Effects of psychotropic drugs on Nuclear Factor kappa B.

Mental disorders affect millions of people worldwide and are associated with a huge suffering and unbearable burden for patients and their care givers. The pathophysiology of mental disorders is not fully understood. In recent years, accumulating data suggest that inflammation may play a role in the pathogenesis of these illnesses and that psychotropic drugs exert some anti-inflammatory effects. Nuclear Factor κB (NF-κB) is a cellular pathway that has a prominent influence on immune and inflammatory responses in humans. Numerous studies examined the effects of psychotropic drugs on different inflammatory mediators (particularly cytokines) both in vitro and in vivo. However, relatively few studies investigated the effects of those drugs on NF-κB. This is quite surprising considering the pivotal role of NF-κB in promoting inflammation. The aim of this article is to review the data over the effects of psychotropic drugs on the NF-κB pathway. Overall, the summarized studies suggest that some psychotropic drugs (such as lithium and imipramine) exert potent inhibitory effects on NF-κB, while the results on other drugs are not conclusive and occasionally contradicting. The discrepancy in the results of different studies seems to derive from the various experimental conditions under which the drugs were tested.

Molecular effects of lithium are partially mimicked by inositol-monophosphatase (IMPA)1 knockout mice in a brain region-dependent manner.

We have previously shown that homozygote knockout (KO) of inositol-monophosphatase1 (IMPA1) results in lithium (Li)-like behavior. We now aimed to find out whether Li-treated mice and IMPA1 KO mice exhibit neurochemical similarity at the gene- and protein-expression level. Hippocampal and frontal cortex B-cell lymphoma (Bcl-2), Bcl-2-associated X protein (BAX), P53, Perodoxin2 (PRDX2), myristoylated alanine-rich C kinase substrate (MARCKS) and neuropeptide Y (NPY) mRNA levels, and hippocampal, frontal cortex and hypothalamic cytokine levels, all previously reported to be affected by lithium treatment, were measured in three groups of mice: wildtype (WT) on regular-food (RF), WT on Li-supplemented food (Li-treated) and IMPA1-KOs. Hippocampal and frontal cortex Bcl-2 and MARCKS were the only genes commonly affected (downregulated) by Li and IMPA1 KO; Bcl-2 - by 28% and 19%, respectively; MARCKS - by about 20% in both regions. The effect of Li and of IMPA1 KO on cytokine levels differed among the three brain areas studied. Only in the hippocampus both interventions exerted similar effects. Frontal cortex cytokine levels were unaffected neither by Li nor by IMPA1 KO. Similar changes in Bcl-2 and MARCKS but not in PRDX2 and NPY following both Li-treatment and IMPA1 KO suggest a mechanism different than inositol-monophosphatase1 inhibition for Li׳s effect on the latter genes. The cytokine levels results suggest that the mechanism mediating Li׳s effect on the inflammatory system differs among brain regions. Only in the hippocampus the results favor the involvement of the phosphatidylinositol (PI) cycle.

Lithium attenuates lipopolysaccharide-induced hypothermia in rats.

BACKGROUND: Changes in body temperature are common features among patients with sepsis and septic shock. Similarly, systemic administration of bacterial endotoxin (lipopolysaccharide, LPS) to rats leads to an initial hypothermia followed by elevation in body temperature. These changes in body temperature are accompanied by increased levels of prostaglandin E2 (PGE2) in the hypothalamus. OBJECTIVE: This study examined the effects of lithium and SB216763 - two different glycogen synthase kinase (GSK)-3 inhibitors - on LPS-induced changes in body temperature and hypothalamic PGE2 levels in endotoxemic rats. MATERIALS AND METHODS: Endotoxemia was induced by intraperitoneal injection of LPS (10 mg/kg). Lithium (100 mg/kg) and SB216763 (5 mg/kg) were administered at 2 h before LPS. Body temperature and mortality were monitored during 48 h after LPS injection. In another protocol, rats were sacrificed at 2 h post LPS injection and then, blood, liver and hypothalamus were extracted for inflammatory mediators determination. RESULTS: Lithium but not SB216763 significantly reduced LPS-induced hypothermia, while both compounds did not alter the subsequent elevation in body temperature. Moreover, only lithium significantly reduced hypothalamic PGE2 levels. On the other hand, both compounds significantly reduced plasma, hepatic and hypothalamic tumor necrosis factor-α and decreased plasma PGE2 levels. Both compounds did not alter LPS-induced mortality. CONCLUSIONS: These results suggest that the attenuation of LPS-induced hypothermia by lithium may derive from its reduction of hypothalamic PGE2 levels.

Vagotomy attenuates the effect of lipopolysaccharide on body temperature of rats in a dose-dependent manner.

There is a growing body of evidence suggesting that vagal afferents play a major role in peripheral-neural communication. This study was undertaken to determine whether a dose-dependent effect of lipopolysaccharide (LPS) on vagotomy-induced febrile unresponsiveness exists, and to examine the effect of vagotomy on LPS-induced increase in hypothalamic prostaglandin E2 (HT PGE2) production. Vagotomized and sham-operated rats were subjected to two experimental protocols. In the first, vagotomized and sham-operated rats were injected intraperitoneally with different doses of LPS (200, 500 and 1000 microg/kg) in order to examine the dose-dependent effect of LPS on the biphasic febrile response of the rats. In the second protocol, vagotomized and sham-operated rats were injected intraperitoneally with LPS (500 microg/kg). Two hours post injection, body temperature was measured, the rats were decapitated and blood was collected. Simultaneously, the rats' hypothalami were excised and incubated for 1 h in a Krebs-Henseleit buffer. Next, HT PGE2 was determined by radioimmunoassay. Vagotomy-induced gastric enlargement was then measured to examine the correlation between the magnitude of the enlargement and that of the vagotomy-related febrile unresponsiveness. It was found that vagotomized-induced febrile unresponsiveness is a dose-dependent effect. Subdiaphragmatic resection of the vagus prevented the biphasic febrile response caused by the lowest dose (200 microg/kg) of LPS, whereas the highest dose of LPS (1000 microg/kg) caused a similar biphasic febrile response in both vagotomized and sham-operated rats. Indeed, vagotomy attenuates LPS-induced increase in HT PGE2, and blocks the hypothermic phase of the febrile response. On the other hand, no correlation between gastric enlargement and febrile unresponsiveness was found. The results of the present study may cast further light on the crucial role of the vagus nerve as a peripheral-neural pathway in the mediation of the febrile response.

A reduction of tumor necrosis factor-alpha in paw exudate of lipopolysaccharide treated rats by nimesulide.

TNF-alpha is considered to play a pivotal role in many inflammatory and illness states. In our previous study we found that nimesulide, a COX-2 selective inhibitor, prevents the lipopolysaccharide-induced elevation in plasma TNF-alpha in rats. The present study was undertaken to elucidate the effect of nimesulide on TNF-alpha levels in the paw exudate of rats pretreated with lipopolysaccharide (LPS). Rats were injected (subplantar) with LPS (100 microg/paw) in the right hind, which resulted in a prominent increase in paw exudate TNF-alpha levels, peaked at one hour post injection. In rats pretreated with nimesulide (30 mg/kg, i.p.), the elevation in TNF-alpha in the paw exudate was significantly reduced, as compared to the LPS treated group. These results further stress the multiple antiinflammatory effects of nimesulide.

Time-dependent effect of LPS on PGE2 and TNF-alpha 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 (PGE2) and tumor necrosis factor alpha (TNF-alpha) production by rat glial brain culture. A concentration of 10 microg/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-alpha production was tested. Stimulation of rat glial cells with LPS resulted in different time-dependent production patterns of PGE2 and TNF-alpha The time course of TNF-alpha 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-alpha levels, while INDO caused a greater elevation in TNF-alpha levels. These results may cast further light on the LPS-induced production of PGE2 and TNF-alpha by rat glial cell cultures and the relation between the two systems.