Interplay between endothelin and erythropoietin in astroglia: the role in protection against hypoxia.

We show that, under in vitro conditions, the vulnerability of astroglia to hypoxia is reflected by alterations in endothelin (ET)-1 release and capacity of erythropoietin (EPO) to regulate ET-1 levels. Exposure of cells to 24 h hypoxia did not induce changes in ET-1 release, while 48-72 h hypoxia resulted in increase of ET-1 release from astrocytes that could be abolished by EPO. The endothelin receptor type A (ETA) antagonist BQ123 increased extracellular levels of ET-1 in human fetal astroglial cell line (SV-FHAS). The survival and proliferation of rat primary astrocytes, neural precursors, and neurons upon hypoxic conditions were increased upon administration of BQ123. Hypoxic injury and aging affected the interaction between the EPO and ET systems. Under hypoxia EPO decreased ET-1 release from astrocytes, while ETA receptor blockade enhanced the expression of EPO mRNA and EPO receptor in culture-aged rat astroglia. The blockade of ETA receptor can increase the availability of ET-1 to the ETB receptor and can potentiate the neuroprotective effects of EPO. Thus, the new therapeutic use of combined administration of EPO and ETA receptor antagonists during hypoxia-associated neurodegenerative disorders of the central nervous system (CNS) can be suggested.

Age-dependent astroglial vulnerability to hypoxia and glutamate: the role for erythropoietin.

Extracellular accumulation of toxic concentrations of glutamate (Glu) is a hallmark of many neurodegenerative diseases, often accompanied by hypoxia and impaired metabolism of this neuromediator. To address the question whether the multifunctional neuroprotective action of erythropoietin (EPO) extends to the regulation of extracellular Glu-level and is age-related, young and culture-aged rat astroglial primary cells (APC) were simultaneously treated with 1mM Glu and/or human recombinant EPO under normoxic and hypoxic conditions (NC and HC). EPO increased the Glu uptake by astrocytes under both NC and especially upon HC in culture-aged APC (by 60%). Moreover, treatment with EPO up-regulated the activity of glutamine synthetase (GS), the expression of glutamate-aspartate transporter (GLAST) and the level of EPO mRNA. EPO alleviated the Glu- and hypoxia-induced LDH release from astrocytes. These protective EPO effects were concentration-dependent and they were strongly intensified with age in culture. More than a 4-fold increase in apoptosis and a 2-fold decrease in GS enzyme activity was observed in APC transfected with EPO receptor (EPOR)-siRNA. Our in vivo data show decreased expression of EPO and a strong increase of EPOR in brain homogenates of APP/PS1 mice and their wild type controls during aging. Comparison of APP/PS1 and age-matched WT control mice revealed a stronger expression of EPOR but a weaker one of EPO in the Alzheimer's disease (AD) model mice. Here we show for the first time the direct correlation between the extent of differentiation (age) of astrocytes and the efficacy of EPO in balancing extracellular glutamate clearance and metabolism in an in-vitro model of hypoxia and Glu-induced astroglial injury. The clinical relevance of EPO and EPOR as markers of brain cells vulnerability during aging and neurodegeneration is evidenced by remarkable changes in their expression levels in a transgenic model of AD and their WT controls.

Pharmacokinetics and safety of a single intravenous dose of the antibiotic tigecycline in patients with cirrhosis.

Tigecycline belongs to a new class of tetracyclines, the glycylcyclines, less than 20% of which is metabolized in the liver. Twenty-five patients with cirrhosis with varying degrees of functional hepatic reserve (Child-Pugh A, n = 10; B, n = 10; C, n = 5) and 23 healthy adults, matched by age, sex, weight, and smoking habits, received 100 mg of tigecycline infused intravenously over 60 minutes. Serum and urine samples were collected up to 120 hours after dosing. Pharmacokinetic data were derived using noncompartmental methods. The most common treatment-emergent adverse events in healthy volunteers were nausea (56.5%), vomiting (21.7%), and headache (21.7%) and in the patients with cirrhosis, albuminuria (12%). Mean (± 1 SD) tigecycline clearance values were 29.8 ± 11.3 L/h in healthy subjects and 31.2 ± 13.9 L/h (Child-Pugh A), 22.1 ± 9.3 L/h (Child-Pugh B), and 13.5 ± 2.7 L/h (Child-Pugh C) in the patients. A single intravenous dose of tigecycline 100 mg was safe and well-tolerated in patients with cirrhosis with varying degrees of hepatic functional reserve. No adjustment of tigecycline maintenance dosage is warranted in patients with compensated or moderately decompensated cirrhosis; doses should be reduced by 50%, to 25 mg, every 12 hours in patients with severely decompensated disease.