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Aims: Growing evidence suggests an association between the use of sedative‐hypnotic medications and risk of dementia. The aim of this study is to examine this association using a meta‐analysis approach. Methods: MEDLINE (PubMed) and Scopus were systematically searched for studies published in English only. The quality of studies was evaluated using the Newcastle‐Ottawa scale, and an overall odds ratio was pooled using a random‐effects model. Results: A total of 35 articles were included in the analysis. Pooled odds ratios (ORs) for dementia from all records were (OR; 1.33, 95% CI 1.19–1.49) for benzodiazepine (BZD) combined use (Subgroup‐1), (OR: 1.46, 95% CI 1.23–1.73) for short‐acting BZD use (Subgroup‐2), (OR: 1.72, 95% CI 1.48–1.99) for long‐acting BZD use (Subgroup‐3), (OR: 1.13, 95% CI 0.97–1.32) for BZDs without specification of duration of action (Subgroup‐4), (OR: 1.64, 95% CI 1.13–2.38) for the combined BZDs and Z‐drugs, (OR: 1.43, 95% CI 1.17–1.74) for Z‐drugs only, (OR: 1.14, 95% CI 0.88–1.46) for antidepressant use, (OR: 0.97, 95% CI 0.68–1.39) for antipsychotic use and (OR: 0.98, 95% CI 0.85–1.13) for anticonvulsant use. When sensitivity analysis was performed, association between overall use of BZDs and short‐acting BZDs with the increased risk of dementia disappeared after exclusion of studies that were not adjusted for age covariate (OR: 1.2, 95% CI 1.0–1.44) and (OR: 1.22, 95% CI 0.75–2.01), respectively. Adjustment for protopathic bias by introduction of a lag period showed no evidence of increased risk of dementia with the use of BZDs (Subgroup‐1) (OR: 1.14, 95% CI 0.82–1.58), Z‐drugs (OR: 1.29, 95% CI 0.78–2.13), and combined BZDs and Z‐drugs (OR: 1.51, 95% CI 0.91–2.53). Combined use of BZDs and Z‐drugs showed more positive association when only studies of non‐user design were analysed (OR: 2.75, 95% CI 2.23–3.39). Conclusions: All the investigated sedative‐hypnotics showed no association with increased risk of dementia except for BZDs. However, the observed association with BZDs did not persist after exclusion of studies with potential reverse causation and confounding by indication. Therefore, this association needs to be assessed carefully in future research. [ABSTRACT FROM AUTHOR]

Anti‐CD52 antibody (anti‐CD52‐Ab) leads to a rapid depletion of T and B cells, followed by reconstitution of immune cells with tolerogenic characteristics. However, very little is known about its effect on innate immune cells. In this study, experimental autoimmune encephalomyelitis mice were administered murine anti‐CD52‐Ab to investigate its effect on dendritic cells and monocytes/macrophages in the periphery lymphoid organs and the central nervous system (CNS). Our data show that blood and splenic innate immune cells exhibited significantly increased expression of MHC‐II and costimulatory molecules, which was associated with increased capacity of activating antigen‐specific T cells, at first day but not three weeks after five daily treatment with anti‐CD52‐Ab in comparison with controls. In contrast to the periphery, microglia and infiltrating macrophages in the CNS exhibited reduced expression levels of MHC‐II and costimulatory molecules after antibody treatment at both time‐points investigated when compared to controls. Furthermore, the transit response of peripheral innate immune cells to anti‐CD52‐Ab treatment was also observed in the lymphocyte‐deficient SCID mice, suggesting the changes are not a direct consequence of the mass depletion of lymphocytes in the periphery. Our study demonstrates a dynamic and tissue‐specific modulation of the innate immune cells in their phenotype and function following the antibody treatment. The findings of differential modulation of the microglia and infiltrating macrophages in the CNS in comparison with the innate immune cells in the peripheral organs support the CNS‐specific beneficial effect of alemtuzumab treatment on inhibiting neuroinflammation in multiple sclerosis patients. [ABSTRACT FROM AUTHOR]

Mitogen-activated protein kinases (MAPKs) regulate brain function and their dysfunction is implicated in a number of brain disorders, including Alzheimer's disease. Thus, there is great interest in understanding the signaling systems that control MAPK function. One family of proteins that contribute to this process, the mitogen-activated protein kinase phosphatases (MKPs), directly inactivate MAPKs through dephosphorylation. Recent studies have identified novel functions of MKPs in development, the immune system, and cancer. However, a significant gap in our knowledge remains in relation to their role in brain functioning. Here, using transgenic mice where the Dusp4 gene encoding MKP-2 has been knocked out (MKP-2-/- mice), we show that long-term potentiation is impaired in MKP-2-/- mice compared with MKP-2+/+ controls whereas neuronal excitability, evoked synaptic transmission, and paired-pulse facilitation remain unaltered. Furthermore, spontaneous EPSC (sEPSC) frequency was increased in acute slices and primary hippocampal cultures prepared from MKP-2-/- mice with no effect on EPSC amplitude observed. An increase in synapse number was evident in primary hippocampal cultures, which may account for the increase in sEPSC frequency. In addition, no change in ERK activity was detected in both brain tissue and primary hippocampal cultures, suggesting that the effects of MKP-2 deletion were MAPK independent. Consistent with these alterations in hippocampal function, MKP-2-/- mice show deficits in spatial reference and working memory when investigated using the Morris water maze. These data show that MKP-2 plays a role in regulating hippocampal function and that this effect may be independent of MAPK signaling. [ABSTRACT FROM AUTHOR]

Abstract: Two-pore potassium (K2P) ion channels and P2Y receptors modulate the activity of neurones and are targets for the treatment of neuronal disorders. Here we have characterised their interaction. In cells coexpressing the Gαi-coupled hP2Y12 receptor, ADP and ATP significantly inhibited hK2P2.1 currents. This was abolished by pertussis toxin (PTX), the hP2Y12 antagonist AR-C69931MX, the hP2Y1 antagonist MRS2179 and by mutating potential PKA/PKC phosphorylation sites in the channel C terminal. In cells coexpressing the Gαq/11-coupled hP2Y1 receptor, ADP and ATP also inhibited hK2P2.1 currents, which were abolished by MRS2179, but unaffected by AR-C69931MX and PTX. When both receptors were coexpressed with K2P2.1 channels, ADP-induced inhibition was antagonised by AR-C69913MX and MRS2179, but not PTX. Thus, both Gαq/11- and Gαi-coupled P2Y receptors inhibit K2P channels and the action of hP2Y12 receptors appears to involve co-activation of endogenous hP2Y1 receptors. This represents a novel mechanism by which P2Y receptors may modulate neuronal activity. [Copyright &y& Elsevier]

Abstract: Two-pore domain potassium (K2P) channels are proposed to underlie the background or leak current found in many excitable cells. Extensive studies have been performed investigating the inhibition of K2P2.1 by Gαq- and Gαs-coupled G-protein-coupled receptors (GPCRs), whereas in the present study we investigate the mechanisms underlying Gαi/Gαo-coupled GPCR increases in K2P2.1 activity. Activation of mGlu4 increases K2P2.1 activity, with pharmacological inhibition of protein kinases and phosphatases revealing the involvement of PKA whereas PKC, PKG or protein phosphatases play no role. Mutational analysis of potential C-terminal phosphorylation sites indicates S333 to control approximately 70%, with S300 controlling approximately 30% of the increase in K2P2.1 activity following mGlu4 activation. These data reveal that activation of mGlu4 leads to an increase in K2P2.1 activity through a reduction in C-terminal phosphorylation, which represents a novel mechanism by which group III mGlu receptors may regulate cell excitability and synaptic activity. [Copyright &y& Elsevier]

Multi-wavelength standing wave (SW) microscopy and interference reflection microscopy (IRM) are powerful techniques that use optical interference to study topographical structure. However, the use of more than two wavelengths to image the complex cell surface results in complicated topographical maps, and it can be difficult to resolve the three-dimensional contours. We present a simple image processing method to reduce the thickness and spacing of antinodal fringes in multi-wavelength interference microscopy by up to a factor of two to produce clearer and more precise topographical maps of cellular structures. We first demonstrate this improvement using model non-biological specimens, and we subsequently demonstrate the benefit of our method for reducing the ambiguity of surface topography and revealing obscured features in live and fixed-cell specimens.

Protease-activated receptors (PARs) are a novel family of G-protein coupled receptors (GPCRs) whose activation requires the cleavage of the N-terminus by a serine protease. However, recent evidence reveals that alternative routes of activation also occur, that PARs signal via multiple pathways and that pathway activation is activator- dependent. Given our increased understanding of PAR function both under physiological and pathophysiological conditions, one aspect that has remained constant is the link between PAR2 and inflammation. PAR2 is expressed in immune cells of both the innate and adaptive immune system and has been shown to play a role in several peripheral inflammatory conditions. PAR2 is similarly expressed on astrocytes and microglia within the CNS and its activation is either protective or detrimental to CNS function depending on the conditions or disease state investigated. With a clear similarity between the function of PAR2 on both immune cells and CNS glial cells, here we have reviewed their roles in both these systems. We suggest that the recent development of novel PAR2 modulators, including those that show biased signalling, will further increase our understanding of PAR2 function and the development of potential therapeutics for CNS disorders in which inflammation is proposed to play a role.