Increased systemic and brain cytokine production and neuroinflammation by endotoxin following ethanol treatment

Abstract Background Cytokines and alcohol share a common modulation of inflammation and hormones as well as being implicated in multiple diseases, but the mechanisms are poorly understood. The purpose of this study was to investigate the interaction of liver, serum and brain cytokines as well as whether ethanol would potentiate endotoxin (Lipopolysaccharide, LPS) responses once ethanol had cleared. Methods Male C57BL/6J mice were treated intragastrically with water (control) or ethanol (5 g/kg, i.g., 25% ethanol, w/v), with volumes matched, for 1 day or daily for 10 days. Mice were then injected intraperitoneally with saline (control) or LPS (3 mg/kg, i.p.) in saline 24 hrs after the last dose of ethanol. Gene expression and protein synthesis of proinflammatory cytokines and anti-inflammatory cytokine, oxidative enzymes, microglial activation and inhibition of neurogenesis were examined using real-time PCR, ELISA, and immunohistochemistry. Results LPS increased proinflammatory cytokines (TNFα, MCP-1, IL-1β) several fold in liver, brain and serum at 1 hr. Ethanol is known to increase liver cytokines and alter the risk of multiple chronic diseases. Ten daily doses of ethanol increased brain and liver TNFα, and pretreatment with ethanol potentiated LPS-induced increases in TNFα, MCP-1, IL-1β in liver, serum and brain. Proinflammatory cytokine levels in liver and serum returned to basal levels within a day, whereas brain proinflammatory cytokines remained elevated for long periods. IL-10, an anti-inflammatory cytokine, is reduced in brain by ethanol and LPS, while brain proinflammatory cytokines remain increased, whereas liver IL-10 is increased when proinflammatory cytokines have returned to control levels. Activation of brain microglia indicated by morphological changes, reduced neurogenesis and increased brain expression of COX-2 and gp91phox NADPH oxidase subunit mRNA were found in the 10 daily doses of ethanol-pretreated LPS group. Conclusion Acute increases in serum cytokines induce long lasting increases in brain proinflammatory cytokines. Ten daily doses of ethanol exposure results in persistent alterations of cytokines and significantly increases the magnitude and duration of central and peripheral proinflammatory cytokines and microglial activation. Ethanol induced differential anti-inflammatory cytokine IL-10 responses in liver and brain could cause long lasting disruption of cytokine cascades that could contribute to protection or increased risk of multiple chronic diseases

Emerging targets for addiction neuropharmacology: From mechanisms to therapeutics

Drug abuse represents a considerable burden of disease and has enormous economic impacts on societies. Over the years, few medications have been developed for clinical use. Their utilization is endowed with several limitations, including partial efficacy or significant side effects. On the other hand, the successful advancement of these compounds provides an important proof of concept for the feasibility of drug development programs in addiction. In recent years, a wealth of information has been generated on the psychological mechanisms, genetic or epigenetic predisposing factors, and neurobiological adaptations induced by drug consumption that interact with each other to contribute to disease progression. It is now clear that addiction develops through phases, from initial recreational use to excessive consumption and compulsive drug seeking, with a shift from positive to negative reinforcement driving motivated behaviors. A greater understanding of these mechanisms has opened new vistas in drug development programs. Researchers' attention has been shifted from investigation of classical targets associated with reward to biological substrates responsible for negative reinforcement, impulse loss of control, and maladaptive mechanisms resulting from protracted drug use. From this research, several new biological targets for the development of innovative therapies have started to emerge. This chapter offers an overview of targets currently under scrutiny for the development of new medications for addiction. This work is not exhaustive but rather it provides a few examples of how this research has advanced in recent years by virtue of studies carried out in our laboratory

Effects of 10 daily doses of ethanol exposure on LPS-induced liver, serum and brain IL-1production

Male C57BL/6J mice were treated intragastrically with ethanol (5 g/kg, i.g.) for 10 days and injected intraperitoneally (i.p.) with LPS (3 mg/kg) 24 hrs after ethanol treatment. Liver, serum and brain samples were collected 1 hr after LPS injection. LPS significantly increased IL-1protein in liver, serum and brain after 10 days of ethanol administration compared with LPS alone treatment. The results are the means ± SEM of two experiments performed with 6 mice each group. * P < 0.05, ** P < 0.01, compared with the saline control mice. P < 0.05, P < 0.01, compared with LPS-treated mice.<p><b>Copyright information:</b></p><p>Taken from "Increased systemic and brain cytokine production and neuroinflammation by endotoxin following ethanol treatment"</p><p>http://www.jneuroinflammation.com/content/5/1/10</p><p>Journal of Neuroinflammation 2008;5():10-10.</p><p>Published online 18 Mar 2008</p><p>PMCID:PMC2373291.</p><p></p

Ten daily doses of ethanol administration potentiated LPS-induced brain TNFα, MCP-1 and IL-1production that remained elevated at 1 week

Male C57BL/6J mice were treated intragastrically with ethanol (5 g/kg, i.g.) for 10 days and were injected intraperitoneally (i.p.) with LPS at indicated doses 24 hrs after ethanol treatment. Brains were collected at 1 week after LPS injection. The levels of TNFα, MCP-1 and IL-1protein were measured by ELISA. (A) In the10-dose ethanol pre-treated group, brain TNFprotein significantly increased in a LPS dose-dependent manner. (B) Exposure to 10 daily doses of ethanol resulted in a significant increase in brain MCP-1 in a LPS dose-dependent manner. (C) Brain IL-1protein synthesis was also enhanced by ethanol pre-treatment. The results are the means ± SEM (n = 6 per group). * P < 0.05, ** P < 0.01, compared with the saline controls.P < 0.05, P < 0.01, compared with the corresponding LPS-treated group.<p><b>Copyright information:</b></p><p>Taken from "Increased systemic and brain cytokine production and neuroinflammation by endotoxin following ethanol treatment"</p><p>http://www.jneuroinflammation.com/content/5/1/10</p><p>Journal of Neuroinflammation 2008;5():10-10.</p><p>Published online 18 Mar 2008</p><p>PMCID:PMC2373291.</p><p></p

Effects of a single dose of ethanol exposure on LPS-induced liver, serum and brain TNFα production

Male C57BL/6J mice were treated intragastrically with ethanol (5 g/kg, i.g.) for one day. Mice were injected intraperitoneally (i.p.) with LPS (3 mg/kg) 24 hrs after ethanol treatment. Liver, serum and brain samples were collected at 1 hr post LPS treatment. Analysis of TNFα and MCP-1 protein was conducted by ELISA. (A) LPS and ETOH-LPS rapidly increased liver, serum and brain TNFα protein. (B) MCP-1 protein in liver, serum and brain was increased after LPS treatment alone or combined LPS and ethanol treatments. The results are the means ± SEM (n = 6 per group). * P < 0.05, ** P < 0.01, compared with the saline controls.<p><b>Copyright information:</b></p><p>Taken from "Increased systemic and brain cytokine production and neuroinflammation by endotoxin following ethanol treatment"</p><p>http://www.jneuroinflammation.com/content/5/1/10</p><p>Journal of Neuroinflammation 2008;5():10-10.</p><p>Published online 18 Mar 2008</p><p>PMCID:PMC2373291.</p><p></p

Effects of 10 daily doses of ethanol on IL-10 in brain and liver at 1 week after LPS treatment

Male C57BL/6J mice were treated intragastrically with ethanol (5 g/kg, i.g.) for 10 days and were injected intraperitoneally (i.p.) with LPS at the indicated doses 24 hrs after ethanol treatment. Brains and livers were collected at 1 week after LPS injection. The level of IL-10 protein was measured by ELISA. (A) Ten doses of ethanol decreased brain IL-10 and enhanced LPS-induced decrease in IL-10 in a LPS dose-dependent manner at 1 week after LPS treatment. (B) There was a significant increase in liver IL-10 protein in 10 daily doses of ethanol, LPS (0.3 and 3 mg/kg) and ETOH-LPS groups. P < 0.05, ** P < 0.01, compared with the saline controls.P < 0.05, P < 0.01, compared with the corresponding LPS-treated group.<p><b>Copyright information:</b></p><p>Taken from "Increased systemic and brain cytokine production and neuroinflammation by endotoxin following ethanol treatment"</p><p>http://www.jneuroinflammation.com/content/5/1/10</p><p>Journal of Neuroinflammation 2008;5():10-10.</p><p>Published online 18 Mar 2008</p><p>PMCID:PMC2373291.</p><p></p

Effects of 10 daily doses of ethanol exposure on LPS-induced liver, serum and brain TNFα and MCP-1 production

Male C57BL/6J mice were treated intragastrically with ethanol (5 g/kg, i.g.) daily for 10 days and injected intraperitoneally (i.p.) with LPS (3 mg/kg) 24 hrs after ethanol treatment. Liver, serum and brain samples were collected 1 hr post LPS treatment. TNFα and MCP-1 protein was determined by ELISA. (A) In 10-day ethanol pre-treated group, LPS significantly increased liver, serum and brain TNFα protein compared with LPS alone group. (B) Exposure to 10 daily doses of ethanol resulted in a significant increase in MCP-1 protein in liver, serum and brain. The results are the means ± SEM of two experiments performed with 6 mice each group. * P < 0.05, ** P < 0.01, compared with the saline controls. P < 0.05, P < 0.01, compared with LPS-treated group.<p><b>Copyright information:</b></p><p>Taken from "Increased systemic and brain cytokine production and neuroinflammation by endotoxin following ethanol treatment"</p><p>http://www.jneuroinflammation.com/content/5/1/10</p><p>Journal of Neuroinflammation 2008;5():10-10.</p><p>Published online 18 Mar 2008</p><p>PMCID:PMC2373291.</p><p></p

A single dose of ethanol treatment enhanced LPS-induced IL-1protein in brain and serum, but not in liver

Male C57BL/6J mice were treated intragastrically with ethanol (5 g/kg, i.g.) for one day. Mice were injected intraperitoneally (i.p.) with LPS (3 mg/kg) 24 hrs after ethanol treatment. Liver, serum and brain samples were collected at 1 hr after LPS injection. Liver, serum and brain IL-1protein was measured by ELISA. (A) A single ethanol dose increased LPS-induced brain IL-1production. (B) A single dose of ethanol increased LPS-induced IL-1protein in serum. (C) A single dose of ethanol did not show potentiation to LPS-stimulated increase in IL-1protein in liver. The results are the means ± SEM (n = 6 per group). * P < 0.05, ** P < 0.01, compared with the saline controls.P < 0.05, P < 0.01, compared with LPS-treated group.<p><b>Copyright information:</b></p><p>Taken from "Increased systemic and brain cytokine production and neuroinflammation by endotoxin following ethanol treatment"</p><p>http://www.jneuroinflammation.com/content/5/1/10</p><p>Journal of Neuroinflammation 2008;5():10-10.</p><p>Published online 18 Mar 2008</p><p>PMCID:PMC2373291.</p><p></p