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.
- Treatment for Stroke
Lund University, Sweden
Time : 12:10-12:40
Saema Ansar has completed her PhD at Lund University, Sweden in 2007 and has performed two post-doctoral studies one at Department of Neurology at Heidelberg University, Germany and one at Glostrup Research Institute, Copenhagen University, Denmark. She has well-recognized experience in the field of stroke, vascular research, pharmacology, drug delivery and advanced imaging technology such as MRI. She has outstanding research management, team-leader and supervision skills and has supervised more than 15 graduate and undergraduate students. She has published more than 22 papers in reputed journals and 30 abstracts in international conferences.
Stroke accounts for 1.1 million deaths and is the foremost cause of disability in EU. It is an enormous economic, clinical and social burden; so far therapeutic options are limited. It is clear that new strategies are needed given the disappointing lack of success of the enormous research effort focused on potential neuroprotective agents. Unfortunately, all neuroprotective agents have failed to show any beneficial activity in patients with stroke. Stroke is first and foremost a vascular disease, and our unique focus is on stroke-related responses of the vascular wall. This represents a paradigm shift in approach, which is generating promising results. We recently discovered that inhibition of the MEK signaling pathway in the cerebral vasculature improves acute outcome in all types of experimental stroke. These exciting initial findings are propelling our current research program. To successfully develop our novel treatment strategy, we need to more fully understand the consequences of MEK inhibition on stroke outcome. Whether the benefits of early treatment with MEK1/2 inhibitors persist beyond the subacute phase and not negatively interfere with later recovery processes is not known. Therefore, the aim of this study was to determine the post-stroke consequences of MEK inhibition over extended time periods. Acute treatment with a specific MEK1/2 inhibitor U0126 significantly improved long-term functional recovery, reduced infarct size and promotes neurovascular protection and angiogenesis. These results provide new insights of using this treatment and are therefore a promising strategy for stroke.
University of Haifa, Israel
Title: Are there Differences between Acute and Home-dowelling Stroke clients on their Executive Functions skills?
Time : 12:40-13:10
Prof. Josman has completed her PhD from New York University and postdoctoral studies from Hebrew University. She is a Professor of Occupational Therapy in the University of Haifa, Israel. She also serves as Director of their Ph.D. program. Prof. Josman is an internationally recognized leader, scholar and educator in the area of cognitive rehabilitation and published more than 80 papers. Her research investigates cognition, metacognition, executive functions and their influence on everyday life. Her work is based on an ecologically-valid assessment of cognitive impairments to performance-based assessments, utilizing innovative methods and tools, inter alia Virtual Reality, for evaluation and intervention.
University of Haifa, Faculty of Social Welfare & Health Sciences, Haifa, Israel Executive functions are defined as higher-order functions necessary for performing complex or non-routine tasks. Post-stroke people are often encumbered by impaired executive functions which hinder their capacity to return to everyday life functioning. During the rehabilitation process, clinicians strive to engage stroke clients in complex functional activities which are neither time-consuming nor expensive, yet are geared specifically to train and augment executive functions. Employing functional virtual environments is becoming an increasingly important training solution. The current study objectives were to (1) describe the respective executive performance profiles for two samples of post-stroke clients, and (2) to investigate their distinctive performance of acute and home-dwelling stroke clients, using a virtual supermarket platform for assessing executive functions. Method: Two groups were included in this study: 35 acute post-stroke participants (29 men and 6 women, mean age ± SD 65.54, ±11.29 years). The home dowelling group included 24 participants (22 men and 2 women, mean age ± SD = 58.9 ± 5.5 years). Instrument: Virtual Action Planning - Supermarket (VAP-S) is a virtual supermarket developed as a clinically-sound and ecologically valid research tool for assessing executive functions. The VAP-S task performance for each participant is gauged using eight outcome measures recorded by computer. Results: Significant differences were found between the average age and year of education of the two groups. A MANCOVA test revealed significant between group performance differences, F(6, 45)= 6.98, p=.001, ES-η2= .29, with the home-dwelling stroke clients performing better than the acute group. No effects for age and years of education were found. Conclusion: Executive functions, such as efficiency and time performance do improve over time. Is this improvement attributable to the rehabilitation process? Or alternately does brain recovery expedite better executive functioning? Investigating the neural correlates of executive functions during performance of everyday activities is proposed as a further key step in research of people following stroke.
Florida Atlantic University, USA
Title: Neuroprotective targeting of mitochondrial and ER stress pathways in rodent models of stroke.
Time : 14:20-14:50
Dr. Howard Prentice obtained his Ph.D. from the University of London, UK and after post-doctoral training in the USA held a faculty position at the University of Glasgow, UK from 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. From 2013-2014 he was visiting associate professor at Harvard Medical School, Boston. Dr. Prentice has more than 60 peer reviewed publications. He has been serving on study sections for the American Heart Association and the NIH and on editorial boards of several international scientific journals.
Available stroke treatments are largely ineffective and the time window for efficacy for TPA is limited to a few hours. To investigate new treatments for stroke we have compared administration of the amino acid taurine with a novel multi-drug combination in rodent models targeting both mitochondrial pathways and endoplasmic reticulum (ER) stress signaling pathways. Taurine has been shown to prevent calcium overload in neural cells by blocking transport through calcium channels including the L-, P/Q- and N-type calcium channels and the NMDA receptor channel. In a transient focal ischemia stroke model taurine elicits protection by inhibiting both the IRE-1 and ATF-6 ER stress pathways. Our multi-drug treatment involves three components: 1) granulocyte-colony stimulating factor (G-CSF) which elicits neuroprotection via inhibition of ER stress pathways and by inducing stem cell mobilization 2) DETC-MeSO which acts as a partial NMDA antagonist and prevents apoptosis by inhibiting the PERK pathway but not the ATF-6 pathway and 3) sulindac which has been reported to act as a preconditioning agent and in the stroke model elicits induction of pro-survival proteins including Hsp27 and Akt as well as inhibiting the ER stress pathway component ATF-6. While each of the components of the multidrug treatment individually can elicit protection, lower doses used in combination shoe promise for eliciting synergistic pro-survival responses through targeting of key downstream stress responses. The interventions tested augment expression of pro-survival molecules at the same time as inhibiting important pro-death responses including mitochondrial dysfunction, calcium overload and apoptosis elicited through ER stress signaling.
East Kent Hospitals University NHS Foundation Trust, UK
Title: Use of the novel optokinetic chart stimulation based OKCSIB protocol for upper limb recovery in dense acute strokes: Insights for future research from a case control series
Time : 14:50-15:20
Benjamin Chitambira completed his BSc Physiotherapy Honours degree from the University of Zimbabwe in 1995. He also completed a Postgraduate Certificate in Healthcare Leadership from the Open University in the UK in 2014. With over 19 years’ experience as a neuro-physiotherapist, he has been carrying out research on optokinetic chart stimulation as a clinical specialist physiotherapist in the Richard Stevens Stroke Unit for over 8 tears. With over 9 papers published in peer reviewed journals, he has been a peer reviewer for reputable journals and now serves as an editorial board member of peer reviewed journals.
Background: This presentation aims to report on the use of optokinetic chart stimulation based OKCSIB protocol for upper limb recovery in dense acute strokes as well as discuss insights for future research. Methods: The optokinetic chart is made of laminated A4 paper. It consists of repeated bundles of the colours of the rainbow. The chart is placed 20 centimetres in front of a patient’s face. It is moved from side to side at approximately one cycle per second for 3 minutes. This is followed by moving the chart up and down for 3 minutes and then forwards and backwards for another 3 minutes. The affected paralysed hand was also used for aiding balance by holding on during sensory interaction for balance for 3 minutes. This was then followed by 5 repetitions each for specific active-assisted anti-gravity extensor exercises of the upper limb. Results: Dense acute strokes treated by the OKCSIB protocol had statistically significant upper limb recovery when compared to those treated by conventional neurophysiotherapy (P < 0.05). The OKCSIB protocol also led to statistically significant prevention of affected hand spasticity (p < 0.05) Conclusion: Optokinetic chart stimulation shows promise as a novel recovery focused upper limb rehabilitation intervention. The key to these results may be in the restoration of anti-gravity extensor tone by cortico-vestibulospinal descending motor output to the affected upper limb. Further research with fully powered randomized controlled trials is required to provide evidence for its inclusion in future guidelines.
Brigham and Women’s Hospital/Harvard Medical School, USA
Title: Identification of Melatonin Receptor 1A Agonists as Neuroprotective Agents in Experimental Models of Ischemic Injury
Time : 15:20-15:50
Xin Wang is Director of Neuroapoptosis Drug Discovery Laboratory, Department of Neurosurgery, Brigham and Women’s Hospital/Harvard Medical School. She received her PhD from Hebrew University of Jerusalem. She did her Postdoctoral training at University of Michigan and Harvard Medical School. She has published about 70 peer-reviewed articles 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 for institutes or foundations including NIH, DOD, BSF, and others, and invited reviewer for 30 peer-reviewed journals.
The identification of neuroprotective agents for stroke remains elusive. We therefore test whether melatonin receptor 1A agonists melatonin, N-acetyl-serotonin (NAS), and ramelteon are neuroprotective in experimental models of ischemic injury. We demonstrate that melatonin, or NAS, or ramelteon inhibits cell death induced by oxygen-glucose deprivation or H2O2 in primary cerebrocortical neurons and primary hippocampal neurons in vitro, and organotypic hippocampal slice cultures ex vivo. We further found that melatonin and NAS reduce hypoxia/ischemia injury in the middle cerebral artery occlusion mouse model of cerebral ischemia in vivo. Our data show that melatonin and NAS are neuroprotective by inhibiting the mitochondrial cell death pathway including the inhibition of the release of apoptogenic factors cytochrome c, Smac, and apoptosis-inducing factor from mitochondria to cytoplasm, and activation of caspase-3, -9. Furthermore, pro–IL-1 processing, and activation of caspase -1 are evaluated in melatonin-mediated neuroprotection. Moreover, we demonstrate that the neuroprotective effects of NAS may result from the influence of mitochondrial permeability transition pore opening, mitochondrial fragmentation, as well as the suppression of the autophagic cell death pathway under stress conditions by increasing LC3-II and Beclin-1 levels and decreasing p62 level. Taken together, we conclude that melatonin receptor 1A agonists melatonin, NAS, and ramelteon have the potential as the novel therapies for ischemic injury.
University of Kyiv, Ukraine
Title: Disorders of glial neocortex homeostasis under reproduction of acute cerebro-vascular pathology in rats
Time : 15:50-16:20
Makarenko O M has got his PhD degree at the Moscow Medical Stomatological Institute and MD degree from the Institute of Higher Nervous Activity in Moscow. He carries out his Post-doctorate researches at the Institute of Higher Nervous Activity and T G Shevchenko National University of Kiev. He is a Professor of the Psychology Department and the author of more than 100 articles in reputed journals and 4 monographs.
Study was conducted on 30 male rats who were subjected to acute hemorrhagic stroke (HS) simulation. In 10 days with these animals we modeled repeated intracerebral post-traumatic hematoma again. Th e quantitative and qualitative glial analysis of the sensomotor cortex areas of the ipsilateral and contralateral (control) brain hemispheres was carried out: Glial Formula (GF) (the quantitative (percentage) content of glial cells in relation to the total of gliocytes and neurons (GF=astrocytes (A)+oligodendrocytes (O)+microgliocytes (M)); Glial Index Quantitative (GIQ) (a ratio of the sum of one type of gliocytes to another: GIQ1=A/M, GIQ2=O/M, GIQ3=A/O. Th e glial analysis under primary acute HS in the ipsilateral hemisphere in comparison with the contralateral one: GF: Th e number of astrocytes was less (by 34.18%), of oligodendrocytes was less (by 27.97%), of microgliocytes was bigger (by 27.11%) and of pyramidal neurons was less (by 52.13%). GIQ: Decrease of the GIQ1 (by 51.8%), decrease of the GIQ2 (by 18.3%), minor changes of the GIQ3 (by 5.08%). Th e glial analysis under repeated acute HS in the ipsilateral hemisphere in comparison with the contralateral one: GF: Th e number of astrocytes was less (by 64.3%), of oligodendrocytes was bigger (by 37.7%), of microgliocytes was bigger (by 45.75%) and pyramidal neurons were less (by 42.4%). GIQ: Decrease of the GIQ1 (by 79.71%), decrease of the GIQ2 (by 47.7%) anddecrease of the GIQ3 (by 82.4%).
Andreas H. Leischker studied medicine at University Mainz, Germany and Memorial University Newfoundland/Canada. After completing his residency in Internal Medicine in Frankfurt/Germany he specialized in Geriatrics and Internal Medicine. He worked as consultant in Internal Medicine in Germany and at King Faisal Specialist Hospital and Research Centre in Riyadh/Saudi Arabia. He is leader of the working group “Neurology” of the German Geriatric Society, Head of the Department of Geriatrics, Alexianer Krefeld GmbH and Head of the geriatric rehabilitation Department of the Alexianer Tönisvorst GmbH
Nutrition is of upmost importance in patients with acute stroke. Delivery of nutrition as well as withholding nutrition may seriously harm patients with acute stroke. In contrast to many other diseases, there were no clinical guidelines on nutrition in acute stroke.. In clinical practice, nursing staff, speech-language therapists, nutritionists and physicians are often unassertive how to deliver nutritional support for patients with acute stroke. Key questions include the timing of enteral nutrition, screening and assessment for dysphagia, indication and timing of placement of nasogastric tube versus PEG for stroke patients, swallowing training during in patients with nasogastric tubes, oral nutritional supplements, and texture modification/thickening of fluids. The author (AL) was asked by the steering committees of the German Society for Neurology, the German Society for Nutritional Medicine and the German Geriatric Society to develop evidence based guideline on nutrition for patients with acute stroke. This guideline was published 2007. To our knowledge, this was the first clinical guideline on this topic. Implementation of the guideline in Germany changed clinical practice significantly: For example it was clinical practice to place a PEG tube in patients with severe dysphagia early, after implementation the placement of nasogastric tubes was state of the art. The guideline was updated starting 2010 and finally published in English language 2013. Currently, a European ESPEN guideline on this topic is in progress.
Neurosurgeon views stroke to identify any underlying surgically correctable pathology. This talk describes my personal opinion regarding the surgical management of stroke. Vascular accidents such as aneurysms, AVMs and angiomas constitute a major proportion of surgical problems. Recent technical developments have changed the approach to these problems. Haemorrhage in a malignant tumour is not uncommon. Often the diagnosis is delayed due to difficulties in recognising this condition. Surgical treatment of intracerebral haemorrhage is still a controversial subject. The outcome of such a treatment is often poor. Role of surgery in acute cerebellar bleed is limited. Decompression to reduce raised ICP has improved the survival rates. The neurological improvement and quality of survival are generally disappointing. Endovascular treatment of vascular occlusion has encouraging results. The attractive concept of revascularisation is not always supported by favourable outcomes. The presentation highlights the changing trends in the surgical management of strokes.