ABSTRACT
Minocycline is a semi-synthetic tetracycline that inhibits bacterial protein synthesis and hence is used for the treatment of many infectious diseases. Over the years, many other interesting properties of minocycline have been identified and been used to make patents which include anti-inflammatory, anti-apoptotic, matrix metalloproteinase inhibitor and free oxygen radical scavenger activity. Ischemia-reperfusion injury is a concern for almost every clinical specialty and minocycline seems to be an attractive cytoprotective agent that can ameliorate the damage due to these properties. Ischemia-reperfusion injury is a complex process and involves various pathways that lead to cell death. This review focuses on the body of evidence describing various proposed mechanisms of action of minocycline and its current experimental use in various animal models of ischemia-reperfusion injury.
Subject(s)
Anti-Bacterial Agents/pharmacology , Minocycline/pharmacology , Reperfusion Injury/drug therapy , Animals , Apoptosis/drug effects , Cytoprotection/drug effects , Disease Models, Animal , Humans , Patents as Topic , Reperfusion Injury/physiopathologyABSTRACT
Urocortin is a 40 amino acid peptide of the corticotrophin-releasing factor (CRF) family that is synthesized and released by cardiac myocytes. Endogenous urocortin expression is increased during ischemia/reperfusion (I/R) and addition of exogenous urocortin reduces cell death caused by I/R injury. Studies have also showed that the protective action of urocortin is mediated by the activation of ERK1/2. We discovered that a non-receptor tyrosine kinase, Src, is involved in the urocortin-induced activation of ERK1/2 in mouse atrial HL-1 myocytes. The selective Src family kinase inhibitor, PP2, reduced the urocortin-induced phosphorylation of ERK1/2, and so did the expression of a dominant-negative mutant of Src in transfected HL-1 cells. Inhibition of Src by PP2 also reduced urocortin's protective effects in HL-1 cells after hypoxia/reoxygenation (H/R), as assessed by flow cytometry and caspase-3 activation assay. Titration studies indicated that as little as 10(-8)M urocortin was sufficient to induce Src activation. Maximal phosphorylation/activation of Src and ERK1/2 were both detected after 5 min incubation with urocortin. These effects of urocortin were largely mediated by CRF receptor-1, although a minor contribution of CRF receptor-2 cannot be excluded. Here we report for the first time that short-term treatment with urocortin causes rapid phosphorylation of Src, and that the urocortin-activated Src kinase serves as an upstream modulator of ERK1/2 activation, playing an essential role in urocortin-mediated cardioprotection.
Subject(s)
Myocytes, Cardiac/drug effects , Urocortins/pharmacology , src-Family Kinases/metabolism , Animals , Cardiotonic Agents/pharmacology , Cells, Cultured , Cytoprotection/drug effects , Dose-Response Relationship, Drug , Enzyme Activation/drug effects , Enzyme Activation/physiology , Heart/drug effects , Heart/physiology , Mice , Mitogen-Activated Protein Kinase 3/metabolism , Myocardium/metabolism , Myocytes, Cardiac/cytology , Myocytes, Cardiac/metabolism , Protein Kinase Inhibitors/pharmacology , Receptors, Corticotropin-Releasing Hormone/metabolism , Urocortins/physiology , src-Family Kinases/antagonists & inhibitors , src-Family Kinases/physiologyABSTRACT
Although the lower trunk brachial plexus palsy known as Klumpke's palsy is a familiar and challenging entity to the medical community, relatively little is known about Dr. Augusta Déjerine-Klumpke. Dr. Déjerine-Klumpke influenced generations of physicians with her contributions to the description and treatment of neurological diseases. We review the legacy of Dr. Déjerine-Klumpke by focusing on the life, career, and medical contributions of this remarkable woman, using translations of the French manuscripts composed at various times in her career. These publications, combined with the existing English-language literature that provides a tribute to her contributions as both a scientist and physician, give an insight into the condition that carries her name.
