Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

Adenosine is a neuromodulator that operates via the most abundant inhibitory adenosine A1 receptors (A1Rs) and the less abundant, but widespread, facilitatory A2ARs. It is commonly assumed that A1Rs play a key role in neuroprotection since they decrease glutamate release and hyperpolarize neurons. In fact, A1R activation at the onset of neuronal injury attenuates brain damage, whereas its blockade exacerbates damage in adult animals. However, there is a down-regulation of central A1Rs in chronic noxious situations. In contrast, A2ARs are up-regulated in noxious brain conditions and their blockade confers robust brain neuroprotection in adult animals. The brain neuroprotective effect of A2AR antagonists is maintained in chronic noxious brain conditions without observable peripheral effects, thus justifying the interest of A2AR antagonists as novel protective agents in neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease, ischemic brain damage and epilepsy. The greater interest of A2AR blockade compared to A1R activation does not mean that A1R activation is irrelevant for a neuroprotective strategy. In fact, it is proposed that coupling A2AR antagonists with strategies aimed at bursting the levels of extracellular adenosine (by inhibiting adenosine kinase) to activate A1Rs might constitute the more robust brain neuroprotective strategy based on the adenosine neuromodulatory system. This strategy should be useful in adult animals and especially in the elderly (where brain pathologies are prevalent) but is not valid for fetus or newborns where the impact of adenosine receptors on brain damage is different

Vital capacity and COPD: the Swedish CArdioPulmonary bioImage Study (SCAPIS)

Kjell Torén,1 Anna-Carin Olin,1 Anne Lindberg,2 Jenny Vikgren,3 Linus Schiöler,1 John Brandberg,3 Åse Johnsson,3 Gunnar Engström,4 H Lennart Persson,5 Magnus Sköld,6 Jan Hedner,7 Eva Lindberg,8 Andrei Malinovschi,8 Eeva Piitulainen,9 Per Wollmer,9 Annika Rosengren,10 Christer Janson,8 Anders Blomberg,2 Göran Bergström10 1Section of Occupational and Environmental Medicine, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 2Department of Public Health and Clinical Medicine, Division of Medicine/Respiratory Medicine, Umeå University, Umeå, 3Department of Radiology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 4Department of Clinical Science, Malmö, Lund University, Lund, 5Department of Respiratory Medicine and Department of Medicine and Health Sciences, Linköping University, Linköping, 6Respiratory Medicine Unit, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, 7Department of Internal Medicine/Lung Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 8Department of Medical Sciences, Clinical Physiology and Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, 9Department of Translational Medicine, Lund University, Malmö, 10Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden Background: Spirometric diagnosis of chronic obstructive pulmonary disease (COPD) is based on the ratio of forced expiratory volume in 1 second (FEV1)/vital capacity (VC), either as a fixed value <0.7 or below the lower limit of normal (LLN). Forced vital capacity (FVC) is a proxy for VC. The first aim was to compare the use of FVC and VC, assessed as the highest value of FVC or slow vital capacity (SVC), when assessing the FEV1/VC ratio in a general population setting. The second aim was to evaluate the characteristics of subjects with COPD who obtained a higher SVC than FVC.Methods: Subjects (n=1,050) aged 50–64 years were investigated with FEV1, FVC, and SVC after bronchodilation. Global Initiative for Chronic Obstructive Lung Disease (GOLD) COPDFVC was defined as FEV1/FVC <0.7, GOLDCOPDVC as FEV1/VC <0.7 using the maximum value of FVC or SVC, LLNCOPDFVC as FEV1/FVC below the LLN, and LLNCOPDVC as FEV1/VC below the LLN using the maximum value of FVC or SVC.Results: Prevalence of GOLDCOPDFVC was 10.0% (95% confidence interval [CI] 8.2–12.0) and the prevalence of LLNCOPDFVC was 9.5% (95% CI 7.8–11.4). When estimates were based on VC, the prevalence became higher; 16.4% (95% CI 14.3–18.9) and 15.6% (95% CI 13.5–17.9) for GOLDCOPDVC and LLNCOPDVC, respectively. The group of additional subjects classified as having COPD based on VC, had lower FEV1, more wheeze and higher residual volume compared to subjects without any COPD.Conclusion: The prevalence of COPD was significantly higher when the ratio FEV1/VC was calculated using the highest value of SVC or FVC compared with using FVC only. Subjects classified as having COPD when using the VC concept were more obstructive and with indications of air trapping. Hence, the use of only FVC when assessing airflow limitation may result in a considerable under diagnosis of subjects with mild COPD. Keywords: obstructive, epidemiology, general population, air trapping, spirometry, slow vital capacity, asthm

Gender differences and determinants of aerobic fitness in children aged 8-11 years.

Previous studies of gender differences in maximum oxygen uptake have come to different conclusions. Limited data exists where the determinants of maximum oxygen uptake have been evaluated in a comprehensive manner. Thus, we examined 248 children (140 boys and 108 girls), aged 7.9-11.1 years. Body composition was determined by dual-energy X-ray absorptiometry, measured variables were total body fat (TBF) and lean body mass (LBM). Maximal oxygen uptake (VO2peak) was measured by indirect calorimetry during a maximal cycle exercise test. Daily physical activity was assessed by accelerometers and duration of vigorous activity per day (VPA) was calculated. Left ventricular inner diastolic diameter (LVDD) was measured by echocardiography. Lung function was evaluated with spirometric testing and whole body plethysmography. Boys had between 8 and 18% higher values than girls for VO2peak, dependent upon whether VO2peak was expressed in absolute values or scaled to body mass, LBM or if allometric scaling was used. In multiple regression analysis absolute values of aerobic fitness were independently related to LBM, maximal heart rate (Max HR), gender, LVDD, and VPA. Furthermore, when VO2peak was scaled to body mass it was independently related to In TBF, Max HR, gender, VPA, and LVDD. Lung function had no relation to VO2peak. Our study concludes that body composition is the main predictor for VO2peak, in children aged 8-11 years, whereas VPA or LVDD has only a modest impact. Existing gender differences in VO2peak cannot be explained only by differences in body composition, physical activity, or heart size

Lung microdialysis—A powerful tool for the determination of exogenous and endogenous compounds in the lower respiratory tract (mini-review)

In vivo measurement of concentrations of drugs and endogenous substances at the site of action has become a primary focus of research. In this context the minimal invasive microdialysis (MD) technique has been increasingly employed for the determination of pharmacokinetics in lung. Although lung MD is frequently employed to investigate various drugs and endogenous substances, the majority of lung MD studies were performed to determine the pharmacokinetic profile of antimicrobials that can be related to the importance of respiratory tract infections. For the lower respiratory tract various methods, such as surgical collection of whole lung tissue and bonchoalveolar lavage (BAL), are currently available for the determination of pharmacokinetics of antimicrobials. Head-to-head comparison of pharmacokinetics of antibiotics in lung revealed high differences between MD and conventional methods. MD might be regarded as a more advantageous approach because of its higher anatomical resolution and the ability to obtain dynamic time-vs-concentration profiles within one subject. However, due to ethical objections lung MD is limited to animals or patients undergoing elective thoracic surgery. From these studies it was speculated that the concentrations in healthy lung tissue may be predicted reasonably by the measurement of concentrations in skeletal muscle tissue. However, until now this was only demonstrated for β-lactam antibiotics and needs to be confirmed for other classes of antimicrobials. In conclusion, the present review shows that MD is a promising method for the determination of antimicrobials in the lung, but might also be applicable for measuring a wide range of other drugs and for the investigation of metabolism in the lower respiratory tract

PPARγ agonists as therapeutics for the treatment of Alzheimer’s disease

Alzheimer’s disease (AD) is characterized by the deposition of β-amyloid within the brain parenchyma and is accompanied by the impairment of neuronal metabolism and function, leading to extensive neuronal loss. The disease involves the perturbation of synaptic function, energy, and lipid metabolism. The development of amyloid plaques results in the induction of a microglial-mediated inflammatory response. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor whose biological actions are to regulate glucose and lipid metabolism and suppress inflammatory gene expression. Thus, agonists of this receptor represent an attractive therapeutic target for AD. There is now an extensive body of evidence that has demonstrated the efficacy of PPARγ agonists in ameliorating disease-related pathology and improved learning and memory in animal models of AD. Recent clinical trials of the PPARy agonist rosiglitazone have shown significant improvement in memory and cognition in AD patients. Thus, PPARγ represents an important new therapeutic target in treating AD