Day 2 :
University of Buenos Aires, Argentina
Keynote: Degenerative modifications in synapses and related structures induced by experimental perinatal asphyxia in rat: Correlative light and electron microscopy studies.
Time : 10:15 -10:55
I completed my PhD at the De Robertis Institute, School of Medicine-University of Buenos (UBA). I performed my postdoctoral studies at University of California San Diego, School of Medicine (UCSD-NCMIR) and Karolinska Institute, Department of Neuroscience. for 8 years focusing my research on cell biology of dendritic spines combining electron tomography and 3-D reconstruction techniques. When I returned to Argentina in 2007 I applied my broad experience in electron microscopy to study the mechanisms involved in pathophysiology of the perinatal asphyxia. Since 2018 I am director of Institute of Research in Cardiology, and Professor of Histology and Cell Biology, School of Medicine (UBA). I published 85 papers in reputed journals and has been invited in more than 14 international symposiums. I have been serving in the editorial in board of several scientific journal. I addition I was president of Interamerican Committe of Societies for Microscopy (CIASEM) for the period 2015-2017 .
Statement of the Problem: Diminish in the oxygen levels prompted short and long-term alterations in synapses and related structures that are related to neuronal dysfunction and death. Perinatal asphyxia (PA) is an obstetric complication produced by an impaired gas exchange that lead to neonatal mortality and is a determinant factor for neurodevelopmental disorders. Since pathophysiological mechanisms triggered by PA are not still totally unveiled, we investigated the changes in the cytoskeleton organization in the nervous tissue.
Methodology & Theoretical Orientation: For this study, we used a well-established murine model of PA. After one, 2, 4 and 6 months of severe PA (20 min) rats were sacrificed and their brains were analyzed by combining photooxidation, conventional electron microscopy, and 3-D reconstruction techniques.
Findings: After one month of PA, we found an increase in the F-actin staining in neostriatal and hippocampal dendritic spines together with some filopodia-likes structures, a typical embryonic type of spines in photooxidated tissue. In contrast, after second month of PA, spines were less consistent stained. In addition, we observed an increment of marker for neuronal and glial dysfunction such as GFAP, neurofilament and MAP-2. These modifications were more striking defined after 4 months of PA. After 6 months of PA post-synaptic densities (PSDs) in neostriatum were highly modified. Using three-D reconstructions and electron tomography we were able to find clear signs of degeneration in the asphyctic PSDs
Conclusion & Significance: Therefore, we hypothesize that the cytoskeletal changes induced by PA in the rat CNS could lead to the dramatic modifications in synapse and related structures that trigger neuronal damage. In addition, electron tomography, 3-D reconstruction and photooxidation contributed to dissect critical alterations generated by PA that are not easily displayed using conventional microscopic techniques. development.
University of California, USA
Keynote: Statin Toxicity: First report of atorvastatin, but not pravastatin, induced ultrastructural and functional changes in cardiac mitochondria
Time : 11:10 -11:50
Dr. Alice Zemljic-Harpf has obtained her Medical Degree from the Medical University Graz, Austria in 1997. She conducted her postdoctoral studies in molecular cardiology at the Cedars-Sinai Medical Center Los Angeles (1999-2000), UCLA (2000-2003) and UCSD, School of Medicine. She is the director of The Cardiovascular Physiology and Imaging Unit at the Cardiac/Neuro Protection Laboratories at UCSD, Department of Anesthesiology. She has published 24 papers in high-impact pier reviewed journals (Circulation, Circulation Research, Glia, Cerbarl Cortex, The FASEB Journa, Heart Rhythm, The American Journal of Pathology, etc.). Her most recent work on atoravstatin induced adverse events gains international attention.
Background: Statins are amongst the most widely prescribed drugs to reduce LDL-cholesterol for the treatment of cardiovascular disease. Approximately one in five people in the United States between the ages of 45 and 75 take a statin. Like all drugs, statins can cause harmful side effects, such as muscle pain/weakness (statin myopathy), fatigue, nerve pain, and cognitive impairment. Because statin-induced myopathy is known to be associated with reduced oxidative phosphorylation in mitochondria of skeletal muscle we hypothesized that similar effects would occur in cardiac muscle.
Methods and Results: When male mice underwent atorvastatin and pravastatin administration per os for up to 7 months, only long-term atorvastatin, but not pravastatin administration induced: 1) elevated serum creatine kinase, 2) swollen, misaligned, size variable, and disconnected cardiac mitochondria, 3) altered ER-structure, 4) repression of mitochondrial and endoplasmatic reticulum related genes, and 5) 21% increased mortality in cardiac-specific vinculin knockout- mice.
Neonatal cardiac ventricular myocytes were treated with atorvastatin and pravastatin for 48hours. Both statins induced ER-stress, but only atorvastatin: 1) inhibited of ERK1/2T202/Y204, AktSer473 and mTOR signaling, 2) reduced protein abundance of caveolin-1, dystrophin, epidermal growth factor receptor and insulin receptor-β, 3) decreased RhoA activation, and 4) induced apoptosis. In cardiomyocyte-equivalent HL-1 cells atorvastatin, but not pravastatin, reduced mitochondrial oxygen consumption.
Conclusion and Clinical Implication: Skeletal muscle biopsies from patients with statin myopathy show increased lipid storage and alters mitochondrial structure. We are the first to demonstrate in vivo that long-term atorvastatin administration altered cardiac ultrastructure, a finding with important clinical implications.