Clinical Perspectives and Pearls from the 2015 ESC NSTE-ACS Guidelines

Four years after the latest edition, the 2015 non-ST-segment elevation acute coronary syndromes guidelines of the European Society of Cardiology have been published. Novel aspects include a new diagnostic algorithm for non-ST-segment elevation myocardial infarction using high-sensitivity cardiac troponins as well as guidance on cardiac rhythm monitoring duration. A large section is dedicated to antiplatelet therapy including initiation and duration of dual-antiplatelet therapy as well as the management of patients requiring, at the same time, long-term oral anticoagulation. New sections include the management of antiplatelet agent in patients requiring coronary artery bypass surgery and of acute bleeding events related to antiplatelet agents, vitamin K antagonist (VKA), and non-VKA oral anticoagulant drugs. Current evidence supports the radial access over the femoral one for coronary angiography and percutaneous revascularization.     

First Demonstration of an Increased Serum Level of Reactive Oxygen Species During the Peripartal Period in the Ewes

Reactive Oxygen Species (ROS) are produced during oxidative metabolism, and regulate many biological processes. The acute inflammation characterizing parturition induces many physiological changes. Among them, there is evidence that ROS affect the synthesis of many factors involved in parturition. Our study aims to determine serum levels of ROS in periparturient ewes, as well as to establish a value of reference of their physiological concentration.

ROS determination was performed on blood collected every 12 hours in periparturient twin pregnant ewes. Our results will show a significant increase in ROS concentrations from the beginning to the end of the experiment. This increase may be due to the inflammatory process establishing during parturition.     

Amyloid-β oligomer synaptotoxicity is mimicked by oligomers of the model protein HypF-N

Protein misfolded oligomers are thought to be the primary pathogenic species in many protein deposition diseases. Oligomers by the amyloid-β peptide play a central role in Alzheimer's disease pathogenesis, being implicated in synaptic dysfunction. Here we show that the oligomers formed by a protein that has no link with human disease, namely the N-terminal domain of HypF from Escherichia coli (HypF-N), are also synaptotoxic. HypF-N oligomers were found to (i) colocalize with post-synaptic densities in primary rat hippocampal neurons; (ii) induce impairment of long-term potentiation in rat hippocampal slices; and (iii) impair spatial learning of rats in the Morris Water Maze test. By contrast, the native protein and control nontoxic oligomers had none of such effects. These results raise the importance of using HypF-N oligomers as a valid tool to investigate the pathogenesis of Alzheimer's disease, with advantages over other systems for their stability, reproducibility, and costs. The results also suggest that, in the context of a compromised protein homeostasis resulting from aggregation of the amyloid β peptide, a number of oligomeric species sharing common synaptotoxic activity can arise and cooperate in the pathogenesis of the disease.     

UDP‐glucose enhances outward K+ currents necessary for cell differentiation and stimulates cell migration by activating the GPR17 receptor in oligodendrocyte precursors

In the developing and mature central nervous system, NG2 expressing cells comprise a population of cycling oligodendrocyte progenitor cells (OPCs) that differentiate into mature, myelinating oligodendrocytes (OLGs). OPCs are also characterized by high motility and respond to injury by migrating into the lesioned area to support remyelination. K⁺ currents in OPCs are developmentally regulated during differentiation. However, the mechanisms regulating these currents at different stages of oligodendrocyte lineage are poorly understood. Here we show that, in cultured primary OPCs, the purinergic G‐protein coupled receptor GPR17, that has recently emerged as a key player in oligodendrogliogenesis, crucially regulates K⁺ currents. Specifically, receptor stimulation by its agonist UDP‐glucose enhances delayed rectifier K⁺ currents without affecting transient K⁺ conductances. This effect was observed in a subpopulation of OPCs and immature pre‐OLGs whereas it was absent in mature OLGs, in line with GPR17 expression, that peaks at intermediate phases of oligodendrocyte differentiation and is thereafter downregulated to allow terminal maturation. The effect of UDP‐glucose on K⁺ currents is concentration‐dependent, blocked by the GPR17 antagonists MRS2179 and cangrelor, and sensitive to the K⁺ channel blocker tetraethyl‐ammonium, which also inhibits oligodendrocyte maturation. We propose that stimulation of K⁺ currents is responsible for GPR17‐induced oligodendrocyte differentiation. Moreover, we demonstrate, for the first time, that GPR17 activation stimulates OPC migration, suggesting an important role for this receptor after brain injury. Our data indicate that modulation of GPR17 may represent a strategy to potentiate the post‐traumatic response of OPCs under demyelinating conditions, such as multiple sclerosis, stroke, and brain trauma.     

Adenosine A2A receptors and brain injury: broad spectrum of neuroprotection, multifaceted actions and "fine tuning" modulation

This review summarizes recent developments that have contributed to understand how adenosine receptors, particularly A2A receptors, modulate brain injury in various animal models of neurological disorders, including Parkinson's disease (PD), stroke, Huntington's disease (HD), multiple sclerosis, Alzheimer's disease (AD) and HIV-associated dementia. It is clear that extracellular adenosine acting at adenosine receptors influences the functional outcome in a broad spectrum of brain injuries, indicating that A2A Rs may modulate some general cellular processes to affect neuronal cells death. Pharmacological, neurochemical and molecular/genetic approaches to the complex actions of A2A receptors in different cellular elements suggest that A2A receptor activation can be detrimental or protective after brain insults, depending on the nature of brain injury and associated pathological conditions. An interesting concept that emerges from these studies is A2A R's ability to fine tune neuronal and glial functions to produce neuroprotective effects. While the data presented here clearly highlight the complexity of using adenosinergic agents therapeutically in PD and other neurodegenerative disorders and point out many areas for further inquiry, they also confirm that adenosine receptor ligands, particularly A2A receptor ligands, have many promising characteristics that encourage the pursuit of their therapeutic potential.