Adrenergic Receptors as Pharmacological Targets for Neuroinflammation and Neurodegeneration in Parkinson’s Disease

Inflammation is a key component of the dopaminergic neurodegeneration seen in progressive Parkinson’s disease (PD). The presence of activated glial cells, the participation of innate immune system, increased inflammatory molecules such as cytokines and chemokines, and increased oxidative stress and reactive oxygen species are the main neuroinflammatory characteristics present in progressive PD. Therapeutic targets which suppress pro-inflammatory responses by glial cells (mainly microglia) have been shown to be effective treatments for slowing or eliminating the progressive degeneration of neurons within the substantia nigra. In this chapter, we will detail a specific anti-inflammatory therapy using agonists to β2-adrenergic receptors that have been shown to be effective treatments for models of dopaminergic neurodegeneration and that have had efficacy in patients with progressive PD. We will also detail the possible molecular mechanisms of action of this therapeutic in stopping or reversing inflammation within the CNS

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 p47phox and p67phox 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 β2-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

Performance management in context: formative cross-functional performance monitoring for improvement and the mediating role of relational coordination in hospitals

Recent research suggests that to fully realise its potential, performance management should be bespoke to the social context in which it operates. Here we analyse factors supporting the use of performance data for improvement. The study purposively examines a developmentally oriented performance management system with cross-functional goals. We suggest that these system characteristics are significant in interdependent work contexts, such as healthcare. We propose and test that (a) relational coordination helps employees work effectively to resolve issues identified through formative and cross-functional performance monitoring and (b) that this contributes to better outcomes for both employees and patients. Based on survey data from management and care providers across Irish acute hospitals, the study found that perceptions of relational coordination mediated the link between formative cross-functional performance monitoring and employee outcomes and partially mediated the link between formative cross-functional performance monitoring and patient care respectively. Our findings signal potential for a more contextually driven and interdependent approach to the alignment of management and human resource management practices. While relational coordination is important in healthcare, we also note potential to identify other social drivers supporting productive responses to performance monitoring in different contexts

Sinomenine, a natural dextrorotatory morphinan analog, is anti-inflammatory and neuroprotective through inhibition of microglial NADPH oxidase

<p>Abstract</p> <p>Background</p> <p>The mechanisms involved in the induction and regulation of inflammation resulting in dopaminergic (DA) neurotoxicity in Parkinson's disease (PD) are complex and incompletely understood. Microglia-mediated inflammation has recently been implicated as a critical mechanism responsible for progressive neurodegeneration.</p> <p>Methods</p> <p>Mesencephalic neuron-glia cultures and reconstituted cultures were used to investigate the molecular mechanisms of sinomenine (SN)-mediated anti-inflammatory and neuroprotective effects in both the lipopolysaccharide (LPS)- and the 1-methyl-4-phenylpyridinium (MPP⁺)-mediated models of PD.</p> <p>Results</p> <p>SN showed equivalent efficacy in protecting against DA neuron death in rat midbrain neuron-glial cultures at both micro- and sub-picomolar concentrations, but no protection was seen at nanomolar concentrations. The neuroprotective effect of SN was attributed to inhibition of microglial activation, since SN significantly decreased tumor necrosis factor-α (TNF-α, prostaglandin E₂(PGE₂) and reactive oxygen species (ROS) production by microglia. In addition, from the therapeutic point of view, we focused on sub-picomolar concentration of SN for further mechanistic studies. We found that 10^-14M of SN failed to protect DA neurons against MPP⁺-induced toxicity in the absence of microglia. More importantly, SN failed to show a protective effect in neuron-glia cultures from mice lacking functional NADPH oxidase (PHOX), a key enzyme for extracellular superoxide production in immune cells. Furthermore, we demonstrated that SN reduced LPS-induced extracellular ROS production through the inhibition of the PHOX cytosolic subunit p47^{<it>phox</it>}translocation to the cell membrane.</p> <p>Conclusion</p> <p>Our findings strongly suggest that the protective effects of SN are most likely mediated through the inhibition of microglial PHOX activity. These findings suggest a novel therapy to treat inflammation-mediated neurodegenerative diseases.</p

Inhibition of Ly-6A antigen expression prevents T cell activation

Antisense oligonucleotides complementary to the 5' end of the mRNA encoding the Ly-6A protein were used to block the expression of that protein. Using this approach we could inhibit the expression of Ly-6A by 60-80% in antigen-primed lymph node (LN) T cells as well as in the D10 T cell clone. Inhibition of Ly-6 expression resulted in the inability to restimulate in vitro, antigen-primed T cells. It also blocked the activation of normal spleen cells by Con A, monoclonal antibody (mAb) to CD3, and mAb to Ly-6. In contrast, stimulation of normal spleen cells with the pharmacological agents PMA + ionomycin were unaffected by the inhibition of Ly-6 expression. Similar results were obtained with the D10 T cell clone; stimulation with Con A + interleukin 1 (IL-1), antigen-presenting cells (APC), or the clonotypic antibody + IL-1 was greatly reduced in the presence of antisense oligonucleotides to Ly-6. Stimulation with PMA + ionomycin was again unaffected. We also studied the effect of antisense oligonucleotides on stimulation of preactivated D10 cells. Preactivation of D10 cells with Con A + IL-1 renders them receptive to secondary stimulation by other lymphokines. In this case, antisense oligonucleotides to Ly-6 had no effect on secondary activation with IL-2, IL-4 + IL-1, or PMA + ionomycin. We conclude from these studies that Ly-6 expression is required for T cell receptor (TCR)-mediated T cell activation

Neuroinflammation is a key player in Parkinson’s disease and a prime target for therapy

Parkinson's disease (PD) is a neurodegenerative movement disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra and depletion of dopamine in the striatum, which lead to pathological and clinical abnormalities. Increasing evidence has demonstrated that inflammation is the fundamental process contributing to neuron death in PD. Neuroinflammation, which is characterized by activated microglia and infiltrating T cells at sites of neuronal injury, is a prominent contributor to the pathogenesis of progressive PD. Microglia play a critical role in forming a self-propelling cycle leading to sustained chronic neuroinflammation and driving the progressive neurodegeneration in PD. This activation depends heavily on the respiratory burst within the microglia, which in turn regulates a number of downstream pro-inflammatory activities. On the other hand, the adaptive immune responses, most notably T cells, are now emerging as important components of the inflammatory response that contribute to the pathogenesis of PD. This review paper focus on the understanding of the inflammatory etiology of PD, as well as the molecular signaling involved in this inflammatory response, with the aim to provide more effective treatments to slow down or halt the progression of chronic inflammation-induced CNS disorders, such as 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, IKKβ, 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 IKKβ 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

Hybrid healthcare governance for improvement? Combining top-down and bottom-up approaches to public sector regulation

Improving healthcare governance is an enduring challenge for policy-makers. We consider two national healthcare regulators adopting novel ‘hybrid’ regulatory control strategies in pursuit of improvement. Hybrids combine elements usually found separately. Scotland and Ireland’s regulators combine: (1) top-down formal regulatory mechanisms deterring breaches of protocol and enacting penalties where they occur (e.g. standard-setting, monitoring, accountability); and (2) bottom-up capacity building and persuasive encouragement of adherence to guidance by professional self-determination, implementation and improvement support (e.g. training, stimulating interventions). We identify socio-historical contextual factors constraining and enabling regulatory hybridity, whether and how it can be recreated, and circumstances when the approaches might be delivered separately. Using our findings, we develop a goal-oriented governance framework illustrating distinct, yet complementary, national and local organizational roles: (1) ensuring the adoption and implementation of best-practice, (2) enabling and (3) empowering staff to adapt and add to national mandates and (4) embedding cultures of improvement

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

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