Abstract
Since 1998, the biannual International Symposium on Neuroprotection and Neurorepair, also known as the Magdeburg Meeting series, has provided a platform for the discussion of recent advances in basic and translational stroke research. The 2010 meeting reviewed highly relevant topics, including astrogliosis and microgliosis, neuroimmunological processes, cell-based therapies, novel imaging approaches, mechanisms of poststroke regeneration and metabolic phenomena in neuroprotection. It further focused on common pitfalls and opportunities in the translational process, from preclinical research to clinical application.
Background information & meeting aims
Despite decades of thorough research, immediate thrombolysis using recombinant tissue plasminogen activator is currently the only approved therapy for ischemic stroke. New insights into the pathophysiology of the disease are needed to facilitate the development of treatment approaches. The 6th International Symposium on Neuroprotection and Neurorepair was organized by Georg Reiser (Otto-von-Guericke-University Magdeburg, Magdeburg, Germany), Klaus Reymann (Leibniz Institute for Neurobiology, Magdeburg, Germany) and Johannes Boltze (Fraunhofer Institute for Cell Therapy and Immunology, and Translational Centre for Regenerative Medicine, Leipzig, Germany) and was held in the Baltic city of Rostock-Warnemünde in October 2010. The meeting brought together many of the world’s leading experts from the fields of basic and translational stroke research and provided capacious insights into recent advances in the field. This article summarizes relevant sessions that may be of particular interest to the scientific community. For colleagues who were unable to attend the meeting, all of the abstracts were published in the October 2010 issue of Restorative Neurology and Neuroscience.
Lost in translation: stroke research & how it should be done
Several promising therapeutic strategies for stroke successfully evaluated in animal models later failed to provide a benefit for human stroke patients. Improving our concepts of preclinical research strategies will, therefore, be pivotal for achieving translational success. Ideas on how this could be achieved were discussed during the first conference day. The opening lecture by James McCulloch (University of Edinburgh, Scotland, UK) emphasized the role of novel imaging techniques, such as diffusion tensor imaging, and new pharmaceutical targets, such as the apoptogenic Bcl-2-associated protein X. Paying more attention to white matter damage and utilizing animal models of chronic hypoperfusion may generate knowledge leading to novel strategies for the treatment of stroke and other neurodegenerative diseases. Ulrich Dirnagl (Charité Universitätsmedizin, Berlin, Germany) addressed important therapeutic improvements based on preclinical research, giving clear evidence for successful translation. Preventing poststroke immunosuppression and catabolism, which have been underestimated for years, clearly enhances survival and improves outcome in animal models and human patients. Quality assurance criteria for preclinical stroke research published by the Stroke Treatment Academic and Industry Round (STAIR) table and Stem Cell Therapy as an Emerging Paradigm in Stroke (STEPS) committees were reviewed by Boltze, who illustrated the pitfalls and problems in common preclinical study designs that may lead to false-positive results. The session was concluded with an intensive discussion between the speakers and audience that also pointed at an obvious discrepancy between adequate study designs and available funding, which, at least to date, significantly hinders the full implementation of quality assurance criteria. Concepts for translational stroke research were also addressed by Marc Fisher (UMASS/Memorial Healthcare, MA, USA), who introduced a plenary discussion on the topic. Interdisciplinary work of basic researchers and stroke clinicians, as well as learning from successfully translated approaches, were decided to be essential for developing novel therapies.
Astrogliosis, microglia & immune modulation after stroke
Astrocytes and microglia become activated in affected tissue and have traditionally been hypothesized to counter regeneration Citation[1,2]. However, recent data indicate that the role of those cells is much more complex than originally anticipated. Michael Sofroniew (University of California Los Angeles, CA, USA) pointed out that astrocyte ablation aggravates ischemic damage and diminishes functional regeneration. Furthermore, astrocytes play a critical role in balancing innate and adaptive immune responses following brain trauma and stroke. Anna Planas (Institute for Biomedical Research of Barcelona, Barcelona, Spain) reviewed the role of resident inflammatory microglia and emphasized the potential of anti-inflammatory interventions for enhancing poststroke neurogenesis and recovery. Roland Veltkamp (University Heidelberg, Heidelberg, Germany) demonstrated that regulatory T cells can diminish ischemic damage by inhibiting leukocyte trafficking to the ischemic brain. Michal Schwartz (The Weizmann Institute of Science, Revohot, Israel) reported that immigrating immune cells, in particular T cells, support neurogenesis, enhance cognitive functions and are essential for maintaining brain plasticity. Impressive data for both the beneficial and detrimental effects of systemic immune responses and glial reactivity were presented. This demonstrated the strong demand for a deeper understanding of the modulation and impact of those processes.
Facilitating recovery: current concepts for stem cell applications following stroke
Cell-based approaches are an emerging paradigm in stroke research. The first studies are underway to assess safety, practicability and even efficacy of autologous adult cell populations, such as mononuclear cells and mesenchymal stem cells Citation[3]. Approaches using embryonic and fetal stem cells or progenitors derived thereof are at the gate to application in Phase I/II clinical trials. Some of the most promising approaches were reported by several speakers. Studies using induced pluripotent stem cells were presented by Koji Abe (National Hospital Organization Okayama Medical Center, Okayama, Japan) and Brigitte Onteniente (Centre de Recherches en Psychiatrie et Neurosciences, Paris, France). These cells are generated by the (mostly vector-based) introduction of characteristic pluripotency genes into somatic cells and represent a very interesting alternative to embryonic stem cells, which are hampered by ethical concerns and lack the opportunity for autologous application. Olle Lindvall (Wallenberg Neuroscience Center and Lund Stem Cell Center, University Hospital, Lund, Sweden), a pioneer in clinical stem cell transplantation, emphasized the enhancement of poststroke neurogenesis and the survival of neurons rather than graft-based replacement as a promising strategy. Gary Steinberg (Stanford University School of Medicine, CA, USA) summarized research activities from his group investigating embryonic-stem-cell-derived precursors. The cells promote functional recovery by enhancing brain plasticity and facilitating axonal remodeling even when transplanted in subacute stroke stages, and are being used in a clinical study in the near future Citation[4]. David Hess (Medical College of Georgia, GA, USA) discussed the role of mesenchymal stem cells for stroke treatment, not only focusing on preclinical and clinical data, but also reviewing relevant regulatory aspects for clinical translation.
Mitochondria & metabolism: novel molecular targets for neuroprotection
Understanding of the complex response of the neurovascular unit to ischemic injury is still incomplete, thus demanding additional research. Activation of the transcription factor, PPAR, was reported by Regis Bordet (Université de Lille II, Lille, France) to protect brain capillary endothelial cells in the BBB from oxygen–glucose deprivation-induced hyperpermeability, shedding new light on the problem of BBB hyperpermeability in stroke. Cerebral gene expression is influenced by sublethal preconditioning, inducing tolerance against future ischemic events Citation[5]. Small noncoding RNAs (miRNAs) were recently demonstrated to control mRNA translation. Raghu Vemuganti (University of Wisconsin, WI, USA) reported that alterations in miRNAs are decisive for induction of ischemic tolerance. Mitochondria are control points within the cascade of neuronal death and play a central role in swinging the balance in favor of either the survival or death of brain cells. Furthermore, mitochondrial dysfunction is a common characteristic of neurodegenerative diseases. However, the causes of dysfunction remain a mystery. Ella Bossy-Wetzel (University of Central Florida, FL, USA) suggested that a better understanding of mitochondrial fission and fusion and the regulatory factors involved may lead to improved treatments for many neurodegenerative diseases. The neuroprotective role of connexins in the CNS was illuminated by Taizen Nakase (Research Institute for Brain and Blood Vessels, Akita, Japan). Nakase demonstrated that enhanced connexin 43 (Cx43) immunoreactivity occurs in penumbral areas in the human brain following ischemia, suggesting that the brain may generate neuronal protection by increasing the levels of Cx43 and amplifying the astrocytic gap junctional–intercellular communication under hypoxic conditions. Georg Reiser, together with colleagues from the Russian Academy of Science Pushchino (Pushchino, Russia), recently extended the protective function of Cx43 to brain mitochondria. This is complementary to the other findings of the group, highlighting the mitochondrial permeability transition as a broad target for neuroprotection. Costantino Iadecola (Weill Cornell Medical College, NY, USA) demonstrated that the prostaglandin E2 type 1 receptor plays a substantial role in neuroprotection following experimental stroke in mice. EP1 receptor inhibition is a potentially valuable strategy for neuroprotection in a time window of 12 h, which deserves further preclinical investigation.
Seeing is believing: imaging techniques in neuroscience
In the last decade, imaging techniques such as MRI have emerged as essential tools for studying structural and functional processes in the brain. Owing to continuous methodological improvements, the impact of imaging on research is expected to increase even further. Numerous recent developments from the field were presented at the conference. Jens Neumann (Leibniz Institute for Neurobiology, Magdeburg, Germany) presented immune cell interactions and early extravasation of neutrophils in vital tissue by intracranial two-photon microscopy. The further development of this approach with transgene-labeled cells gives a higher quality of examination of inflammatory processes after stroke. Rudolf Graf (Max Planck Institute for Neurological Research, Cologne, Germany) presented data from studies using multimodal imaging of cortical spreading depression in acute stroke. Concentrically propagating peri-infarct depressions modulate the evolution of the ischemic lesion. In addition, circumferential cortical spreading depression propagation is a cause of secondary lesion enlargement. Albrecht Stroh (Technical University Munich, Munich, Germany) presented data on long-term cell tracking in vivo, including visualization of systemically injected mononuclear spleen cells that homed to an ischemic focus. Impressive examples for single-cell imaging using high-field MRI were given by Alan Koretsky (National Institute of Neurological Disorders and Stroke, NIH, MD, USA). He also introduced recent developments in iron particle microfabrication. Owing to different shapes and sizes, those particles have discriminable signal response characteristics when used as contrast agents, allowing the addition of ‘color’ to magnetic resonance images, and may be used for multipopulation cell trafficking studies.
Rewiring & regeneration: understanding poststroke functional recovery
It is well known that regenerative processes determine functional regeneration in the poststroke brain; however, the complex causal relationships are poorly understood. Matthias Endres (Charité Universitätsmedizin) provided novel insights into poststroke depressions that are evident in up to 50% of stroke patients Citation[6]. Poststroke depressions reduce functional outcome and enhance morbidity and mortality, thus requiring further research on pathophysiology, prevention and treatment. Thomas Carmichael (University of California Los Angeles) reported that axonal sprouting facilitating motor recovery after stroke is a well-orchestrated process in specific motor, premotor and somatosensory circuits. Astrocyte-borne ephrin A5, a ligand of the axonal growth inhibitor EphA4, and behavioral activity balance axonal sprouting after focal cerebral ischemia. Compensative motor behavior is a major component of functional recovery. Otto Witte (University of Jena, Jena, Germany), focusing on functional regeneration in the older brain, demonstrated that this compensation is limited in older individuals. While it is known that plasticity can also partially compensate dysfunctions in the aged brain Citation[7], more research is needed to characterize the regenerative environment in older subjects. Denis Vivien (University of Caen, Caen, France) emphasized detrimental aspects of tissue plasminogen activator, which can facilitate cell death by increasing calcium influx into neurons. Vivien also suggested an antibody-based approach that may prevent detrimental effects of tissue plasminogen activator following stroke.
Future perspectives for stroke research & neuroscience
The meeting was concluded by Evan Snyder (Burnham Institute for Medical Research, CA, USA) who discussed the developmental programs in stem cells during embryogenesis. Deeper insight into these mechanisms may be the key to success in translational neuroscience and could generate future concepts by which to achieve real poststroke regeneration by tissue replacement.
Conclusion
Intensive discussions between delegates demonstrated the interest of the participants in the topics addressed. Many attendees stated that the meeting was very interactive, informative and encouraging, and that it shall be continued in the future. Thus, the meeting organizers are happy to announce the 7th International Symposium on Neuroprotection and Neurorepair, which will be held on 2–5 May 2012 in Potsdam, Germany. This next meeting will also consider topics such as aging and vascular dementia.
Acknowledgements
We wish to acknowledge Antje Dreyer, Teresa von Geymüller, Manuela Jaklin, Ulrich Schröder, Vilia Zeisig, Caroline Zscheile and the Eventlab congress organizing team for their continuous and exceptional support.
Financial & competing interests disclosure
The meeting organizers are grateful for a generous grant provided by the Deutsche Forschungsgemeinschaft (RE563/17-1) and for contributions of industrial sponsors. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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