ABSTRACT
PURPOSE: Neuronal inflammation is caused by systemic inflammation and induces cognitive dysfunction. IL-6 plays a crucial role in therapies for neuronal inflammation and cognitive dysfunction. Remifentanil, an ultra-short-acting opioid, controls inflammatory reactions in the periphery, but not in the brain. Therefore, the anti-inflammatory effects of remifentanil in neuronal tissue and the involvement of cAMP in these effects were investigated in the present study. METHODS: Mice were divided into 4 groups: control, remifentanil, LPS, and LPS + remifentanil. Brain levels of pro-inflammatory cytokine mRNA, and serum levels of corticosterone, catecholamine and IL-6 were measured in the 4 groups. The co-localization of IL-6 and astrocytes in the mouse brain after the LPS injection was validated by immunostaining. LPS and/or remifentanil-induced changes in intracellular cAMP levels in cultured glial cells were measured, and the effects of cAMP on LPS-induced IL-6 mRNA expression levels were evaluated. RESULTS: Remifentanil suppressed increase in IL-6 mRNA levels in the mouse brain, and also inhibited the responses of plasma IL-6, corticosterone, and noradrenaline in an inflammatory state. In the hypothalamus, IL-6 was localized in the median eminence, at which GFAP immunoreactivity was specifically detected. In cultured cells, remifentanil suppressed increase in IL-6 mRNA levels and intracellular cAMP levels after the administration of LPS, and this enhanced IL-6 mRNA expression in response to LPS. CONCLUSION: Remifentanil suppressed increase in IL-6 mRNA levels in the brain in an inflammatory state, and this effect may be attributed to its direct action on neuronal cells through the inhibition of intracellular cAMP rather than corticosterone.
Subject(s)
Cyclic AMP/metabolism , Inflammation/pathology , Interleukin-6/genetics , Remifentanil/pharmacology , Animals , Brain/metabolism , Cells, Cultured , Corticosterone/blood , Cytokines/metabolism , Hypothalamus/metabolism , Lipopolysaccharides/pharmacology , Male , Mice , Norepinephrine/blood , RNA, Messenger/metabolism , RatsABSTRACT
CONTEXT: Brain oxidative reactions are involved in epilepsy as well as neurodegenerative diseases. In animal convulsion models, some anticonvulsants have been found to suppress oxidative reactions associated with convulsions. However, the effect of anticonvulsants on brain oxidative reactions has not fully been clarified. OBJECTIVE: Midazolam and phenobarbital are often used as an intravenous anesthetic, and are known to have anticonvulsive effect, but antioxidative effect of these drugs has rarely been studied. Thus, the purpose of this study was to evaluate the effects of these drugs on the degree of convulsions and brain oxidative reactions in an animal convulsion model. MATERIALS AND METHODS: In order to evaluate brain oxidative reactions, we measured malondialdehyde (MDA) level and heme oxygenase (HO)-1 mRNA expression level in the brain of mice in a convulsion model generated by a single injection of pentylenetetrazole (PTZ). We evaluated the effects of midazolam and phenobarbital on the degree of PTZ-induced convulsions and on the changes in brain MDA level and HO-1 mRNA expression level. RESULTS: After PTZ injection, severe convulsions were observed in all mice. MDA level was increased in the whole brain, while HO-1 mRNA expression level was increased only in the hippocampus. Both midazolam and phenobarbital prevented the convulsions and suppressed the increase in both MDA level and HO-1 mRNA expression level in the brain. CONCLUSION: In this study, both midazolam and phenobarbital suppressed PTZ-induced MDA and HO-1 reactions in the brain, suggesting that these drugs inhibit brain oxidative reactions in a convulsion model.
Subject(s)
Brain/drug effects , Brain/metabolism , Midazolam/pharmacology , Pentylenetetrazole/pharmacology , Phenobarbital/pharmacology , Seizures/metabolism , Animals , Cerebral Cortex/metabolism , Disease Models, Animal , Gene Expression/drug effects , Gene Expression/genetics , Heme Oxygenase-1/genetics , Hippocampus/metabolism , Hypothalamus/metabolism , Male , Malondialdehyde/metabolism , Mice , Midazolam/therapeutic use , Oxidation-Reduction/drug effects , Phenobarbital/therapeutic use , Seizures/chemically induced , Seizures/diagnosis , Seizures/prevention & control , Treatment OutcomeABSTRACT
Iron is known to be involved in neuronal diseases such as neurodegenerative diseases, brain ischemia and epilepsy. However, it is unclear if a high level of peripheral iron induces these pathological conditions. Since ferric nitrilotriacetate (Fe-NTA), a low molecule iron chelate, causes kidney carcinoma and diabetes in animals due to its strong and unique oxidative stress, it is also considered to cause pathological conditions in the brain. Therefore, we studied brain changes after intraperitoneal (i.p.) injection of Fe-NTA. We investigated iron distribution in the brain and evaluated heme oxygenase (HO)-1 mRNA, IL-6 mRNA and 4-hydroxy-2-nonenal (4-HNE) quantitatively. In addition, changes in muscarinic acetylcholine receptor mRNAs were measured. It was found that iron was localized in the cortex and the hypothalamus, but not in other areas of the brain. HO-1 was induced in both the cortex and hypothalamus, and the levels of IL-6 and 4-HNE were raised in the hypothalamus, but not in the cortex. In the cortex, expression in M1 and M2 mAChRs were suppressed. In conclusion, iron reached the brain parenchyma after i.p. injection of Fe-NTA, and Fe-NTA caused oxidative reactions and suppression of mAChRs in the brain.
Subject(s)
Brain/drug effects , Brain/metabolism , Ferric Compounds/pharmacology , Iron Chelating Agents/pharmacology , Nitrilotriacetic Acid/analogs & derivatives , Oxidative Stress/drug effects , Aldehydes/metabolism , Animals , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Ferric Compounds/administration & dosage , Heme Oxygenase (Decyclizing)/genetics , Histocytochemistry , Hypothalamus/drug effects , Hypothalamus/metabolism , Immunoblotting , Injections, Intraperitoneal , Interleukin-6/genetics , Iron/metabolism , Iron Chelating Agents/administration & dosage , Male , Nitrilotriacetic Acid/administration & dosage , Nitrilotriacetic Acid/pharmacology , Polymerase Chain Reaction , Rats , Rats, Sprague-DawleyABSTRACT
The expression of interleukin-1 beta (IL-1beta) mRNA was compared in the brain of inflammatory susceptible LEW/N and resistant F344/N rats at 3, 6, and 12 h after peripheral administration of lipopolysaccharide (LPS) or saline. No differences between strains were observed in the circumventricular organs (CVOs) and choroid plexus. At 12 h after LPS administration, increased IL-1beta mRNA expression was detected in the hypothalamus of LEW/N rats. In contrast, increased IL-1beta mRNA expression was detected in the cerebral cortex of F344/N rats. These data show region-specific differences of IL-1beta mRNA expression in the brain of these rat strains that differ in their susceptibility to inflammation.