Day 1 :
Florida Atlantic University, USA
Keynote: Novel strategies for stroke therapy based on targeting of mitochondrial dysfunction and ER stress signaling pathways
Time : 10:30-11:10
Howard Prentice obtained his Ph.D. from the University of London, UK and after post-doctoral training in the USA he held faculty position at the University of Glasgow, UK\\r\\nfrom 1993-2000. He then joined Florida Atlantic University in Boca Raton where he is currently Associate Professor of Biomedical Sciences in the College of Medicine.\\r\\nFrom 2013-2014 he was visiting Associate Professor at Harvard Medical School, Boston. He has more than 60 peer reviewed publications. He has been serving on study\\r\\nsections for the American Heart Association and the NIH and on editorial boards of several international scientifi c journals.
There is a major need for new stroke therapies, and current treatments involving tissue plasminogen activator (tPA) are dependent\\r\\nupon administration within small time-window aft er stroke onset. We have employed the neuroprotective agents taurine and\\r\\nS-Methyl-N, N-diethylthiocarbamate (DETC-MeSO) either individually, or as part of particular combination therapies, to elicit\\r\\nneuroprotection in a transient focal ischemia rat stroke model. Individually, taurine can protect neurons against ischemia through\\r\\npreventing calcium overload and through inhibiting pro-apoptotic processes. In our studies on endoplasmic reticulum (ER) stress\\r\\npathways, we have demonstrated that taurine elicits neuroprotection by inhibiting two ER stress pathways, namely ATF6 and\\r\\nIRE-1 pathways, without altering the contribution of the PERK pathway. DETC-MeSO, the active metabolite of disulfi ram, is\\r\\na partial antagonist of glutamate receptors and was previously shown to be eff ective in reducing seizures. In our stroke model,\\r\\nDETC-MeSO administered individually, protected through inhibiting ER stress markers including p-PERK, p-eIF2-alpha, XBP-1\\r\\nand CHOP. Using a multi-drug combination consisting of DETC-MeSO and the stem cell mobilizing agent granulocyte colony\\r\\nstimulating factor (G-CSF), in addition to the preconditioning agent sulindac, we found that infarct size was markedly decreased\\r\\nin the stroke model relative to sham controls. With administration of these agents prior to reperfusion, multidrug treatment was\\r\\nfound, at 4 days aft er the ischemic episode, to elicit decreases in GRP78, eIF-2-alpha and IRE-1, both in core and penumbra. Th e\\r\\nmulti-drug combination was highly eff ective at decreasing infarct size, either under conditions of prior administration, or with\\r\\nadministration of the drug combination 24 hours aft er reperfusion. Our novel therapeutic agents were found to decrease infarct\\r\\nsize, to elicit protection through decreasing levels of pro-apoptotic components and furthermore to diff erentially target specifi c\\r\\nER stress pathways.
Harvard Medical School, USA
Keynote: N-acetyl-serotonin and melatonin offer neuroprotection in experimental models of ischemic injury
Time : 11:30-12:10
Xin Wang is Director of Neuroapoptosis Drug Discovery Laboratory, Department of Neurosurgery, Brigham and Women’s Hospital/Harvard Medical School. She received\\r\\nher PhD from Hebrew University of Jerusalem. She did her Postdoctoral training at University of Michigan and Harvard Medical School. She has published about 70 peerreviewed\\r\\narticles and has served as the Guest Editor, Handling Editor, and Editorial Board Member for a number of peer-reviewed journals, as well as the scientist reviewer\\r\\nfor institutes or foundations including NIH, DOD, BSF, and others, and invited reviewer for 30 peer-reviewed journals.
The identifi cation of neuroprotective agents for stroke remains elusive. We therefore test whether melatonin receptor 1A agonists\\r\\nN-acetyl-serotonin (NAS) and melatonin are neuroprotective in experimental models of ischemic injury.\\r\\nWe demonstrate that NAS and melatonin inhibits cell death induced by oxygen-glucose deprivation or H2O2 in primary\\r\\ncerebrocortical neurons and primary hippocampal neurons in vitro, and/or organotypic hippocampal slice cultures ex vivo. We\\r\\nfurther found that NAS and melatonin reduce hypoxia/ischemia injury in the middle cerebral artery occlusion mouse model of\\r\\ncerebral ischemia in vivo. Our data show that NAS and melatonin are neuroprotective by inhibiting the mitochondrial cell death\\r\\npathway including the inhibition of the release of apoptogenic factors cytochrome c, Smac, and apoptosis-inducing factor from\\r\\nmitochondria to cytoplasm, and activation of caspase-3, -9. Furthermore, pro–IL-1 processing, and activation of caspase -1 are\\r\\nevaluated in melatonin-mediated neuroprotection. Moreover, we demonstrate that the neuroprotective eff ects of NAS may result\\r\\nfrom the infl uence of mitochondrial permeability transition pore opening, mitochondrial fragmentation, as well as the suppression\\r\\nof the autophagic cell death pathway under stress conditions by increasing LC3-II and Beclin-1 levels and decreasing p62 level.\\r\\nTaken together, we conclude that melatonin receptor 1A agonists NAS and melatonin have the potential as the novel therapies for\\r\\nischemic injury.