Anti-Inflammatory Effects of GPR55 Agonists and Antagonists in LPS-Treated BV2 Microglial Cells.

Chronic inflammation is driven by proinflammatory cytokines such as interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and chemokines, such as c-c motif chemokine ligand 2 (CCL2), CCL3, C-X-C motif chemokine ligand 2 (CXCL2), and CXCL10. Inflammatory processes of the central nervous system (CNS) play an important role in the pathogenesis of various neurological and psychiatric disorders like Alzheimer's disease, Parkinson's disease, and depression. Therefore, identifying novel anti-inflammatory drugs may be beneficial for treating disorders with a neuroinflammatory background. The G-protein-coupled receptor 55 (GPR55) gained interest due to its role in inflammatory processes and possible involvement in different disorders. This study aims to identify the anti-inflammatory effects of the coumarin-based compound KIT C, acting as an antagonist with inverse agonistic activity at GPR55, in lipopolysaccharide (LPS)-stimulated BV2 microglial cells in comparison to the commercial GPR55 agonist O-1602 and antagonist ML-193. All compounds significantly suppressed IL-6, TNF-α, CCL2, CCL3, CXCL2, and CXCL10 expression and release in LPS-treated BV2 microglial cells. The anti-inflammatory effects of the compounds are partially explained by modulation of the phosphorylation of p38 mitogen-activated protein kinase (MAPK), p42/44 MAPK (ERK 1/2), protein kinase C (PKC) pathways, and the transcription factor nuclear factor (NF)-κB, respectively. Due to its potent anti-inflammatory properties, KIT C is a promising compound for further research and potential use in inflammatory-related disorders.

Modulation of neuroinflammation and oxidative stress by targeting GPR55 - new approaches in the treatment of psychiatric disorders.

Pharmacological treatment of psychiatric disorders remains challenging in clinical, pharmacological, and scientific practice. Even if many different substances are established for treating different psychiatric conditions, subgroups of patients show only small or no response to the treatment. The neuroinflammatory hypothesis of the genesis of psychiatric disorders might explain underlying mechanisms in these non-responders. For that reason, recent research focus on neuroinflammatory processes and oxidative stress as possible causes of psychiatric disorders. G-protein coupled receptors (GPCRs) form the biggest superfamily of membrane-bound receptors and are already well known as pharmacological targets in various diseases. The G-protein coupled receptor 55 (GPR55), a receptor considered part of the endocannabinoid system, reveals promising modulation of neuroinflammatory and oxidative processes. Different agonists and antagonists reduce pro-inflammatory cytokine release, enhance the synthesis of anti-inflammatory mediators, and protect cells from oxidative damage. For this reason, GPR55 ligands might be promising compounds in treating subgroups of patients suffering from psychiatric disorders related to neuroinflammation or oxidative stress. New approaches in drug design might lead to new compounds targeting different pathomechanisms of those disorders in just one molecule.

Anti-Neuroinflammatory Effects of a Macrocyclic Peptide-Peptoid Hybrid in Lipopolysaccharide-Stimulated BV2 Microglial Cells.

Inflammation processes of the central nervous system (CNS) play a vital role in the pathogenesis of several neurological and psychiatric disorders like depression. These processes are characterized by the activation of glia cells, such as microglia. Clinical studies showed a decrease in symptoms associated with the mentioned diseases after the treatment with anti-inflammatory drugs. Therefore, the investigation of novel anti-inflammatory drugs could hold substantial potential in the treatment of disorders with a neuroinflammatory background. In this in vitro study, we report the anti-inflammatory effects of a novel hexacyclic peptide-peptoid hybrid in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. The macrocyclic compound X15856 significantly suppressed Interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), c-c motif chemokine ligand 2 (CCL2), CCL3, C-X-C motif chemokine ligand 2 (CXCL2), and CXCL10 expression and release in LPS-treated BV2 microglial cells. The anti-inflammatory effects of the compound are partially explained by the modulation of the phosphorylation of p38 mitogen-activated protein kinases (MAPK), p42/44 MAPK (ERK 1/2), protein kinase C (PKC), and the nuclear factor (NF)-κB, respectively. Due to its remarkable anti-inflammatory properties, this compound emerges as an encouraging option for additional research and potential utilization in disorders influenced by inflammation, such as depression.

The VertiGO! Trial protocol: A prospective, single-center, patient-blinded study to evaluate efficacy and safety of prolonged daily stimulation with a multichannel vestibulocochlear implant prototype in bilateral vestibulopathy patients.

BACKGROUND: A combined vestibular (VI) and cochlear implant (CI) device, also known as the vestibulocochlear implant (VCI), was previously developed to restore both vestibular and auditory function. A new refined prototype is currently being investigated. This prototype allows for concurrent multichannel vestibular and cochlear stimulation. Although recent studies showed that VCI stimulation enables compensatory eye, body and neck movements, the constraints in these acute study designs prevent them from creating more general statements over time. Moreover, the clinical relevance of potential VI and CI interactions is not yet studied. The VertiGO! Trial aims to investigate the safety and efficacy of prolonged daily motion modulated stimulation with a multichannel VCI prototype. METHODS: A single-center clinical trial will be carried out to evaluate prolonged VCI stimulation, assess general safety and explore interactions between the CI and VI. A single-blind randomized controlled crossover design will be implemented to evaluate the efficacy of three types of stimulation. Furthermore, this study will provide a proof-of-concept for a VI rehabilitation program. A total of minimum eight, with a maximum of 13, participants suffering from bilateral vestibulopathy and severe sensorineural hearing loss in the ear to implant will be included and followed over a five-year period. Efficacy will be evaluated by collecting functional (i.e. image stabilization) and more fundamental (i.e. vestibulo-ocular reflexes, self-motion perception) outcomes. Hearing performance with a VCI and patient-reported outcomes will be included as well. DISCUSSION: The proposed schedule of fitting, stimulation and outcome testing allows for a comprehensive evaluation of the feasibility and long-term safety of a multichannel VCI prototype. This design will give insights into vestibular and hearing performance during VCI stimulation. Results will also provide insights into the expected daily benefit of prolonged VCI stimulation, paving the way for cost-effectiveness analyses and a more comprehensive clinical implementation of vestibulocochlear stimulation in the future. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04918745. Registered 28 April 2021.

AMPK Activation by Cimicifuga racemosa Extract Ze 450 Is Associated with Metabolic Effects and Cellular Resilience against Age-Related Pathologies in Different Tissue Cell Types.

Cimicifuga racemosa extracts (CREs) have gained well-established use for the treatment of menopausal symptoms such as hot flushes and excessive sweating, and weight gain. While the clinical effects of CREs have been well documented, the mechanisms underlying these effects are largely unknown. More recently, the metabolic effects of the CRE Ze 450 were demonstrated in cultured cells in vitro and in mouse models of obesity in vivo. At the molecular level, metabolic regulation, enhanced insulin sensitivity, and increased glucose uptake were linked to the activation of AMP-activated protein kinase (AMPK). Therefore, we tested the effects of Ze 450 on AMPK phosphorylation and thus activation in cells from different tissues, i.e., murine C2C12 myoblast cells, human HEPG2 liver cells, mouse HT22 neuronal cells, and in murine 3T3L1 adipocytes. Using a FRET-based HTRF-assay, we found that Ze 450 induced AMPK phosphorylation and the activation of this key enzyme of metabolic regulation in cells from various different tissues including C2C12 (muscle), HEPG2 (liver), HT22 (hippocampal), and 3T3-L1 (adipocyte) cells. In C2C12 muscle cells, enhanced AMPK activation was accompanied by reduced mitochondrial respiration and enhanced glucose uptake. Further, Ze 450 enhanced the resilience of the cells against oxidative death induced by ferroptosis inducers erastin or RSL3. Our findings suggest a general effect of Cimicifuga racemosa on AMPK activation in different tissues and across species. This may have a significant impact on expanded therapeutic applications of Ze 450, since AMPK activation and the related metabolic effects have been previously associated with anti-aging effects and the prevention of the metabolic syndrome.

Optimizing vestibular implant electrode positioning using fluoroscopy and intraoperative CT imaging.

PURPOSE:  Vestibular implant electrode positioning close to the afferent nerve fibers is considered to be key for effective and selective electrical stimulation. However, accurate positioning of vestibular implant electrodes inside the semicircular canal ampullae is challenging due to the inability to visualize the target during the surgical procedure. This study investigates the accuracy of a new surgical protocol with real-time fluoroscopy and intraoperative CT imaging, which facilitates electrode positioning during vestibular implant surgery. METHODS:  Single-center case-controlled cohort study with a historic control group at a tertiary referral center. Patients were implanted with a vestibulocochlear implant, using a combination of intraoperative fluoroscopy and cone beam CT imaging. The control group consisted of five patients who were previously implanted with the former implant prototype, without the use of intraoperative imaging. Electrode positioning was analyzed postoperatively with a high-resolution CT scan using 3D slicer software. The result was defined as accurate if the electrode position was within 1.5 mm of the center of the ampulla. RESULTS: With the new imaging protocol, all electrodes could be positioned within a 1.5 mm range of the center of the ampulla. The accuracy was significantly higher in the study group with intraoperative imaging (21/21 electrodes) compared to the control group without intraoperative imaging (10/15 electrodes), (p = 0.008). CONCLUSION:  The combined use of intraoperative fluoroscopy and CT imaging during vestibular implantation can improve the accuracy of electrode positioning. This might lead to better vestibular implant performance.

Cx3cr1 deficiency interferes with learning- and direct current stimulation-mediated neuroplasticity of the motor cortex.

Microglia are essential contributors to synaptic transmission and stability and communicate with neurons via the fractalkine pathway. Transcranial direct current stimulation [(t)DCS], a form of non-invasive electrical brain stimulation, modulates cortical excitability and promotes neuroplasticity, which has been extensively demonstrated in the motor cortex and for motor learning. The role of microglia and their fractalkine receptor CX3CR1 in motor cortical neuroplasticity mediated by DCS or motor learning requires further elucidation. We demonstrate the effects of pharmacological microglial depletion and genetic Cx3cr1 deficiency on the induction of DCS-induced long-term potentiation (DCS-LTP) ex vivo. The relevance of microglia-neuron communication for DCS response and structural neuroplasticity underlying motor learning are assessed via 2-photon in vivo imaging. The behavioural consequences of impaired CX3CR1 signalling are investigated for both gross and fine motor learning. We show that DCS-mediated neuroplasticity in the motor cortex depends on the presence of microglia and is driven in part by CX3CR1 signalling ex vivo and provide the first evidence of microglia interacting with neurons during DCS in vivo. Furthermore, CX3CR1 signalling is required for motor learning and underlying structural neuroplasticity in concert with microglia interaction. Although we have recently demonstrated the microglial response to DCS in vivo, we now provide a link between microglial integrity and neuronal activity for the expression of DCS-dependent neuroplasticity. In addition, we extend the knowledge on the relevance of CX3CR1 signalling for motor learning and structural neuroplasticity. The underlying molecular mechanisms and the potential impact of DCS in rescuing CX3CR1 deficits remain to be addressed in the future.

Punicalagin attenuates myocardial oxidative damage, inflammation, and apoptosis in isoproterenol-induced myocardial infarction in rats: Biochemical, immunohistochemical, and in silico molecular docking studies.

Myocardial infarction (MI) is a life-threatening ischemic disease and is one of the leading causes of morbidity and mortality worldwide. Punicalagin (PU), the major ellagitannin found in pomegranates, is characterized by multiple antioxidant activities. The aim of this study is to assess the protective effects of PU against isoproterenol (ISO)-induced acute myocardial damage and to investigate its underlying vascular mechanisms using rat model. METHODS: Rats were randomly divided into five groups and were treated orally (p.o.) with PU (25 and 50 mg/kg) for 14 days. ISO was administered subcutaneously (S.C.) (85 mg/kg) on the 15th and 16th days to induce Myocardial infarction. Cardiac markers, oxidative stress markers, and inflammatory cytokines levels were determined in the heart tissue. Immunohistochemistry analysis was performed to determine the protein expression pathways of inflammation, apoptosis and oxidative stress (Nuclear factor erythroid 2-related factor 2 (Nrf-2), and heme oxygenase-1 (HO-1) in all the groups. In silico study was carried out to evaluate the molecular interaction of PU with some molecular targets. RESULTS: Our results showed that ISO-induced cardiac tissue injury was evidenced by increased serum creatine kinase-MB (CK-MB), cardiac troponin I (cTnI), and lactate dehydrogenase (LDH), associated with several histopathological changes. ISO also induced an increase of MDA, PCO, NO, and 8-hydroxy-2-deoxyguanosine (8-OHdG), along with a decrease of antioxidant enzyme activities in the myocardial tissues. In addition, an increase of TNF-α, NF-κB, IL-6, IL-1ß, iNOS, Nrf2 and (HO-1) was observed. Pre-treatment with PU reduced myocardial infract area, ameliorated histopathological alterations in myocardium, and decreased activities of myocardial injury marker enzymes in ISO-induced rats. In addition, PU remarkably restored ISO-induced elevation of lipid peroxidation and decrease of antioxidants, significantly reduced myocardial pro-inflammatory cytokines concentrations in this animal model. Molecular docking analysis of PU with protein targets showed potent interactions with negative binding energies. In conclusion, PU can protect the myocardium from oxidative injury, inflammatory response, and cell death induced by ISO by upregulating Nrf2/HO-1 signaling and antioxidants.

Licochalcone A Inhibits Prostaglandin E2 by Targeting the MAPK Pathway in LPS Activated Primary Microglia.

Neuroinflammation and oxidative stress are conditions leading to neurological and neuropsychiatric disorders. Natural compounds exerting anti-inflammatory and anti-oxidative effects, such as Licochalcone A, a bioactive flavonoid present in a traditional Chinese herb (licorice), might be beneficial for the treatment of those disorders. Therefore, this study aimed to investigate the anti-inflammatory and anti-oxidative effects of Licochalcone A in LPS-activated primary rat microglia. Licochalcone A dose-dependently prevented LPS-induced PGE2 release by inhibiting the arachidonic acid (AA)/cylcooxygenase (COX) pathway decreasing phospholipase A2, COX-1, and COX-2 protein levels. Furthermore, LPS-induced levels of the cytokines IL-6 and TNFα were reduced by Licochalcone A, which also inhibited the phosphorylation and, thus, activation of the mitogen-activated protein kinases (MAPK) p38 MAPK and Erk 1/2. With the reduction of 8-iso-PGF2α, a sensitive marker for oxidative stress, anti-oxidative effects of Licochalcone A were demonstrated. Our data demonstrate that Licochalcone A can affect microglial activation by interfering in important inflammatory pathways. These in vitro findings further demonstrate the potential value of Licochalcone A as a therapeutic option for the prevention of microglial dysfunction related to neuroinflammatory diseases. Future research should continue to investigate the effects of Licochalcone A in different disease models with a focus on its anti-oxidative and anti-neuroinflammatory properties.

Altered cytokine levels in the cerebrospinal fluid of adult patients with autism spectrum disorder.

BACKGROUND: Despite intensive research, the etiological causes of autism spectrum disorder (ASD) remain elusive. Immunological mechanisms have recently been studied more frequently in the context of maternal autoantibodies and infections, as well as altered cytokine profiles. For the detection of immunological processes in the central nervous system, analyses of cerebrospinal fluid (CSF) are advantageous due to its proximity to the brain. However, cytokine studies in the CSF of ASD patients are sparse. METHODS: CSF was collected from a patient sample of 24 adults (m = 16, f = 8, age: 30.3 ± 11.6 years) with ASD and compared to a previously published mentally healthy control sample of 39 neurological patients with idiopathic intracranial hypertension. A magnetic bead multiplexing immunoassay was used to measure multiple cytokines in CSF. RESULTS: Significantly decreased interferon-γ-induced protein-10 (p = 0.001) and monocyte chemoattractant protein-1 (p = 0.041) levels as well as significantly higher interleukin-8 levels (p = 0.041) were detected in patients with ASD compared with the control group. CONCLUSION: The main finding of this study is an altered cytokine profile in adult patients with ASD compared to the control group. This may indicate immune dysregulation in a subgroup of adult ASD patients. Further studies in larger cohorts that examine a broader spectrum of chemokines and cytokines in general are needed to detect possible specific immune signatures in ASD.

Effectiveness and Safety of CT-Guided Facet Joint Cyst Rupture for Radicular Pain as First Choice Therapy: A Retrospective Analysis.

OBJECTIVE: To evaluate effectiveness and safety of computed tomography (CT)-guided cyst rupture with intraarticular contrast-enhanced injection of steroid and local anesthetic as first choice therapy in patients with facet joint cyst-induced radicular pain. DESIGN: Retrospective data set analysis. SETTING: University hospital. SUBJECTS: One hundred and twenty-one patients suffering from radicular pain attributable to facet joint cysts were included. METHODS: The rate of patients without following surgery was assessed and defined as surrogate to measure effectiveness. Patients' characteristics, procedure-associated complications, technical aspects, and imaging findings on magnetic resonance imaging (MRI) were analyzed. A subgroup of 65 patients (54%) underwent telephone interview to assess pain relief and clinical outcome measured by Numeric Rating Scale and Oswestry Disability Index. Analyses between the groups with and without surgery were performed by Fisher exact test and two-sample unpaired t-test, respectively. RESULTS: The effectiveness of CT-guided cyst rupture was found to be 66.1%. Procedure-induced pain yielded in premature abort in two cases (1.7%). The detection of epidural contrast agent was statistically significantly associated with no need for surgery (P = .010). The cyst level was associated with the status of following surgery (P = .026), that is, cysts at lower lumbar spine were easier to rupture than cysts at other locations (cervical, thoracic, or upper lumbar spine). No further significant association was found. CONCLUSIONS: CT-guided cyst rupture as the first-choice therapy in patients with cyst-induced radicular pain was safe and effective. Successful cyst rupture was associated with no need for surgery. Cysts at lower lumbar spine revealed the highest success rate.

Neurodegeneration Markers in the Cerebrospinal Fluid of 100 Patients with Schizophrenia Spectrum Disorder.

BACKGROUND: Schizophrenia spectrum disorders (SSD) can be associated with neurodegenerative processes causing disruption of neuronal, synaptic, or axonal integrity. Some previous studies have reported alterations of neurodegenerative markers (such as amyloid beta [Aß], tau, or neurofilaments) in patients with SSD. However, the current state of research remains inconclusive. Therefore, the rationale of this study was to investigate established neurodegenerative markers in the cerebrospinal fluid (CSF) of a large group of patients with SSD. STUDY DESIGN: Measurements of Aß1-40, Aß1-42, phospho- and total-tau in addition to neurofilament light (NFL), medium (NFM), and heavy (NFH) chains were performed in the CSF of 100 patients with SSD (60 F, 40 M; age 33.7 ± 12.0) and 39 controls with idiopathic intracranial hypertension (33 F, 6 M; age 34.6 ± 12.0) using enzyme-linked immunoassays. STUDY RESULTS: The NFM levels were significantly increased in SSD patients (P = .009), whereas phospho-tau levels were lower in comparison to the control group (P = .018). No other significant differences in total-tau, beta-amyloid-quotient (Aß1-42/Aß1-40), NFL, and NFH were identified. CONCLUSIONS: The findings argue against a general tauopathy or amyloid pathology in patients with SSD. However, high levels of NFM, which has been linked to regulatory functions in dopaminergic neurotransmission, were associated with SSD. Therefore, NFM could be a promising candidate for further research on SSD.

Cannabidiol markedly alleviates skin and liver fibrosis.

Cannabidiol (CBD) has been suggested as a potential therapy for inflammatory and fibrotic diseases. Cannabidiol was demonstrated to reduce alcohol-induced liver inflammation and steatosis but its specific activity on the fibrotic process was not investigated. Herein, the antifibrotic effects of cannabidiol in the skin were analysed in vitro using NIH-3T3 fibroblasts and human dermal fibroblasts and in vivo using the bleomycin-induced model of skin fibrosis. In a second model, non-alcoholic liver fibrosis was induced in mice by CCl4 exposure. Cannabidiol was administered daily, intraperitoneally in mice challenged with bleomycin and orally in CCl4 mice, and skin and liver fibrosis and inflammation were assessed by immunochemistry. Cannabidiol inhibited collagen gene transcription and synthesis and prevented TGFß-and IL-4 induced fibroblast migration. In the bleomycin model, cannabidiol prevented skin fibrosis and collagen accumulation around skin blood vessels, and in the CCl4 model cannabidiol significantly attenuated liver fibrosis measured by picrosirius red and Tenascin C staining and reduced T cell and macrophage infiltration. Altogether, our data further support the rationale of the medicinal use of this cannabinoid, as well as cannabis preparations containing it, in the management of fibrotic diseases including Systemic Sclerosis and Non-Alcoholic Fatty Liver Disease.

Antibody indices of infectious pathogens from serum and cerebrospinal fluid in patients with schizophrenia spectrum disorders.

INTRODUCTION: Infectious and immunological theories of schizophrenia have been discussed for over a century. Contradictory results for infectious agents in association with schizophrenia spectrum disorders (SSDs) were reported. The rationale of this study was to investigate intrathecal antibody synthesis of the most frequently discussed neurotropic pathogens using a pathogen-specific antibody index (AI) in patients with SSD in comparison to controls. METHODS: In 100 patients with SSD and 39 mentally healthy controls with idiopathic intracranial hypertension (IIH), antibodies against the herpesviruses EBV, CMV, and HSV 1/2 as well as the protozoan Toxoplasma gondii, were measured in paired cerebrospinal fluid (CSF) and serum samples with ELISA-kits. From these antibody concentrations the pathogen-specific AIs were determined with the assumption of intrathecal antibody synthesis at values > 1.5. RESULTS: No significant difference was detected in the number of SSD patients with elevated pathogen-specific AI compared to the control group. In a subgroup analysis, a significantly higher EBV AI was observed in the group of patients with chronic SSD compared to patients with first-time SSD diagnosis (p = 0.003). In addition, two identified outlier EBV patients showed evidence for polyspecific immune reactions (with more than one increased AI). CONCLUSIONS: Evidence for the role of intrathecal EBV antibody synthesis was found in patients with chronic SSD compared to those first diagnosed. Apart from a possible infectious factor in SSD pathophysiology, the evidence for polyspecific immune response in outlier patients may also suggest the involvement of further immunological processes in a small subgroup of SSD patients.

The Evaluation of the Effects of Two Probiotic Strains on the Oral Ecosystem: A Randomized Clinical Trial.

Introduction: In the current study, we evaluated the effectiveness of two well-defined probiotic strains, Lactobacillus paracasei LPc-G110 (CCTCC M 2013691) and Lactobacillus plantarum GOS42 (DSM 32131), during an experimental gingivitis challenge. The primary objective was to evaluate clinically the effectiveness of lozenges containing one of the two oral probiotic strains, compared with placebo lozenges, on the gingival bleeding (bleeding on marginal probing; BOMP change) after a two-week experimental gingivitis period. The secondary objectives were to assess the effects of the test products on gingival health (Modified Gingival Index; MGI), dental plaque accumulation and fluorescence, and the dynamics of immunological and microbiological aspects after the wash-in phase, followed by a two-week period refraining from oral hygiene and a two-week wash-out phase. Methods: This single-center challenge intervention study was a triple-blind randomized placebo-controlled clinical trial with three parallel groups. The full study population consisted of 117 healthy 18-55 years old human volunteers. Subjects were instructed to use one lozenge, 3 times daily after each meal, containing either L. plantarum, L. paracasei, or lozenges without probiotics (placebo group). After a 2-week wash-in period, the subjects were requested to refrain from any form of oral hygiene for 2 weeks. Results: There were no differences in the primary outcome (BOMP change) among the groups. However, gingival health (MGI) in individuals from the groups exposed to the test products recovered better from experimental gingivitis than the individuals in the placebo group (p = 0.021, one-way ANOVA). The two test products inhibited pro-inflammatory cytokine IL-1ß production, measured in saliva, during the experimental gingivitis period. Both test strains significantly reduced bacterial DNA in tongue samples and L. paracasei strain showed stronger microbiome-modulating potential than the L. plantarum strain. Conclusions: The two tested lozenges with the L. paracasei or L. plantarum strains did show potential for beneficial effects for the oral health of the host during experimental gingivitis to the oral ecosystem.

The Value of APTw CEST MRI in Routine Clinical Assessment of Human Brain Tumor Patients at 3T.

BACKGROUND: With fast-growing evidence in literature for clinical applications of chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI), this prospective study aimed at applying amide proton transfer-weighted (APTw) CEST imaging in a clinical setting to assess its diagnostic potential in differentiation of intracranial tumors at 3 tesla (T). METHODS: Using the asymmetry magnetization transfer ratio (MTRasym) analysis, CEST signals were quantitatively investigated in the tumor areas and in a similar sized region of the normal-appearing white matter (NAWM) on the contralateral hemisphere of 27 patients with intracranial tumors. Area under curve (AUC) analyses were used and results were compared to perfusion-weighted imaging (PWI). RESULTS: Using APTw CEST, contrast-enhancing tumor areas showed significantly higher APTw CEST metrics than contralateral NAWM (AUC = 0.82; p < 0.01). In subgroup analyses of each tumor entity vs. NAWM, statistically significant effects were yielded for glioblastomas (AUC = 0.96; p < 0.01) and for meningiomas (AUC = 1.0; p < 0.01) but not for lymphomas as well as metastases (p > 0.05). PWI showed results comparable to APTw CEST in glioblastoma (p < 0.01). CONCLUSIONS: This prospective study confirmed the high diagnostic potential of APTw CEST imaging in a routine clinical setting to differentiate brain tumors.

Turmeric Extract (Curcuma longa) Mediates Anti-Oxidative Effects by Reduction of Nitric Oxide, iNOS Protein-, and mRNA-Synthesis in BV2 Microglial Cells.

Plant-derived products have been used since the beginnings of human history to treat various pathological conditions. Practical experience as well as a growing body of research suggests the benefits of the use of turmeric (Curcuma longa) and some of its active components in the reduction of oxidative stress, a mechanism leading to neurodegeneration. In this current study, we investigated the effects of a preparation of Curcuma longa, and its constituents curcumin, tetrahydrocurcumin, and curcumenol, in one of the molecular pathways leading to oxidative stress, which is the release of NO, a free radical involved in stress conditions, using the BV2 microglial cell line. The concentration-dependent reduction of NO is linked to reduced amounts of iNOS protein- and mRNA-synthesis and is possibly mediated by the phosphorylation of mitogen-activated protein kinases (MAPK) such as p42/44 or p38 MAPK. Therefore, the use of turmeric extract is a promising therapeutic option for diseases linked to the dysregulation of oxidative stress, with fewer side-effects in comparison to the currently used pharmacotherapeutics.

Functional Selectivity of Coumarin Derivates Acting via GPR55 in Neuroinflammation.

Anti-neuroinflammatory treatment has gained importance in the search for pharmacological treatments of different neurological and psychiatric diseases, such as depression, schizophrenia, Parkinson's disease, and Alzheimer's disease. Clinical studies demonstrate a reduction of the mentioned diseases' symptoms after the administration of anti-inflammatory drugs. Novel coumarin derivates have been shown to elicit anti-neuroinflammatory effects via G-protein coupled receptor GPR55, with possibly reduced side-effects compared to the known anti-inflammatory drugs. In this study, we, therefore, evaluated the anti-inflammatory capacities of the two novel coumarin-based compounds, KIT C and KIT H, in human neuroblastoma cells and primary murine microglia. Both compounds reduced PGE2-concentrations likely via the inhibition of COX-2 synthesis in SK-N-SH cells but only KIT C decreased PGE2-levels in primary microglia. The examination of other pro- and anti-inflammatory parameters showed varying effects of both compounds. Therefore, the differences in the effects of KIT C and KIT H might be explained by functional selectivity as well as tissue- or cell-dependent expression and signal pathways coupled to GPR55. Understanding the role of chemical residues in functional selectivity and specific cell- and tissue-targeting might open new therapeutic options in pharmacological drug development and might improve the treatment of the mentioned diseases by intervening in an early step of their pathogenesis.

Immunosuppressive activity of non-psychoactive Cannabis sativa L. extract on the function of human T lymphocytes.

BACKGROUND: Cannabis sativa L. extracts (CSE) are used for treating inflammatory conditions, but little is known about their immunomodulatory effects. We investigated a novel CSE with high (14%) CBD and low (0.2%) THC concentration in comparison with pure CBD on primary human lymphocytes. METHODS: Proliferation, cell cycle distribution, apoptosis/necrosis and viability were analysed with standard methods. Genotoxicity was evaluated with the comet-assay. The effect on T lymphocyte activation was evaluated via CD25/CD69 marker expression, degranulation assays and the production of cytokines. The influence on the transcription factors was analysed using Jurkat reporter cell lines. Specific CB2 receptor antagonist SR144528 and TRPV1 receptor antagonist A78416B were used to study the involvement of CB2 or TRPV1 receptors. RESULTS: CSE inhibited the proliferation of activated T lymphocytes in a dose-dependent manner without inducing apoptosis, necrosis, or affecting cell viability and DNA integrity. The inhibitory effect was mediated via the suppression of T lymphocytes activation, particularly by the suppression of CD25 surface marker expression. Furthermore, CSE interferes with the functionality of the T lymphocytes, as indicated by inhibition of degranulation, IL-2, and IFN-γ production. AP-1-and-NFAT-reporter activation was reduced implicating an AP-1-and-NFAT-mediated mode of action. The effects were in part reversed by SR144528 and A78416B, showing that the effects were mainly mediated by CB2 and TRPV1 receptors. CONCLUSION: CSE and CBD have immunomodulatory effects and interfere with the activation and functionality of T lymphocytes. A comparison between CSE and CBD suggests that the immunosuppressive effect of CSE is mostly due to the effect of CBD.

CB2 and toll-like receptors crosstalk in microglia.

Microglia play a major role in certain neuropathological conditions. In a recent paper, Reusch et al. demonstrated how signaling pathways downstream of cannabinoid type 2 (CB2) and toll-like receptors (TLRs) converge in these cells. The findings suggest that CB2 receptors play a permissive role in microglia activation mediated by TLRs.