The Effect of Low-Intensity Pulsed Ultrasound on Temporomandibular Joint Arthritis in Juvenile Rats.

Juvenile idiopathic arthritis is an inflammatory disease that can affect the temporomandibular joint (TMJ) and lower jaw growth. Better treatment options are needed, so this study investigated the effect of low-intensity pulsed ultrasound (LIPUS) on TMJ arthritis. Seventy-two 3-week-old male Wistar rats were in vivo microcomputed tomography (micro-CT) scanned and divided into eight groups (n = 9). These groups were Group 1-TMJ arthritis and immediate LIPUS treatment (20 min/day, 4 weeks); Group 2-immediate LIPUS treatment and no TMJ arthritis; Group 3-TMJ arthritis and no LIPUS; Group 4-no TMJ arthritis and no LIPUS; Group 5-TMJ arthritis and LIPUS treatment with a delayed start by 4 weeks; Group 6-Delayed LIPUS and no TMJ arthritis; Group 7-TMJ arthritis and no (delayed) LIPUS; and Group 8-no TMJ arthritis and no (delayed) LIPUS. Ex vivo micro-CT scanning was completed, and samples were prepared for tissue analysis. Synovitis was observed in the TMJ arthritis (collagen-induced arthritis [CIA]) groups, but the severity appeared greater in the groups without LIPUS treatment. Fibrocartilage and hypertrophic cell layer thicknesses in the CIA group without LIPUS treatment were significantly greater (p < 0.05). Proteoglycan staining appeared greater in the LIPUS groups. Immediate LIPUS treatment increased the expression of type II collagen, type X collagen, and transforming growth factor-beta 1 (TGF-ß1) immunostaining, and CIA (no LIPUS) increased MMP-13, vascular endothelial growth factor, and interleukin-1 beta (IL-1ß) immunostaining. LIPUS treatment prevented growth disturbances observed in the CIA groups (no LIPUS) (p < 0.005). Our results have contributed to the understanding of the uses and limitations of the CIA juvenile rat model and have demonstrated the effects of LIPUS on the TMJ and mandibular growth. This information will help in designing future studies for investigating LIPUS and TMJ arthritis, leading to the development of new treatment options for children with juvenile arthritis in their TMJs.

When are clients helpful? Capitalising on client involvement in professional service delivery.

Professional service firms apply specialist knowledge to create customised solutions to client problems. In their work, teams of professionals undertake projects in which clients may be closely involved in co-creating solutions. However, we know little about the conditions under which client involvement contributes to better performance. We examine the direct and conditional contribution client involvement can make to project success and propose team bonding capital as a moderator. We conduct multi-level analysis of data from 58 project managers and 171 consultants nested in project teams. We find a positive impact of client involvement on both team performance and team member idea creativity. Team bonding capital moderates the relationships client involvement has with both team performance and individual member idea creativity, where the impact of client involvement is greater when team bonding capital is high. Implications for theory and practice are discussed.

Reducing burnout among nurses: The role of high-involvement work practices and colleague support.

BACKGROUND: The impact of human resource practices on nurses' well-being, the underlying mechanisms involved, and the contextual factors that enhance or impede their success are not fully clear. PURPOSE: The aim of this article was to examine a moderated mediation model whereby high-involvement work practices are purported to reduce nurses' burnout via psychological empowerment, and colleague support is expected to moderate the mediating role of psychological empowerment in the high-involvement work practices-burnout link. METHODOLOGY/APPROACH: Structural equation modeling was employed on cross-sectional survey data collected from a large sample of nurses in Canada (N = 2,174). RESULTS: The findings revealed that psychological empowerment partially mediated the association between high-involvement work practices and burnout, whereas colleague support was directly associated with lower burnout rather than exerting a moderating effect. CONCLUSION: The study identifies the universality of high-involvement work practices in alleviating nurses' burnout and highlights the important role of psychological empowerment as an explanatory variable. In addition, colleague support is an important yet independent predictor of nurses' burnout. PRACTICAL IMPLICATIONS: This study identifies a strategy that can be adopted by hospital managers to help protect against nurse burnout while offering insights into the underlying process involved.

Individual variation in role construal predicts responses to third-party biases in hiring contexts.

We theorize that individuals' pre-existing beliefs about the hiring manager role (role construal) are associated with their tendency to condone bias accommodation in hiring contexts, in which a person aligns hiring decisions with the perceived biases of others. In two studies, we focus on human resources (HR) professionals' endorsement of the role demand to prioritize candidate fit with others (e.g., supervisor) when making hiring decisions. Study 1 examined bias accommodation from a vicarious perspective, revealing that role demand endorsement is positively associated with viewing it as acceptable and common for another hiring manager to accommodate third-party bias against women. Study 2 examined bias accommodation experimentally from an actor's perspective, showing lower preference for and selection of a female (vs. male) job candidate in the presence of cues to third-party bias against women, but only when role demand endorsement is relatively high. HR professionals in both studies indicated that third-party bias influences in hiring are relatively common. Responses in Study 2 provide preliminary evidence that the phenomenon of third-party bias accommodation might be relevant in the context of employment discrimination based on group characteristics other than gender (e.g., race/ethnicity, age). We discuss the practical implications of our findings for hiring professionals and for organizations seeking to increase diversity in their workforce.

Collagen-Induced Temporomandibular Joint Arthritis Juvenile Rat Animal Model.

Juvenile idiopathic arthritis can affect the temporomandibular joint (TMJ) can cause growth disturbances of the lower jaw (mandible). The collagen-induced arthritis (CIA) juvenile rat model may be an appropriate model for studying how juvenile arthritis affects this joint during growth. However, studies using this animal model to investigate TMJ arthritis are limited. To validate an animal model for studying TMJ arthritis in growing rats, our study aimed to investigate the changes in mandibular growth and expression of proteins and cytokines in the mandibular condyle of CIA juvenile rat TMJs. A total of 27 male Wistar rats (3 weeks old) were scanned with microcomputed tomography (MicroCT) and divided into three groups (n = 9); CIA was induced in each TMJ in the CIA group, the Saline group received saline injections (sham injections) into their TMJs, and the Healthy group remained untreated (no TMJ injections) as negative controls. After 4 weeks, our results show that mandibular growth was significantly reduced in the CIA group compared with the Saline group (p < 0.01). There was no difference in mandibular growth between the two control groups (Saline and Healthy). Inflamed synovial tissue, cartilage invaginations, and lipid accumulation were observed in the CIA TMJs. Toluidine blue staining revealed decreased proteoglycan production in the CIA cartilage. In addition, immunohistochemistry revealed that type II collagen expression decreased, interleukin-1ß expression increased, and matrix metalloproteinase-13 expression increased in the CIA TMJs in comparison with the two control groups (Saline and Healthy). Immunostaining of tumor necrosis factor-α (TNF-α) was quantified and we showed that TNF-α expression was significantly greater in the CIA cartilage compared with both control groups (p < 0.05), and there was no difference in TNF-α expression between the Saline and Healthy groups. This CIA juvenile rat model of TMJ juvenile arthritis shows that CIA reduced mandibular growth and induced degenerative changes in TMJ condylar cartilage. This new information will help to understand the pathogenesis involved in CIA in juvenile rat TMJs for this animal model to be used in research investigating new therapeutics to treat TMJ juvenile arthritis. Impact statement In this study, the effects of collagen-induced arthritis (CIA) on the temporomandibular joint (TMJ) using a juvenile rat model were investigated. Our results showed that local injection of CIA in the TMJ significantly reduced mandibular growth and caused degenerative changes in condylar cartilage. This information helps to validate this animal model for studying the effect of arthritis in TMJs in growing rats. This model has the potential to be used in future studies to evaluate possible therapies for TMJ arthritis.

Revisiting the Effect of Emotional Labor: A Multi-Level Investigation in Front-Line Service Teams.

The main purpose of this study is to consider individuals in teams and to reexamine how emotional labor affects the performance of front-line service team and team members through emotional exhaustion. Multi-source data collection and a time-lagged research design was adopted to collect data from matched team members and customers nested in 82 front-line service teams in a large electronics provider based in China. The findings show that surface acting increases emotional exhaustion which reduces customer loyalty at the team level and individual task performance at the individual level, supporting a full mediation model. While, deep acting is not associated with emotional exhaustion, it is positively linked with team member's task performance. This study provides evidence for the nested nature of emotional labor and exhaustion in teams.

Low intensity pulsed ultrasound increases mandibular height and Col-II and VEGF expression in arthritic mice.

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic inflammatory disease involving persistent inflammation resulting in cartilage and bone damage. RA can affect the temporomandibular joint (TMJ), and damage to the TMJ condyle can lead to craniofacial developmental disturbances, causing micrognathia, malocclusion, retrognathia, and increased overjet. Current treatments of TMJ arthritis are unsatisfactory. This pilot study aimed to investigate the effect of low intensity pulsed ultrasound (LIPUS) on the mandible and TMJ condyles in an RA mouse model using micro-computed tomography (Micro-CT), histologic, and immunohistochemical analyses. METHODS: MRL-lpr/lpr mice received LIPUS application to their TMJs for 20 min/day for 2 and 4 weeks. Micro-CT analysis measured condylar length and width, posterior mandibular height (P.M.H), mandibular ramus length (M.R.L), effective mandibular length (Ef.M.L), angular process length (A.P.L), mandibular plane (M.P), mandibular axis (M.Ax), and lower incisor height (L.I.H). Condylar cartilage thickness was histologically measured, and type II collagen (Col-II), vascular endothelial growth factor (VEGF), nuclear factor kappa-B ligand (RANKL), and osteoprotegerin (OPG) expression was analyzed using immunohistochemistry. RESULTS: Comparing the LIPUS-treated group with the control, P.M.H, M.R.L, and M.P were significantly greater in the LIPUS-treated group. Immunostaining for Col-II and VEGF was stronger in the LIPUS-treated group after 4 weeks. OPG showed slightly more expression in the LIPUS group. CONCLUSIONS: LIPUS may enhance mandibular and TMJ condylar bone formation in this RA mouse model by preventing any growth disturbances involved in inflammation. Further studies are recommended to analyze the effect of LIPUS on TMJ of RA in other animal models.

Mechanism underlying ß2-AR agonist-mediated phenotypic conversion of LPS-activated microglial cells.

Fundamentally, microglia have two activation states, a pro-inflammatory neurotoxic (M1) and an anti-inflammatory neuroprotective (M2) phenotype, and their conversion from M1-like to M2-like microglia may provide therapeutic benefits to prevent neuronal loss in neurodegenerative diseases such as Parkinson's disease (PD). Previously, we showed that Salmeterol, a long-acting ß2-adrenergic receptor (ß2-AR) agonist, has neuroprotective effects in PD models in vitro and in vivo through the ß-arrestin2-dependent inhibition of pro-inflammatory M1-type mediator production. In the present study, we explored whether Salmeterol can mediate phenotypic conversion in LPS-activated murine microglial BV2 cells from the neurotoxic M1-like to a neuroprotective M2-like phenotype. Salmeterol inhibited the production of LPS-induced mediators of the pro-inflammatory M1 phenotype such as tumor necrosis factor-α (TNF-α), IL-(interleukin) 18, IL-6, chemokines (CCL2, CCL3, CCL4) and reactive oxygen species from BV2 cells. Conversely, treatment with Salmeterol and other ß2-AR agonists robustly enhances the production of the M2 cytokine IL-10 from LPS-activated microglia. In addition, Salmeterol upregulates the expression of arginase-1 and CXCL14. Furthermore, using siRNA approach we found that silencing of the transcription factor Creb abrogates the Salmeterol-mediated production of IL-10 in LPS-activated BV2 cells, but silencing of ß-arrestin2 with Arrb2 siRNA did not. In addition, our data shows conversion from an M1- to M2-like phenotype in LPS-activated microglia by ß2-AR agonists involves activation of the classical cAMP/PKA/CREB as well as the PI3K and p38 MAPK signaling pathways, and provides a novel therapeutic approach targeting microglial cell activation and inducing their phenotypic conversion in the treatment of neuroinflammatory diseases such as PD.

ß-arrestin2 regulates the anti-inflammatory effects of Salmeterol in lipopolysaccharide-stimulated BV2 cells.

Microglial activation contributes to chronic inflammation and neuronal loss in progressive neurodegenerative disorders such as Parkinson's disease (PD). Thus, treatments suppressing microglial activation may have therapeutic benefits to prevent neuronal loss in neurodegenerative diseases. Our previous findings show that Salmeterol, a long-acting ß2-adrenergic receptor (ß2-AR) agonist, is neuroprotective in two distinct animal models of PD, including where lipopolysaccharide (LPS) from E. coli was used to initiate chronic neurodegeneration. Salmeterol was found to be a potent inhibitor of dopaminergic neurodegeneration by regulating the production of pro-inflammatory mediators from activated microglial cells. In the present study, we investigated the molecular basis of the anti-inflammatory effects of Salmeterol on LPS-activated murine microglial BV2 cells. BV2 cells were pretreated with Salmeterol and followed by stimulation with LPS. Salmeterol inhibited LPS-induced release of the pro-inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and nitric oxide from BV2 cells. Additionally, Salmeterol suppressed nuclear translocation of nuclear factor kappa-B (NF-κB) p65 by inhibiting the IκB-α degradation and TAK1 (transforming growth factor-beta-activated kinase1) phosphorylation. We have also found that Salmeterol increases the expression of ß-arrestin2 and enhances the interaction between ß-arrestin2 and TAB1 (TAK1-binding protein), reduced TAK1/TAB1 mediated activation of NFκB and expression of pro-inflammatory genes. Furthermore, silencing of ß-arrestin2 abrogates the anti-inflammatory effects of Salmeterol in LPS-stimulated BV2 cells. Our findings suggest that the anti-inflammatory properties of Salmeterol is ß-arrestin2 dependent and also offers novel therapeutics targeting inflammatory pathways to prevent microglial cell activation and neuronal loss in neuroinflammatory diseases like PD.

Reactive Oxygen Species Mediate Therapeutic Ultrasound-Induced, Mitogen-Activated Protein Kinase Activation in C28/I2 Chondrocytes.

Low-intensity pulsed ultrasound (LIPUS) has been used for the treatment of non-healing fractures because of its therapeutic properties of stimulating enhancing endochondral bone formation. However, its mechanism of action remains unclear. In this study, we hypothesized that LIPUS activates mitogen-activated protein kinases through generation of reactive oxygen species. C28/I2 cells were stimulated with LIPUS for 10 and 20 min, while the control group was treated using a sham LIPUS transducer. Through quantitative reverse transcription polymerase chain reaction and immunoblot analyses, we determined that LIPUS application increased reactive oxygen species generation and cell viability in C28/I2 cells. There were increases in the phosphorylation level of ERK1/2 and in expression of SOX9, COL2 A1 and ACAN genes. These effects were reversed when cells were treated with diphenylene iodonium, which is known to inhibit NADPH oxidase. It was concluded that exposure of chondrocytes to LIPUS led to reactive oxygen species generation, which activated MAPK signaling and further increased chondrocyte-specific gene markers involved in chondrocyte differentiation and extracellular matrix formation.

A national stakeholder consensus study of challenges and priorities for clinical learning environments in postgraduate medical education.

BACKGROUND: High quality clinical learning environments (CLE) are critical to postgraduate medical education (PGME). The understaffed and overcrowded environments in which many residents work present a significant challenge to learning. The purpose of this study was to develop a national expert group consensus amongst stakeholders in PGME to; (i) identify important barriers and facilitators of learning in CLEs and (ii) indicate priority areas for improvement. Our objective was to provide information to focus efforts to provide high quality CLEs. METHODS: Group Concept Mapping (GCM) is an integrated mixed methods approach to generating expert group consensus. A multi-disciplinary group of experts were invited to participate in the GCM process via an online platform. Multi-dimensional scaling and hierarchical cluster analysis were used to analyse participant inputs in regard to barriers, facilitators and priorities. RESULTS: Participants identified facilitators and barriers in ten domains within clinical learning environments. Domains rated most important were those which related to residents' connection to and engagement with more senior doctors. Organisation and conditions of work and Time to learn with senior doctors during patient care were rated as the most difficult areas in which to make improvements. CONCLUSIONS: High quality PGME requires that residents engage and connect with senior doctors during patient care, and that they are valued and supported both as learners and service providers. Academic medicine and health service managers must work together to protect these elements of CLEs, which not only shape learning, but impact quality of care and patient safety.

Role of Reactive Oxygen Species during Low-Intensity Pulsed Ultrasound Application in MC-3 T3 E1 Pre-osteoblast Cell Culture.

We evaluated the activation of mitogen-activated protein kinase (MAPK) activation through reactive oxygen species (ROS) by application of low-intensity ultrasound (LIPUS) to MC-3 T3 E1 pre-osteoblasts. The cells were subjected to one LIPUS application for either 10 or 20 min, and the control group was exposed to a sham transducer. For ROS inhibition, 10 µM diphenylene iodonium (DPI) was added to the cells an hour before LIPUS application. Samples were collected 1, 3, 6, 12 and 24 h after LIPUS application, and cells were evaluated for ROS generation, cell viability, gene expression and MAPK activation by immunoblot analyses. LIPUS caused a significant increase in ROS and cell viability in the non-DPI-treated group. Expression of RUNX2, OCN and OPN mRNA was higher in the LIPUS-treated groups at 1 h in both the DPI-treated and non-DPI-treated groups; RUNX2 and OCN mRNA levels increased at 6 h. ERK1/2 activation was increased in the LIPUS-treated groups. These results indicate that LIPUS activates MAPK by ROS generation in MC-3 T3 E1 pre-osteoblasts.

Salmeterol, a Long-Acting ß2-Adrenergic Receptor Agonist, Inhibits Macrophage Activation by Lipopolysaccharide From Porphyromonas gingivalis.

BACKGROUND: Salmeterol is a long-acting ß2-adrenergic receptor agonist used to treat chronic obstructive pulmonary disease. The authors of the current study previously showed that preincubation of primary microglial-enriched cells with salmeterol could inhibit the inflammatory response induced by Escherichia coli lipopolysaccharide (LPS), a Toll-like receptor (TLR)-4 agonist. In this study, the authors sought to determine if salmeterol had a similar inhibitory effect on the inflammatory response of the murine macrophage cell line RAW264.7 and human monocyte THP-1 to LPS from Porphyromonas gingivalis (PgLPS), an oral microbe implicated in the pathogenesis of periodontal disease. METHODS: RAW264.7 and THP-1 cells were pretreated with salmeterol, followed by PgLPS, and monitored for production of inflammatory mediators by enzyme-linked immunosorbent assay. The nitric oxide concentration and nuclear factor-kappa B (NF-κB) activity were measured by Griess method and secretory alkaline phosphatase reporter activity assay, respectively. Reverse-transcriptase polymerase chain reaction and immunoblot analysis were used to measure messenger RNA and protein levels. Nuclear translocation of NF-κB was detected by immunofluorescence. RESULTS: Pretreatment with salmeterol significantly inhibited production of proinflammatory mediators by RAW264.7 and THP-1 cells. Salmeterol downregulated PgLPS-mediated phosphorylation of the extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase but not p38 mitogen-activated protein kinases (MAPKs). Salmeterol also attenuated activation of NF-κB via inhibition of nuclear translocation of p65-NFκB, the transcriptional activity of NF-κB and IκBα phosphorylation. CONCLUSION: Salmeterol can significantly inhibit activation of macrophage-mediated inflammation by PgLPS, suggesting that use of salmeterol may be an effective treatment in inhibiting or lessening the inflammatory response mediated through TLR pathway activation.

Protocol for a realist review of workplace learning in postgraduate medical education and training.

BACKGROUND: Postgraduate medical education and training (PGMET) is a complex social process which happens predominantly during the delivery of patient care. The clinical learning environment (CLE), the context for PGMET, shapes the development of the doctors who learn and work within it, ultimately impacting the quality and safety of patient care. Clinical workplaces are complex, dynamic systems in which learning emerges from non-linear interactions within a network of related factors and activities. Those tasked with the design and delivery of postgraduate medical education and training need to understand the relationship between the processes of medical workplace learning and these contextual elements in order to optimise conditions for learning. We propose to conduct a realist synthesis of the literature to address the overarching questions; how, why and in what circumstances do doctors learn in clinical environments? This review is part of a funded projected with the overall aim of producing guidelines and recommendations for the design of high quality clinical learning environments for postgraduate medical education and training. METHODS: We have chosen realist synthesis as a methodology because of its suitability for researching complexity and producing answers useful to policymakers and practitioners. This realist synthesis will follow the steps and procedures outlined by Wong et al. in the RAMESES Publication Standards for Realist Synthesis and the Realist Synthesis RAMESES Training Materials. The core research team is a multi-disciplinary group of researchers, clinicians and health professions educators. The wider research group includes experts in organisational behaviour and human resources management as well as the key stakeholders; doctors in training, patient representatives and providers of PGMET. DISCUSSION: This study will draw from the published literature and programme, and substantive, theories of workplace learning, to describe context, mechanism and outcome configurations for PGMET. This information will be useful to policymakers and practitioners in PGMET, who will be able to apply our findings within their own contexts. Improving the quality of clinical learning environments can improve the performance, humanism and wellbeing of learners and improve the quality and safety of patient care. SYSTEMATIC REVIEW REGISTRATION: The review is not registered with the PROSPERO International Prospective Register of Systematic Reviews as the review objectives relate solely to education outcomes.

A phase I clinical trial of systemically delivered NEMO binding domain peptide in dogs with spontaneous activated B-cell like diffuse large B-cell lymphoma.

Activated B-Cell (ABC) Diffuse Large B-Cell Lymphoma (DLBCL) is a common, aggressive and poorly chemoresponsive subtype of DLBCL, characterized by constitutive canonical NF-κB signaling. Inhibition of NF-κB signaling leads to apoptosis of ABC-DLBCL cell lines, suggesting targeted disruption of this pathway may have therapeutic relevance. The selective IKK inhibitor, NEMO Binding Domain (NBD) peptide effectively blocks constitutive NF-κB activity and induces apoptosis in ABC-DLBCL cells in vitro. Here we used a comparative approach to determine the safety and efficacy of systemic NBD peptide to inhibit constitutive NF-κB signaling in privately owned dogs with spontaneous newly diagnosed or relapsed ABC-like DLBCL. Malignant lymph nodes biopsies were taken before and twenty-four hours after peptide administration to determine biological effects. Intravenous administration of <2 mg/kg NBD peptide was safe and inhibited constitutive canonical NF-κB activity in 6/10 dogs. Reductions in mitotic index and Cyclin D expression also occurred in a subset of dogs 24 hours post peptide and in 3 dogs marked, therapeutically beneficial histopathological changes were identified. Mild, grade 1 toxicities were noted in 3 dogs at the time of peptide administration and one dog developed transient subclinical hepatopathy. Long term toxicities were not identified. Pharmacokinetic data suggested rapid uptake of peptide into tissues. No significant hematological or biochemical toxicities were identified. Overall the results from this phase I study indicate that systemic administration of NBD peptide is safe and effectively blocks constitutive NF-κB signaling and reduces malignant B cell proliferation in a subset of dogs with ABC-like DLBCL. These results have potential translational relevance for human ABC-DLBCL.

Potential benefits of therapeutic use of ß2-adrenergic receptor agonists in neuroprotection and Parkinsonµs disease.

The ß2-adrenergic receptor (ß2AR) is a seven-transmembrane (7TM) G-protein coupled receptor that is expressed on cells of the pulmonary, cardiac, skeletal muscle, and immune systems. Previous work has shown that stimulation of this receptor on immune cells has profound effects on the regulatory activity of both adaptive and innate immune cells. This review examines the functional dichotomy associated with stimulation of ß2AR and microglial cells. As well, recent studies targeting these receptors with long-acting agonists are considered with respect to their therapeutic potential in management of Parkinsonµs disease.

Oxidative stress and microglial cells in Parkinson's disease.

Significant evidence has now been accumulated that microglial cells play a central role in the degeneration of DA neurons in animal models of PD. The oxidative stress response by microglial cells, most notably the activity of the enzyme NADPH oxidase, appears to play a central role in the pathology of PD. This oxidative stress response occurs in microglia through the activation of the ERK signaling pathway by proinflammatory stimuli, leading to the phosphorylation and translocation of the p47(phox) and p67(phox) cytosolic subunits, the activation of membrane-bound PHOX, and the production of ROS. Therapeutic anti-inflammatories which prevent DA neurodegeneration in PD, including anti-inflammatory cytokines, morphinan compounds, NADPH oxidase inhibitors, NF-κB inhibitors, and ß2-AR agonists, all function to inhibit the activation of the PHOX in microglial cells. These observations suggest a central role for the oxidative stress response in microglial cells as a mediator or regulator of DA neurodegeneration in PD.

Transcriptional Factor NF-κB as a Target for Therapy in Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative condition characterized by chronic inflammation. Nuclear factor κB (NF-κB) is a family of inducible transcription factors that are expressed in a wide variety of cells and tissues, including microglia, astrocytes, and neurons, and the classical NF-κB pathway plays a key role in the activation and regulation of inflammatory mediator production during inflammation. Activation of the classical NF-κB pathway is mediated through the activity of the IKK kinase complex, which consists of a heterotrimer of IKKα, IKKß, and IKKγ subunits. Targeting NF-κB has been proposed as an approach to the treatment of acute and chronic inflammatory conditions, and the use of inhibitors specific for either IKKß or IKKγ has now been found to inhibit neurodegeneration of TH+ DA-producing neurons in murine and primate models of Parkinson's disease. These studies suggest that targeting the classical pathway of NF-κB through the inhibition of the IKK complex can serve as a useful therapeutic approach to the treatment of PD.

ß2-adrenergic receptor activation prevents rodent dopaminergic neurotoxicity by inhibiting microglia via a novel signaling pathway.

The role of the ß2 adrenergic receptor (ß2AR) in the regulation of chronic neurodegenerative inflammation within the CNS is poorly understood. The purpose of this study was to determine neuroprotective effects of long-acting ß2AR agonists such as salmeterol in rodent models of Parkinson's disease. Results showed salmeterol exerted potent neuroprotection against both LPS and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/1-methyl-4-phenylpyridinium-induced dopaminergic neurotoxicity both in primary neuron-glia cultures (at subnanomolar concentrations) and in mice (1-10 µg/kg/day doses). Further studies demonstrated that salmeterol-mediated neuroprotection is not a direct effect on neurons; instead, it is mediated through the inhibition of LPS-induced microglial activation. Salmeterol significantly inhibited LPS-induced production of microglial proinflammatory neurotoxic mediators, such as TNF-α, superoxide, and NO, as well as the inhibition of TAK1-mediated phosphorylation of MAPK and p65 NF-κB. The anti-inflammatory effects of salmeterol required ß2AR expression in microglia but were not mediated through the conventional G protein-coupled receptor/cAMP pathway. Rather, salmeterol failed to induce microglial cAMP production, could not be reversed by either protein kinase A inhibitors or an exchange protein directly activated by cAMP agonist, and was dependent on ß-arrestin2 expression. Taken together, our results demonstrate that administration of extremely low doses of salmeterol exhibit potent neuroprotective effects by inhibiting microglial cell activation through a ß2AR/ß-arrestin2-dependent but cAMP/protein kinase A-independent pathway.