis that GSK‐3 is required for de novo inositol biosynthesis. The gsk‐3Δ mutant exhibited multiple features of inositol depletion, including defective growth in inositol‐lacking medium, decreased intracellular inositol, increased INO1 and ITR1 expression, and decreased levels of phosphatidylinositol. Treatment of wild‐type cells with a highly specific GSK‐3 inhibitor led to a significant increase in INO1 expression. Supplementation with inositol alleviated the temperature sensitivity of gsk‐3Δ. Activity of myo‐inositol‐3 phosphate synthase, the rate‐limiting enzyme in inositol de novo biosynthesis, was decreased in gsk‐3Δ. These results demonstrate for the first time that GSK‐3 is required for optimal myo‐inositol‐3 phosphate synthase activity and de novo inositol biosynthesis, and that loss of GSK‐3 activity causes inositol depletion.

Time-dependent effect of LPS on PGE2 and TNF-α production by rat glial brain culture: influence of COX and cytokine inhibitors

This study was undertaken to investigate the effect of lipopolysaccharide (LPS) stimulation on the time course of prostaglandin E2 (PGE) and tumor necrosis factor alpha (TNF-α) production by rat glial brain culture. A concentration of 210 µg/ml LPS from Escherichia coli was used as stimulation treatment. The effect of pentoxifylline (PXF), nimesulide (NIM), indomethacin (INDO) and dexamethasone (DEX) on the regulation of PGE2 and TNF-α production was tested. Stimulation of rat glial cells with LPS resulted in different time-dependent production patterns of PGE2 and TNFα. The time course of TNF-α elevation was short, reaching its peak at 6 h post LPS and decreasing to undetectable levels after 24 h. On the other hand, the time course of PGE2 elevation was longer, starting at 6 h post LPS treatment and increasing 100-fold compared with basal levels, 24 h post LPS exposure. The COX inhibitors (NIM and INDO) and DEX were found to inhibit the LPS-induced elevation in PGE2 production, while PXF lacked such an inhibitory effect. Furthermore, NIM, DEX and PXF were found to reduce the LPS-induced elevation in TNF-α levels, while INDO caused a greater elevation in TNF-α levels. These results may cast further light on the LPS-induced production of PGE2 and TNF-α by rat glial cell cultures and the relation between the two systems.

Nimesulide prevents lipopolysaccharide-induced elevation in plasma tumor necrosis factor-α in rats

The present study was undertaken to test the hypothesis of possible inhibitory effect of nimesulide (4-nitro-2-phenoxymethane-sulfoxide) on plasma TNF-alpha level. Male Sprague-Dawley rats were injected intraperitoneally (i.p.) with E. coli lipopolysaccharide (LPS; 1 mg/kg), which resulted in a dramatic increase in plasma TNF-alpha level peaked 60 min post injection (3890+/-280 pg/ml, compared to undetectable values in the control group). Nimesulide (30 mg/kg) injected i.p. 60 min prior to LPS, prevented LPS-induced elevation in plasma TNF-alpha. Nimesulide alone did not alter circulating levels of TNF-alpha. It appears that the anti-inflammatory properties of nimesulide may in part be attributed to its inhibitory effect on TNF-alpha production.

Anti-Inflammatory Activity of Natural Products

This article presents highlights of the published literature regarding the anti-inflammatory activities of natural products. Many review articles were published in this regard, however, most of them have presented this important issue from a regional, limited perspective. This paper summarizes the vast range of review and research articles that have reported on the anti-inflammatory effects of extracts and/or pure compounds derived from natural products. Moreover, this review pinpoints some interesting traditionally used medicinal plants that were not investigated yet.

The effects of hemodialysis on blood glutamate levels in chronic renal failure: Implementation for neuroprotection ☆

PURPOSE The purpose of the present study is to investigate whether hemodialysis (HD) is effective in lowering blood glutamate levels. In addition, we examined the effect of HD on glutamate oxaloacetate transaminase (GOT) and glutamate pyruvate transaminase (GPT) levels in the blood and described the rate and pattern of blood glutamate clearance during HD. MATERIALS AND METHODS Blood samples were taken from 45 patients with stage V chronic kidney disease immediately after initiation of HD and hourly, for a total of 5 blood samples. Samples were sent for determination of glutamate, glucose, GOT, GPT, hemoglobin, hematocrit, urea, and creatinine levels. A blood sample from 25 healthy volunteers without chronic renal failure was used as a control for the determination of baseline blood levels of glutamate, GOT, and GPT. RESULTS Glutamate and GPT levels in patients on HD were higher at baseline compared with healthy controls (P < .001). In the first 3 hours after HD, there was a decrease in blood glutamate levels compared with baseline levels (P < .00001). At the fourth hour, there was an increase in blood glutamate levels compared with the third hour (P < .05). CONCLUSIONS Hemodialysis may be a promising method of reducing blood glutamate levels.

Effects of Nimesulide, a Selective Cyclooxygenase-2 Inhibitor, on Cardiovascular Alterations in Endotoxemia

Prostanoids and cytokines are known to play a pivotal role in the mechanisms leading to endotoxin-induced cardiovascular failure. We investigated the effect of nimesulide (NIM), a selective cyclooxygenase-2 (COX-2) inhibitor, on the cardiovascular alterations occurring during endotoxemia, and on prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels in endotoxemic rats. NIM significantly reduced endotoxin-induced elevation of plasma and myocardial levels of TNF-α, but not those of IL-1β. Searching for the mechanism underlying the anti-TNF-α effect of NIM, it was found that the drug reduced nuclear factor kappa B activation through diminished nuclear levels of p-65 accompanied by a protective effect against the cardiovascular alterations and mortality seen during endotoxemia. In addition, the inhibitory effect of NIM on endotoxin-induced elevation in plasma and hypothalamic levels of PGE2 was noteworthy, and this may suggest that the large amounts of PGE2 observed during endotoxemia are mainly produced via COX-2.