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Chan Chen Yan-hua Li Qiong Zhang Jie-zhong Yu Yong-fei Zhao Cun-gen Ma Bao-guo Xiao 《Acta pharmacologica Sinica》2014,35(11):1428-1438
Aim:
Fasudil, a selective Rho kinase (ROCK) inhibitor, has been shown to alleviate the severity of experimental autoimmune encephalomyelitis (EAE) via attenuating demyelination and neuroinflammation. The aim of this study was to investigate the effects of fasudil on interactions between macrophages/microglia and T cells in a mice EAE model.Methods:
Mouse BV-2 microglia were treated with IFN-γ and fasudil. Cell viability was detected with MTT assay. BV-2 microglia polarization was analyzed using flow cytometry. Cytokines and other proteins were detected with ELISA and Western blotting, respectively. Mice were immunized with MOG35–55 to induce EAE, and then treated with fasudil (40 mg/kg, ip) every other day from d 3 to d 27 pi. Encephalomyelitic T cells were prepared from the spleen of mice immunized with MOG35–55 on d 9 pi.Results:
Treatment of mouse BV-2 microglia with fasudil (15 μg/mL) induced significant phenotype polarization and functional plasticity, shifting M1 to M2 polarization. When co-cultured with the encephalomyelitic T cells, fasudil-treated BV-2 microglia significantly inhibited the proliferation of antigen-reactive T cells, and down-regulated IL-17-expressing CD4+ T cells and IL-17 production. Furthermore, fasudil-treated BV-2 microglia significantly up-regulated CD4+CD25high and CD4+IL-10+ regulatory T cells (Tregs) and IL-10 production, suggesting that the encephalomyelitic T cells had converted to Tregs. In EAE mice, fasudil administration significantly decreased both CD11b+iNOS+ and CD11b+TNF-α+ M1 microglia, and increased CD11b+IL-10+ M2 microglia.Conclusion:
Fasudil polarizes BV-2 microglia into M2 cells, which convert the encephalomyelitic T cells into Tregs in the mice EAE model. 相似文献44.
Li Wan ;Xu Liu ;Zheng Wu ;Wanting Ren ;Shuzhen Kong ;Raya Abou Dargham ;Longzhen Cheng ;Yun Wang 《中国神经科学杂志》2014,(5):866-876
Extrasynaptic GABAA receptors (GABAARs)-mediated tonic inhibition is reported to involve in the patho- genesis of epilepsy. In this study, we used cyclo- thiazide (CTZ)-induced in vitro brain slice seizure model to explore the effect of selective activation of extrasynaptic GABAARS by 4,5,6,7-tetra- hydroisoxazolo[5,4-c] pyridine-3-ol (THIP) on the CTZ-induced epileptiform activity in hippocampal neurons. Perfusion with CTZ dose-dependently induced multiple epileptiform peaks of evoked population spikes (PSs)in CA1 pyramidal neurons, and treatment with THIP (5 μmol/L) significantly reduced the multiple PS peaks induced by CTZ stimulation. Western blot showed that the 6-subunit of the GABAAR, an extrasynaptic specific GABAAR subunit, was also significantly down-regulated in the cell membrane 2 h after CTZ treatment. Our results suggest that the CTZ-induced epileptiform activity in hippocampal CA1 neurons is suppressed by the activation of extrasynaptic GABAARs, and further support the hypothesis that tonic inhibition mediated by extrasynaptic GABAARs plays a prominent role in seizure generation. 相似文献
45.
《Health Policy and Technology》2014,3(4):296-305
BackgroundPersonal smartphones are used frequently by healthcare practitioners in hospitals to assist in the provision of care. Island Health is one of the first health authorities in Canada to endorse the iPhone®smartphone as a potentially valuable tool for clinical practice.ObjectiveTo measure smartphones effect on pharmacists׳ efficiency, to assess pharmacist acceptance of corporate smartphones, and to investigate how these devices are being utilized.MethodsThis multi-center time-trial, survey, and observational prospective study enrolled 90 pharmacists across eight hospitals on Vancouver Island. Participants performed a time-trial of 22 situational drug information questions before and after receiving an iPhone®. They also completed demographic and satisfaction surveys. A subset of 14 of the 90 pharmacists participated in a pre- and post- iPhone® implementation eight hour direct observation study. Lastly, communication data from the phone service provider was collected and analyzed.ResultsSmartphone use was associated with a faster median response time of approximately six minutes for all situational time-trial questions combined (48 min:15 s pre-iPhone® vs. 42 min:18 s post-iPhone®) (p=0.039). Smartphone use did not significantly influence time spent walking to obtain a resource, time spent using computers, or time spent answering of clinical questions during observation. Almost half of pharmacists reported that using the smartphone increased their confidence and competence to resolve drug therapy problems.ConclusionsPharmacists readily accepted smartphones into their practice and felt positively about using them. Smartphones did not improve direct observation measures of workflow, but they did improve pharmacists׳ efficiency in the answering of hypothetical drug information questions (p=0.039). This study indicates that if smartphones are incorporated into pharmacy practice in a structured, organized manner with supports and training in place, smartphone uptake will occur and pharmacists will adapt and incorporate this technology into their daily routine with no predicted deterioration in the quality of their work. The impact of improved efficiency on patient care resulting from an increased reliance on technology and time spent on devices needs to be further assessed. 相似文献
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47.
Assessing cognition and function in Alzheimer's disease clinical trials: Do we have the right tools?
《Alzheimer's & dementia》2014,10(6):853-860
Several lines of evidence from Alzheimer's disease (AD) research continue to support the notion that the biological changes associated with AD are occurring possibly several decades before an individual will experience the cognitive and functional changes associated with the disease. The National Institute on Aging—Alzheimer's Association revised criteria for AD provided a framework for this new thinking. As a result of this growing understanding, several research efforts have launched or will be launching large secondary prevention trials in AD. These and other efforts have clearly demonstrated a need for better measures of cognitive and functional change in people with the earliest changes associated with AD. Recent draft guidance from the US Food and Drug Administration further elevated the importance of cognitive and functional assessments in early stage clinical trials by proposing that even in the pre-symptomatic stages of the disease, approval will be contingent on demonstrating clinical meaningfulness. The Alzheimer's Association's Research Roundtable addressed these issues at its fall meeting October 28–29, 2013, in Washington, D.C. The focus of the discussion included the need for improved cognitive and functional outcome measures for clinical of participants with preclinical AD and those diagnosed with Mild Cognitive Impairment due to AD. 相似文献
48.
Li Wan Xu Liu Zheng Wu Wanting Ren Shuzhen Kong Raya Abou Dargham Longzhen Cheng Yun Wang 《神经科学通报》2014,30(5):866-876
Extrasynaptic GABAA receptors (GABAARs)-mediated tonic inhibition is reported to involve in the pathogenesis of epilepsy. In this study, we used cyclothiazide (CTZ)-induced in vitro brain slice seizure model to explore the effect of selective activation of extrasynaptic GABAARs by 4,5,6,7-tetrahydroisoxazolo[5,4-c] pyridine-3-ol (THIP) on the CTZ-induced epileptiform activity in hippocampal neurons. Perfusion with CTZ dose-dependently induced multiple epileptiform peaks of evoked population spikes (PSs) in CA1 pyramidal neurons, and treatment with THIP (5 μmol/L) significantly reduced the multiple PS peaks induced by CTZ stimulation. Western blot showed that the δ-subunit of the GABAAR, an extrasynaptic specific GABAAR subunit, was also significantly down-regulated in the cell membrane 2 h after CTZ treatment. Our results suggest that the CTZ-induced epileptiform activity in hippocampal CA1 neurons is suppressed by the activation of extrasynaptic GABAARs, and further support the hypothesis that tonic inhibition mediated by extrasynaptic GABAARs plays a prominent role in seizure generation. 相似文献
49.
Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system characterized by recurrent and progressive demyelination, neuroinflammation and oligodendrocyte loss. The cuprizone (CPZ) model is characterized by primary and reversible demyelination, accompanied by oligodendrocyte loss and neuroinflammation. In the current study, we explored the efficiency of Bilobalide in the demyelination and remyelination. The results demonstrate that Bilobalide improved behavioral abnormality and promoted remyelination in the corpus callosum by using Luxol Fast Blue, Black Gold II and myelin basic protein (MBP) staining. We for the first time found that CPZ caused the splenic atrophy and induced the formation of myelin oligodendrocyte glycoprotein (MOG) antibody, which was attenuated by Bilobalide. Thus, Bilobalide decreased the loss of O4+ oligodendrocytes possibly through MOG antibody-dependent cell cytotoxicity. Bilobalide also prevented the infiltration of CD4+ T cells, CD68+ macrophages and B220+ B cells within the brain, and reduced the inflammatory microenvironment mediated with Iba1+iNOS+ and Iba1+NF-kB+ microglia after CPZ challenge, accompanied by the inhibition of IL-1β and IL-6 in the brain. These results identify a potent therapeutic efficiency for Bilobalide and highlight clear pleiotropic effects of the compound beyond specific autoantibody and inflammatory microenvironment in CPZ-mediated demyelination. 相似文献
50.
Functional interactions between the chemokine receptor CXCR4 and opioid receptors have been reported in the brain, leading to a decreased morphine analgesic activity. However the cellular mechanisms responsible for this loss of opioid analgesia are largely unknown. Here we examined whether Src family-kinases (SFK)-linked mechanisms induced by CXCR4 contributed to the loss of acute morphine analgesia and could represent a new physiological anti-opioid signaling pathway. In this way, we showed by immunohistochemistry and western blot that CXCL12 rapidly activated SFK phosphorylation in vitro in primary cultured lumbar rat dorsal root ganglia (DRG) but also in vivo in the DRG and the spinal cord. We showed that SFK activation occurred in a sub population of sensory neurons, in spinal microglia but also in spinal nerve terminals expressing mu-(MOR) and delta-opioid (DOR) receptor. In addition we described that CXCR4 is detected in MOR- and DOR-immunoreactive neurons in the DRG and spinal cord. In vivo, we demonstrated that an intrathecal administration of CXCL12 (1 μg) significantly attenuated the subcutaneous morphine (4 mg/kg) analgesia. Conversely, pretreatment with a potent CXCR4 antagonist (5 μg) significantly enhanced morphine analgesia. Similar effects were obtained after an intrathecal injection of a specific SFK inhibitor, PP2 (10 μg). Furthermore, PP2 abrogated CXCL12-induced decrease in morphine analgesia by suppressing SFK activation in the spinal cord. In conclusion, our data highlight that CXCL12-induced loss of acute morphine analgesia is linked to Src family kinases activation. 相似文献