Depressive symptom-associated IL-1ß and TNF-α release correlates with impaired bronchodilator response and neutrophilic airway inflammation in asthma.

BACKGROUND: Depressive symptoms worsen asthma outcomes; however, the mechanism remains largely unexplored. OBJECTIVE: This study aimed to determine whether depressive symptom-associated immune inflammation correlates with impaired bronchodilator response (BDR) and airway inflammatory phenotypes. METHODS: Eligible adults with asthma (n = 198) underwent clinical assessment, sputum induction and blood sampling. Depressive symptoms were defined by scores on the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D). Pre- and post-bronchodilator spirometry was performed for BDR. Airway inflammatory phenotypes were defined by sputum cell counts. CRP, IL-1ß, IL-5, IL-6, IL-8, TNF-α, IFN-γ, CCL17 and CCL22 in serum and sputum were detected. RESULTS: Compared with the non-depressive group (n = 174), the depressive group (n = 24) exhibited impaired BDR (P = 0.032) and increased sputum neutrophils (P = 0.023), which correlated with the HADS-D scores (P = 0.027 and P = 0.029). Levels of IL-1ß, TNF-α and IFN-γ in the serum and those of IL-1ß and IFN-γ in the sputum were elevated in the depressive group compared to those in the non-depressive group (all P < 0.05). Multiple regression models indicated that TNF-α in the sputum and IL-1ß, IL-6 and IFN-γ in both the serum and sputum were inversely associated with BDR; TNF-α in the sputum and IL-1ß in both the serum and sputum were positively correlated with sputum neutrophils. Mediation analyses revealed that IL-1ß and TNF-α in the sputum and IL-1ß in both the serum and sputum mediate the correlations of the HADS-D scores with BDR and sputum neutrophils, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Asthma patients with depressive symptoms present worse asthma control, which is most likely explained by impaired BDR and neutrophilic airway inflammation. IL-1ß and TNF-α, which are two key pro-inflammatory cytokines that mediate the correlation of depressive symptoms with impaired BDR and neutrophilic airway inflammation, may serve as targeted biomarkers in the neuropsychological phenotype of asthma; however, this result needs to be further validated.

Inhibition of Period1 gene attenuates the morphine-induced ERK-CREB activation in frontal cortex, hippocampus, and striatum in mice.

OBJECTIVE: Recent studies demonstrated that the Period1 gene (Per1) is involved in behavioral alterations induced by addictive drugs. We explored the effects of inhibiting expression in brain of Per1 on morphine conditioned place preference (CPP) and morphine-induced phosphorylation of extracellular signal-regulated kinase (ERK) and cAMP-response element binding protein (CREB) in mice. METHODS: During the first three sessions of conditioning, the male mice were intracerebroventricularlly (i.c.v.) injected with vehicle or deoxyribozyme 164 (DRz164) which cleaves per1 mRNA before subcutaneous (s.c.) injection morphine. The control group was given i.c.v. injection vehicle and s.c. injection saline instead of morphine. After testing CPP, mice were sacrificed and phosphorylated ERK and CREB in the frontal cortex, hippocampus, and striatum were examined by immunohistochemistry. RESULTS: Mice pretreated with DRz164 did not acquire morphine CPP. Pretreatment with DRz164 significant attenuated the morphine-induced activation of ERK and CREB in the frontal cortex, hippocampus, and striatum. CONCLUSIONS: Our results indicated that per1 plays an important role in morphine reward, and ERK-CREB pathway was involved in the effects of per1. We suggested that per1 gene may be a potential treatment target for drug addition.

[A preliminary study on the mechanism of neurotoxicity of MDMA--oxidative stress harm].

OBJECTIVE: Establishing a long-term neurotoxic model to explore the mechanism of neurotoxicity of 3,4-methylenedioxymethamphetamine (MDMA) and the putative protection conferred by Vit C against oxidative stress harm. METHODS: Male Wistar rats were randomly assigned to control group (A) and MDMA treatment groups(B, C, D, E). Rats of group B were given MDMA 20 mg/kg; groups C, D, E were given Vit C 250 mg/kg 30 min before administration of MDMA (Vit C 30 min group) and 3 h (Vit C 3 h group) and 5 h (VitC 5 h group) after administration of MDMA, respectively. Rats of control group were treated with the same volume of saline. Concentrations of ATP and ADP in brain cortex and 5-HT in hippocampus and occipital cortex were measured by high perfor-mance liquid chromatography; the expression of SERT mRNA was detected by in situ hybridization; and the expression of protein GFAP was detected by immunohisto-chemistry. RESULTS: hours after MDMA treatment, the concentration of ATP in brain cortex was lessened, compared with control (P <0.05). On the 7th day after MDMA treatment, the concentration of 5-HT in rat hippocampus and occipital cortex was decreased, compared with control (P<0.05). The expression of SERT mRNA in hippocampus was decreased, whereas the expression of GFAP in brain tissue was increased (P<0.05). The adminstration of Vit C 30 min before MDMA treatment and 3 h after MDMA treatment did not curb the decrease of ATP, 5-HT and the expression of SERT mRNA, but Vit C administrated 5 h after MDMA treatment could curb the decrease of ATP and the functional markers of 5-HT. And Vit C given at three time points did downregulate the GFAP expression. CONCLUSION: MDMA could deplete the direct energetic substance ATP. MDMA could exert neurotoxic effect on 5-HT system. Vit C given 5 h after MDMA administration could provide neuroprotection for ATP and 5-HT system.

[Long-term neurotoxic effects of MDMA result in cortical and hippocampal structural changes].

3,4-Methylenedioxymethamphetamine (MDMA) is a substituted amphetamine with stimulating and hallucinogenic properties. Since MDMA induces "ecstasy" it is extensively used as a "recreational" drug. It has been well established that MDMA is neurotoxic and can result in long-term degeneration of cerebral 5-hydroxytryptamine (5-HT) nerve terminals in many species. The present study was undertaken to investigate the long-term neurotoxic effects of MDMA on cortical and hippocampal structures, by repeatedly administering MDMA in short time. Male Wistar rats were randomly assigned to control group and MDMA-treated group. MDMA (10 mg/kg) was administered to rats of MDMA-treated group, once per hour, total 40 mg/kg; rats of control group were treated with the same volume of saline. Thirty-two weeks after administering MDMA, the expression of serotonin transporter (SERT) mRNA and diazepam binding inhibitor (DBI) mRNA was detected by in situ hybridization. The expression of glial fibrillary acidic protein (GFAP) was detected by immunohistochemistry, and the degeneration of nerve terminals was demonstrated by Bielschowsky and Glee Marsland silver staining. The results showed that the expression of SERT mRNA in hippocampus decreased by 31.96%, while expression of DBI mRNA in neocortex increased by 40.51%, compared with the control group (P<0.05). The expression of GFAP in the brain tissue increased (P<0.05), while significant reduction of the nerve terminals in neocortex was demonstrated by silver staining, compared with the control group. These results suggest that the neurotoxicity of MDMA results in sustained cortical and hippocampal structural changes, which in turn result in disorder of the brain functions.