Activation of EP2 receptor suppresses poly(I: C) and LPS-mediated inflammation in primary microglia and organotypic hippocampal slice cultures: Contributing role for MAPKs.

Brain inflammation is a critical factor involved in neurodegeneration. Recently, the prostaglandin E2 (PGE2 ) downstream members were suggested to modulate neuroinflammatory responses accompanying neurodegenerative diseases. In this study, we investigated the protective effects of prostaglandin E2 receptor 2 (EP2 ) during TLR3 and TLR4-driven inflammatory response using in vitro primary microglia and ex vivo organotypic hippocampal slice cultures (OHSCs). Depletion of microglia from OHSCs differentially affected TLR3 and TLR4 receptor expression. Poly(I:C) induced the production of prostaglandin E2 in OHSCs by increasing cyclooxygenase (COX-2) and microsomal prostaglandin E synthase (mPGES)-1. Besides, stimulation of OHSCs and microglia with Poly(I:C) upregulated EP2 receptor expression. Co-stimulation of OHSCs and microglia with the EP2 agonist butaprost reduced inflammatory mediators induced by LPS and Poly(I:C). In Poly(I:C) challenged OHSCs, butaprost almost restored microglia ramified morphology and reduced Iba1 immunoreactivity. Importantly, microglia depletion prevented the induction of inflammatory mediators following Poly(I:C) or LPS challenge in OHSCs. Activation of EP2 receptor reversed the Poly(I:C)/LPS-induced phosphorylation of the mitogen activated protein kinases (MAPKs) ERK, p38 MAPK and c-Jun N-terminal kinase (JNK) in microglia. Collectively, these data identify an anti-inflammatory function for EP2 signaling in diverse innate immune responses, through a mechanism that involves the mitogen-activated protein kinases pathway.

Poly(I:C) increases the expression of mPGES-1 and COX-2 in rat primary microglia.

BACKGROUND: Microglia recognize pathogen-associated molecular patterns such as double-stranded RNA (dsRNA) present in some viruses. Polyinosinic-polycytidylic acid [poly(I:C)] is a synthetic analog of dsRNA that activates different molecules, such as retinoic acid-inducible gene I, melanoma differentiation-associated gene 5, and toll-like receptor-3 (TLR3). Poly(I:C) increases the expression of different cytokines in various cell types. However, its role in the regulation of the production of inflammatory mediators of the arachidonic acid pathway by microglia is poorly understood. METHODS: In the present study, we evaluated the effect of poly(I:C) on the production of prostaglandin E2 (PGE2) and the inducible enzymes cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) in primary rat microglia. Microglia were stimulated with different concentrations of poly(I:C) (0.1-10 µg/ml), and the protein levels of COX-2 and mPGES-1, as well as the release of PGE2, were determined by western blot and enzyme immunoassay (EIA), respectively. Values were compared using one-way ANOVA with post hoc Student-Newman-Keuls test. RESULTS: Poly(I:C) increased the production of PGE2, as well as mPGES-1 and COX-2 synthesis. To investigate the mechanisms involved in poly(I:C)-induced COX-2 and mPGES-1, we studied the effects of various signal transduction pathway inhibitors. Protein levels of COX-2 and mPGES-1 were reduced by SB203580, SP600125, and SC514 (p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), and IκB kinase (IKK) inhibitors, respectively), as well as by PD98059 and PD0325901 (mitogen-activated protein kinase kinase (MEK) inhibitors). Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, enhanced the synthesis of COX-2. Inhibition of phosphatidylinositol 3-kinase (PI3K) by LY294002 or dual inhibition of PI3K/mTOR (with NVP-BEZ235) enhanced COX-2 and reduced mPGES-1 immunoreactivity. To confirm the data obtained with the inhibitors, we studied the phosphorylation of the blocked kinases by western blot. Poly(I:C) increased the phosphorylation of p38 MAPK, extracellular signal-regulated kinase (ERK), JNK, protein kinase B (Akt), and IκB. CONCLUSIONS: Taken together, our data demonstrate that poly(I:C) increases the synthesis of enzymes involved in PGE2 synthesis via activation of different signaling pathways in microglia. Importantly, poly(I:C) activates similar pathways also involved in TLR4 signaling that are important for COX-2 and mPGES-1 synthesis. Thus, these two enzymes and their products might contribute to the neuropathological effects induced in response to dsRNA, whereby the engagement of TLR3 might be involved.

WHEDA study: effectiveness of occupational therapy at home for older people with dementia and their caregivers--the design of a pragmatic randomised controlled trial evaluating a Dutch programme in seven German centres.

BACKGROUND: A recent Dutch mono-centre randomised controlled trial has shown that occupational therapy improves daily functioning in dementia. The aim of this present study is to compare the effects of the Dutch community occupational therapy programme with a community occupational therapy consultation on daily functioning in older people with mild or moderate dementia and their primary caregivers in a German multi-centre context. METHODS/DESIGN: A multi-centre single blind randomised controlled trial design is being used in seven health care centres (neurological, psychiatric and for older people) in urban regions. Patients are 1:1 randomised to treatment or control group. Assessors are blind to group assignment and perform measurements on both groups at baseline, directly after intervention at 6 weeks and at 16, 26 and 52 weeks follow-up. A sample of 140 community dwelling older people (aged >65 years) with mild or moderate dementia and their primary caregivers is planned. The experimental intervention consists of an evidence-based community occupational therapy programme including 10 sessions occupational therapy at home. The control intervention consists of one community occupational therapy consultation based on information material of the Alzheimer Society. Providers of both interventions are occupational therapists experienced in treatment of cognitively impaired older people and trained in both programmes. 'Community' indicates that occupational therapy intervention occurs in the person's own home. The primary outcome is patients' daily functioning assessed with the performance scale of the Interview for Deterioration in Daily Living Activities in Dementia and video tapes of daily activities rated by external raters blind to group assignment using the Perceive, Recall, Plan and Perform System of Task Analysis. Secondary outcomes are patients' and caregivers' quality of life, mood and satisfaction with treatment; the caregiver's sense of competence, caregiver's diary (medication, resource utilisation, time of informal care); and the incidence of long-term institutionalisation. Process evaluation is performed by questionnaires and focus group discussion. DISCUSSION: The transfer from the Dutch mono-centre design to the pragmatic multi-site trial in a German context implicates several changes in design issues including differences in recruitment time, training of interventionists and active control group treatment.The study is registered under DRKS00000053 at the German register of clinical trials, which is connected to the International Clinical Trials Registry Platform.

Anti-neuroinflammatory effects of Ginkgo biloba extract EGb761 in LPS-activated primary microglial cells.

BACKGROUND: Neuroinflammation is a key factor of Alzheimer's disease (AD) and other neurodegenerative conditions. Microglia are the resident mononuclear immune cells of the central nervous system (CNS). They play an essential role in the maintenance of homeostasis and responses to neuroinflammation. Ginkgo biloba extract EGb 761 is one of the most commonly used natural medicines owing to its established efficacy and remarkable biological activities especially in respect to CNS diseases. However, only few studies have addressed the effects and mechanisms of Ginkgo biloba extract in microglia activation. METHODS: We measured the production of pro-inflammatory mediators and cytokines by ELISA and analyzed gene expressions by qRT-PCR and Western Blot in LPS treated cultured primary rat microglia. RESULTS: The Ginkgo biloba extract EGb 761 significantly inhibited the release of prostaglandin E2 (PGE2) and differentially regulated the levels of pro-inflammatory cytokines. The inhibition of LPS-induced PGE2 release in primary microglia was partially dependent on reduced protein synthesis of mPGES-1 and the reduction in the activation of cytosolic phospholipase A2 (cPLA2) without altering COX-2 enzymatic activity, inhibitor of kappa B alpha (IkappaBalpha) degradation, and the activation of multiple mitogen activated protein kinases (MAPKs). Altogether, we showed that EGb 761 reduces neuro-inflammatory activation in primary microglial cells by targeting PGE2 release and cytokines. CONCLUSION: Ginkgo biloba extract EGb 761 displayed anti-neuroinflammatory activity in LPS-activated primary microglia cells. EGb 761 was able to reduce neuroinflammatory activation by targeting the COX/PGE2 pathway. This effect might contribute to the established clinical cognitive efficacy in Alzheimer's disease, vascular and mixed dementia.

Clinical efficacy and cognitive side effects of bifrontal versus right unilateral electroconvulsive therapy (ECT): a short-term randomised controlled trial in pharmaco-resistant major depression.

BACKGROUND: In most studies right unilateral electroconvulsive therapy (ECT) has been shown to cause fewer cognitive side effects but less antidepressant efficacy compared with bi(fronto)temporal ECT at certain intensities. AIMS: To compare the short-term efficacy and side effects of right unilateral ECT and bifrontal ECT. METHODS: In a double-blind randomised controlled clinical trial, 92 patients diagnosed with pharmaco-resistant major depression received either six right unilateral ECT treatments (250% stimulus intensity of titrated threshold) or six bifrontal ECT (150% of threshold) treatments over a 3-week period. Concomitant psychotropic medications were continued during ECT treatments. The severity of depression and cognitive status was assessed prior to the first ECT and one day after the sixth ECT using the 21-item Hamilton Depression Rating Scale and the modified Mini Mental State Examination. RESULTS: Eight patients did not complete the course of the study due to minor side effects or withdrawal of consent. The mean Hamilton Depression score decreased from 27 to 17 points in both groups of 46 patients, resulting in 12 responders (primary endpoint defined as a decrease >50%) in each patient group (95% confidence interval for the odds ratio from 0.35 to 2.8). There was no reduction in the modified Mini Mental State score (mean score 86 of 100 points). CONCLUSIONS: Both bifrontal and right unilateral electrode placements in ECT were reasonably safe and moderately efficacious in reducing symptoms of pharmaco-resistant major depression.

Interrater Reliability and Concurrent Validity of a New Rating Scale to Assess the Performance of Everyday Life Tasks in Dementia: The Core Elements Method.

Errorless learning (EL) is an instructional procedure involving error reduction during learning. Errorless learning is mostly examined by counting correctly executed task steps or by rating them using a Task Performance Scale (TPS). Here, we explore the validity and reliability of a new assessment procedure, the core elements method (CEM), which rates essential building blocks of activities rather than individual steps. Task performance was assessed in 35 patients with Alzheimer's dementia recruited from the Relearning methods on Daily Living task performance of persons with Dementia (REDALI-DEM) study using TPS and CEM independently. Results showed excellent interrater reliabilities for both measure methods (CEM: intraclass coefficient [ICC] = .85; TPS: ICC = .97). Also, both methods showed a high agreement (CEM: mean of measurement difference [MD] = -3.44, standard deviation [SD] = 14.72; TPS: MD = -0.41, SD = 7.89) and correlated highly (>.75). Based on these results, TPS and CEM are both valid for assessing task performance. However, since TPS is more complicated and time consuming, CEM may be the preferred method for future research projects.

Progesterone increase under DHEA-substitution in males.

Two case reports of men suffering from excessive fatigue and depression are presented, both treated with 50 or 25 mg DHEA per day over a period of 1 year. Under DHEA treatment one subject reported being less tired and the other experienced improved well-being without depressive episodes and an increase in libido. Investigations of sex hormone parameters in plasma before and under treatment revealed a decrease of testosterone and an increase of progesterone in both, possibly dose-dependent to DHEA application. It is hypothesised that the increase of progesterone is parallel to an increase of its metabolite allopregnanolone (which was not determined), that might explain the improvement in well-being. The increase of progesterone under DHEA supplementation in males should receive further attention.

Hemispheric asymmetries of hypometabolism associated with semantic memory impairment in Alzheimer's disease: a study using positron emission tomography with fluorodeoxyglucose-F18.

Considerable disagreement exists about the neuroanatomical basis of conceptual-semantic impairments observed in a subgroup of patients with Alzheimer's disease (AD) at mild to moderate stages of the disease. Several studies of groups of patients have shown correlations between focal hypometabolism or hypoperfusion in left hemispheric areas and measures of verbal semantic memory impairment in AD patients. The question remains, however, whether left hemispheric hypometabolism is sufficient to produce such impairment in the single case and whether nonverbal semantic knowledge is also affected. We used positron emission tomography (PET) with fluorodeoxyglucose-F18 (FDG), statistical parametric mapping (SPM), and tests of verbal and nonverbal semantic memory in 11 AD patients with a mean score on the Mini-Mental State Examination of 22.6 (+/-2.8). Naming impairment was significantly associated with left hemispheric asymmetry of hypometabolism on a single-case basis. Our correlation analysis showed that metabolism in left anterior temporal, posterior inferior temporal, inferior parietal and medial occipital areas (Brodmann areas: 21/38, 37, 40 and 19) correlated with both verbal and nonverbal semantic performance. We conclude that left hemispheric synaptic dysfunction, as measured by regional glucose hypometabolism, was sufficient to produce semantic impairments in our patients. The majority of areas affected in our patients with semantic impairments were involved in multimodal or supramodal (verbal and nonverbal) semantic knowledge.