Congress Chairman Ivan Rektor Masaryk University, Vice-Rector for Development Head, First Department of Neurology, St. Anne's Hospital, Brno, Czech Republic President, European Society for Clinical Neuropharmacology 01
faculty Faculty in alphabetical order Franz Aichner / Austria Anton Alvarez / Spain Leontino Battistin / Italy Christoph Baumgartner / Vienna Ovidiu Băjenaru / Romania Natan Bornstein / Israel Anca Buzoianu / Romania Antonio Federico / Italy Franz Gerstenbrand / Austria Alla Guekht / Russia Volker Hömberg / Germany Conrad E. Johanson / USA Amos Korczyn / Isarel Robert Kuba / Czeck Republic David Mulholland / USA Dafin Mureşanu / Romania Gregory Oxenkrug / USA Bogdan O. Popescu / Romania Ivan Rektor / Czeck Republic Peter Riederer / Germany Nada Sternic / Serbia Klaus Toyka / Germany Laszlo Vecsei / Hungary Le Weidong / USA 02
committees Local Committe e / Austria in alphabetical order President Franz Gerstenbrand /Austria Franz Aichner / Linz Eduard Auff / Vienna Heinrich Binder / Vienna Christoph Baumgartner / Vienna Michael Brainin / Krems Thomas Brücke / Vienna Franz Fazekas / Graz Gunther Ladurner / Salzburg Erwin Ott / Graz Werner Poewe / Innsbruck Gerhard Ransmayer / Linz Leopold Saltuari / Innsbruck Manfred Schmid / Vienna International Committee in alphabetical order President Dafin Mureşanu / Romania Anton Alvarez / Spain Leontino Battistin / Italy Ovidiu Băjenaru / Romania Natan Bornstein / Israel Anca Buzoianu / Romania Antonio Federico / Italy Franz Gerstenbrand / Austria Alla Guekht / Russia Volker Hömberg / Germany Conrad E. Johanson / USA Amos Korczyn / Isarel David Mulholland / USA Gregory Oxenkrug / USA Bogdan O. Popescu / Romania Peter Riederer / Germany Klaus Toyka / Germany Laszlo Vecsei / Hungary 03
organizers / congress venue Organizers Congress Venue Hilton Vienna Hotel Am Stadtpark, A - 1030 Vienna, Austria Telephone: 00 43 (0)1 71700-0 Fax: 00 43 (0)1 713 0691 Email: info.vienna@hilton.com Scientific Secretariate The Society for the Study of Neuroprotection and Neuroplasticity Cluj-Napoca, Romania, 33A Teleorman Street Office phone: +40264431924 E-mail: contact@ssnn.ro Congress Registration Desk All congress materials and documentation will be available at the congress registration desk located at SSNN booth, on the congress area, Hilton Hotel, Vienna. The congress staff will be pleased to help you with all enquiries regarding registration, congress materials and program. Please do not hesitate to contact the staff members if there is anything they can do to make your stay more enjoyable. Opening Hours Tuesday 3rd of March 2009 16: 00 19: 30 Wednesday 4rd of March 2009 8: 30 13: 30 04
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Congress information Participants registration fee includes: Admission to all scientific sessions during the congress. Conference materials (delegate bag, final program and abstract book etc.) Admission to Coffee Breaks On-site registration On-site registration will be processed on a first-come, first-served basis. Priority will be given to pre-registered delegates. Depending on the number of on-site registered delegates, availability of congress bags may be limited. Name badges Participants are kindly requested to wear their name badge at all times during the congress. The badge constiutes admission to the scientific sessions and coffee breaks. Congress language The congress language is English. Simultaneous translation will not be provided. Changes in program The organizers cannot assume liability for any changes in the congress program due to external or unforeseen circumstances. Contact If you need further information regarding technical details, please contact: Ovidiu Selejan/e-mail/ovidius@ssnn.ro For updates and details please visit our website/www.ssnn.ro 07
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SCIENTIFIC PROGRAM
scientific program 3rd of March 2009 Tuesday / Park Congress 1 DEMENTIA Chairpersons: Amos Korczyn, Leontino Battistin 16:00-16:15 16:15-16:30 16:30-16:45 Alla Guekht Amos Korczyn Peter Riederer Seizures and dementia after stroke Is Vascular cognitive impairment a useful concept? Insulin and insulin-receptor dysfunction in an Alzheimer model Discussions 10 min NEUROPROTECTION/ Session 1 Chairpersons: Peter Riederer, Dafin Mureşanu 16:55-17:10 17:10-17:25 17:25-17:40 Bogdan Popescu Klaus Toyka Gregory Oxenkrug A rat model of Parkinson s disease for testing neuroprotective drugs effects of Cerebrolysin The pathogenic role of autoantibodies to amphiphysin in Stiff-Person Syndrome from bed to bench Neuroprotective role (against glaucoma, hypertension and lipid peroxidation - arachidonic acid cascade) of agonists to Melatonin type 3/Quinone Reductase 2 binding site Discussions 10 min 17:50 18:10 COFFEE BREAK STROKE Chairpersons: Franz Aichner, Natan Bornstein 18:10-18:25 18:25-18:40 18:40-18:55 18:55-19:10 Natan Bornstein Ovidiu Băjenaru Franz Aichner Nada Sternic Secondary stroke prevention-update Medical management of brain diseases and metabolic syndrome Thrombolysis in stroke The role of decreased insulin sensitivity as a stroke risk factor Discussions 10 min 11
scientific program 4th of March 2009 Wednesday / Park Congress 1 EBEWE SYMPOSIUM Chairpersons: Amos Korczyn, Anton Alvarez 8:30-8:45 8:45-9:00 9:00-9:15 9:15-9:30 Conrad Johanson Anton Alvarez David Mulholland Leontino Battistin Cerebrolysin Stabilizes Blood-CSF and Blood-Brain interfaces, and reduces neuropathology and sensory-motor malfunctions, in adult rats after traumatic brain injury Neurotrophic treatment for traumatic brain damage Emerging neurotrophic factor drugs in a virtual universe of medication regimens, regulation paradoxes, and e-scams: the case for longitudinal comparisons of internet search results for Cerebrolysin to FDA-Approved Alzheimer s disease drugs A pilot study to evaluate the effects of Cerebrolysin on cognition and qeeg in vascular dementia EPILEPSY Chairpersons: Ivan Rektor, Laszlo Vecsei 09:30-09:45 09:45-10:00 10:00-10:15 10:15-10:30 Ivan Rektor Anca Buzoianu Robert Kuba Baumgartner Christoph Intracranial EEG The importance of pharmacogenetics in the treatment of epilepsy Vagal nerve stimulation in epilepsy and other neurological disorders Current trends in antiepileptic drug treatment Discussions 10 min 10:40 11:00 COFFEE BREAK 12
scientific program 4th of March 2009 Wednesday / Park Congress 1 NEUROPROTECTION/Session 2 Chairpersons: Antonio Federico, Laszlo Vecsei 11:00-11:15 11:15-11:30 11:30-11:45 Antonio Federico Laszlo Vecsei Le-Weidong Diagnosis and treatment of rare neurological diseases: a challenge of neurology CGRP, excitotoxins and excitatotoxin antagonists in migraine Folic acid and vitamin B12 therapy for ALS Discussions 10 min NEUROREHABILITATION Chairpersons: Franz Gerstenbrand, Volker Hömberg 11:55-12:10 12:10-12:25 12:25-12:40 12:40-12:55 Franz Gerstenbrand Volker Hömberg Dafin Mureşanu Leontino Battistin Neurorehabilitation and Space-Neurology Practical pharmacological projects in rehabilitation Understanding neuroplasticity: positive and negative outcomes Beyond the pharmacology in the recovery of stroke Discussions 10 min 13
ABSTRACTS
THROMBOLYSIS IN STROKE Franz T. Aichner Linz, Austria Thrombolysis is an effective and safe therapy for ischemic stroke, whether performed intravenously within 3 hours or intra-arterially within 3 to 6 hours. Metanalysis have provided evidence of an effect of intravenous thrombolysis beyond the 3 hours time-window. The ECASS 3 trial showed clearly that alteplase administered 3 to 4.5 hours after stroke symptom onset is effective. Significantly more patients benefitted versus placebo in terms of excellent recovery (mrs 0-1) at day 90, overall greater functionality / independence at day 90, improved neurological functioning (NIHSS 0-1) or 8 points improvement at day 30 and independence (mrs 1-2) at day 30 in the pp population. There was a low overall incidence (2,4 %) for symptomatic intracerebral haemorrhage with alteplase, however, the mortality rate of 8 % was not different between the treatment arms. The SITS-MOST-data on the 3 to 4.5 hour time window for intravenous thrombolysis underline the results of ECASS 3. We can conclude that there is more time for patients but not for physicians treating patients with acute stroke. Severe strokes were excluded from ECASS 3 (NIHSS 25), that means that the ECASS 3 results are not generalizable to severe strokes. The door to needle time in ECASS was one hour and 25 minutes, which is far too long and is not acceptable. Now, the stroke community is waiting for the guideline update as well as for the EMEA approval of intravenous thrombolysis up to 4.5 hours. In the meantime ECASS 3 was announced by the Lancet as paper of the year. 16
NEUROTROPHIC TREATMENT FOR TRAUMATIC BRAIN DAMAGE Antón Alvarez Department of Neuropharmacology, EuroEspes Biomedical Research Centre, Bergondo, Coruña, Spain Traumatic brain injury (TBI) is an important cause of morbidity and disability in young people. Chronic sequels, including physical, cognitive and behavioural alterations, are present in approximately 25% of the hospitalised TBI survivors. Since neuronal damage caused by TBI is at the basis of all these derangements, a main objective of the pharmacological treatment in TBI is to reduce neurodegeneration. Apart of the pure traumatic injury, there are several pathogenic mechanisms contributing to produce and/or to aggravate brain damage in TBI patients, like excitotoxicity, inflammation, amyloid deposition and dysregulation of trophic factors. Thus, therapeutic strategies for neuroprotection must be oriented to modify pathogenic processes underlying neuronal degeneration and cognitive deficits. Cognitive impairment and electrophysiological abnormalities are constant findings in TBI. Persistent cognitive difficulties are very common and related to severity in postacute TBI patients. Deficits of neuropsychological functioning detected in these patients include problems with attention-arousal and reduced performance on acquisition and memory, psychomotor speed, and executive functions. Some of the quantitative electroencephalographic (qeeg) alterations reported in TBI patients correlate with trauma severity, neuropsychological test scores and outcome measures. In two clinical studies we evaluated the effects of Cerebrolysin (Cere), a pleiotropic compound with neurotrophic activity, on cognitive performance, qeeg parameters and clinical outcome in postacute moderate-severe TBI patients. Cere improved cognitive performance and reduced qeeg slowing, a correlate of cognitive impairment in these patients. Positive changes in attention, mental processing speed and executive functions were observed after Cere treatment. The EEG-activating action of Cere together with its positive effects on cognition and clinical outcome are supporting the neuroprotective-neurotrophic activity of this compound in brain injury and its potential use for improving the functional recovery of TBI patients. 17
BEYOND THE PHARMACOLOGY IN THE RECOVERY OF STROKE Leontino Battistin, A. Cagnin and M. Dam Dept of Neurosciences, Padua University, Padova, Italy A cutting-edge approach in the recovery after stroke includes the use of drugs that may enhance the natural mechanisms of recovery. The most widely investigated drugs are those that increase noradrenergic and serotonergic neurotransmission such d-amphetamine and antidepressat. Both monoamines favour recovery exploiting multifold mechanisms. Noradrenaline might play an important role in cortical reorganization and motor learning. Serotonin stimulates new synaptic contacts, long-term facilitation in sensory motor synapses, and it favors finalistic motor responses in rats. Other neurotransmitter including GABAand dopamine may be harmful to recovery. Post-stroke patients who chronically receive benzodiazepines, antiepileptics, and phenothiazines improve from disability less than those not taking such medicaments. Drugs acting on glutammaergic and cholinergic systems may also be helpful in restorative medicine. However, animal studies indicated that their positive or negative effects on recovery is strictly dependent upon the time of administration after brain injury. Therefore more experimental data are needed before using these medicaments in patients. Different class of drugs that enhances the trophic input in the brain may be relevant to recovery, Namely, growth factors may stimulate neurogenesis, neural repair and rewiring. The better understanding of the mechanisms of recovery after stroke forecast the development of a new restorative therapy approach, more effective than the current ones. The newly proposed therapeutic strategies include Virtual Reality Based Rehabilitation which may provide subjects with artificially augmented feedback that facilitates the reinstatement of the compromised motor skills. 18
CURRENT TRENDS IN ANTIEPILEPTIC DRUG TREATMENT Christoph Baumgartner, 2nd Neurological Department, General Hospital Hietzing with Neurological Center Rosenhuegel, Vienna, Austria Modern antiepileptic drug (AED) treatment should ideally achieve the following goals: The most important goal is seizure-freedom or optimal seizure-control. Furthermore good tolerability, meaning no side effects of AEDs is another important goal. AEDs should be simple to apply both for patients and doctors and therefore should possess favourable pharmacokinetic and pharmacodynamic properties. AEDs should positively influence frequent comorbid conditions (e.g. neuropsychological disturbances, psychiatric comorbidity, sleep disorders and others). AEDs should be tailored to special patient groups, e.g. children, women of childbearing age, older patients or mentally retarded patients. The negative psychosocial implications of epilepsy should be avoided right from the beginning of treatment. Efforts should be made to prevent the increased mortality in epilepsy patients including sudden unexpected death in epilepsy (SUDEP), accidents or suicide. Finally, AEDs with antiepileptogenic and neuroprotective effects should be designed although none of the currently available drugs has proven these latter effects in a clinical setting. Seizure control can be achieved in approximately two thirds of patients, while the remaining one third of patients suffers from difficult-to-treat or medically refractory epilepsy. The majority of patients can be controlled with rather low doses of AEDs, which means that the primary strategy in epilepsy treatment can be summarized as start slow and go low. Patients with idiopathic epilepsies are better to control than patients with cryptogenic and symptomatic epilepsies. In the group with symptomatic epilepsies, patients with mesial temporal sclerosis and focal cortical dysplasia are the most difficult to control. Mechanisms of medically refractoriness can be explained by alterations of the drug target ( target hypothesis ) or by an increased expression of drug transporters pumping away AEDs from the epileptic focus ( transport hypothesis ). Despite the introduction of a large number of new AEDs in recent years, none of the new drugs proved more efficacious than the older established drugs. Nevertheless, some of the new drugs offer significant advantages in terms of tolerability, long-term side effects and pharmacokinetic properties. Side effects of AEDs are more important than seizurefrequency for the quality of life in non-seizure-free epilepsy patients. Therefore in patients in whom seizure freedoml cannot be achieved, a lower dose of AEDs might significantly improve the patient s quality of life without negatively affecting seizure control. 19
METABOLIC SYNDROME AND THE MANAGEMENT OF BRAIN DISEASES Ovidiu Băjenaru*, C.Tiu*, A.Vasilescu**, F.Boghez* * University Hospital of Emergency Bucharest Department of Neurology ** University Hospital of Emergency Bucharest Department of Psychiatry Metabolic syndrome ( MetSy ) is an entity largely recognised as an important risk factor for cardio- and cerebrovascular diseases, and more and more as an independent risk factor for dementia. Observational data during the last few years show also that very active drugs, such as the recent generations of neuroleptics used primarly in psychiatric severe disorders but also in certain instances in some neurological disorders, increase the risk of developing Met Sy and cardiovascular death. Also some sleep disorders and even the invalidity determined by stroke itself could be risk factors for developing Met Sy and through it, the risk of further vascular complications, including vascular death. These data have to be carefully taken into account in the management strategies of some brain diseases. 20
THE IMPORTANCE OF PHARMACOGENETICS IN THE TREATMENT OF EPILEPSY Anca Buzoianu Dept. Clinical Pharmacology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania Epilepsy is one of the most invalidating diseases, which affects approximately 1% of patients in all populations. It has an unforeseeable character, the seizures appearing at the most unexpected moments in ones life, making difficult the patient s social insertion. Anti-epileptic drugs control the majority of varieties of the disease, but like in the case of every treatment, there are unsatisfactory outcomes regarding the efficacy and side effects. Although there are more than 30 antiepileptic drugs, 30% of patients are still resistant to pharmacotherapy. There are important pharmacodynamic and pharmacokinetic variations for a particular antiepileptic drug among different patients because of genetic variations which include metabolization and elimination pathways of the antiepileptic drugs. Pharmacogenomic mapping and the evaluation of pharmacokinetics of the used drugs will help to choose the right medicine at the optimal dose for the existing enzymatic status of a patient. At the same time it will be possible to determine the degree of the correlation between gene polymorphism and drug kinetics, a high correlation will justify the clinical routine use of genotyping, a minimal invasive and cheap method. The polymorphism of the genes that are involved in metabolizing anti-epileptic drugs determine modified activity of the coded enzymes; consequentially differences result regarding the plasmatic concentration of the drugs, and also differences in the therapeutic efficacy and safety, more evident in the case of medicines with narrow therapeutic window. The polymorphisms of the genes coding metabolizing enzymes can produce varieties of these with increased, decreased or missing activity, respectively various phenotypic expressions in individuals: slow, intermediary, rapid and ultra-rapid metabolizers. One third of the patients with epilepsy present refractory forms, with high mortality risks and debilitating psycho-social consequences, the so called refractory epilepsy. Due to the fact that these refractory varieties of the disease are resistant also in the case of association of multiple anti-epileptic drug types, the way of developing this resistance seems to be not specific, considering that different anti-epileptic classes act with different mechanisms. Correlating the results of genotyping CYP2C19, CYP2C9 with those of MDR1 could clarify why the same type of epilepsy can be refractory for one person and responsive for another, if this is a pharmacogenomic phenomenon and it can be explained on these bases. Having more knowledge in pharmacogentics, pharmacoresistant cases and side effects will be pre recognized. Moreover, the identification of a gene and gene product will allow a directed approach towards drug development. 21
RARE NEUROLOGICAL DISEASES: SIENA EXPERIENCE IN DIAGNOSIS, TREATMENT, RESEARCH AND TEACHING Antonio Federico Department of Neurological and Behavioural Sciences, Medical School, University of Siena, Siena, Italy Rare neurological diseases are an heterogeneous group of disorders mainly affecting central, peripheral nervous system and muscle, representing almost 50% of all the rare diseases, and indicating that neurologists are one of the main specialists involving in diagnosis and research. But the classical interest of neurologists is dedicated to the main common diseases as dementia, multiple sclerosis, headache, epilepsy, stroke, avoiding to follow these diseases, that have, taken togheter, an high impact on the health system in Europe as well as in all countries. Rare diseases are also considered orphan diseases, since for few of them a treatment exists. In Europe, like in USA, in the recent years, a great interest has been dedicated to such disorders and the organization of dedicated care systems have been stimulated. In fact, the difficulty of the diagnosis and the need of superspecialization on this topic, lead to the organization of few Centres in the different Countries, that can collect patients and organize a network for diagnosis, treatment and research. We will report our experience in Siena, as a reference Centre for these disorders, for diagnosis and treatment. We will discuss also our experience in teaching in medical school and in PhD programme, for qualification researchers in these topics. Since rare neurological diseases are a nice model for understanding the pathogenesis of more common nervous system dysfunctions, we will report some our research data on the pathogenesis of mitochondrial, lysosomal and peroxisomal diseases and also in some neurogenetic conditions, some of them leading to innovative treatments. Finally, data on the activity of an Information Centre that is able to give informations to patients and doctors will be reported. 22
NEUROREHABILITATION AND SPACE NEUROLOGY DEVELOPMENT OF NEW METHODS 1 2 3 Franz Gerstenbrand, St. Golaszewski, W. Struhal 1 K.Landsteiner Institut, Vienna, Austria 2 Ch.Doppler-Clinic, Salzburg, Austria 3 Neurolog. Dept., LKH Linz, Austria Only a small part of the research in space medicine takes place under the condition of the real microgravity (space flights orbit crew). Most experiments are performed in ground based laboratories using the methods of simulated microgravity (head down tilt system, the dry water immersion model. Functional disorders of the nervous system occur in the real as well as in the simulated micro gravity. The stimulation of the receptors for the gravity receive changed information for the afferent system to the brain, using the proprioceptive system. The proprioception is responsible for the control of the position and the movements in the human body. The human organism is adapted to the normal gravity, the human motoric is controlling the upright position and the dipod-gait. During long-term stay in real microgravity (crew in the ISS) a disturbance in postural control occurs and musculo-sceletal failures are developing. Appropriate countermeasures of astronauts/cosmonauts are necessary to avoid the Cosmonaut-Syndrome (polyneuropathy, primary,muscle atrophies, posterior column disturbances, reduction of cognitive functions and of vigilance). A quick restoration after return to the Earth is normal. The simulated microgravity appears during long-term bed fastness developing the Bed-Rest-Syndrome, with similar symptoms to the Cosmonaut Syndrome (polyneuropathy, primary muscle atrophy, posterior column disturbances, cognitive failures, declining in vigilance and a vegetative dysbalance). The Bed Rest Syndrome can be observed in apallic patients, severe neurological conditions ( stroke, traumatic brain injury etc.) as well as in severe cardio-vascular diseases and last not least in elderly people with a motion deficit. The origin of the Bed Rest Syndrome is the long horizontal position with a diminished influence of the normal gravity. The patho-physiological explanation of the Bed Rest Syndrome and the Cosmonaut Syndrome is the deficit in the stimulation of the proprioceptive system. In neurorehabilitation different methods to stimulate the proprioceptive system are used like the foot sole pressure therapy with vibro stimulation methods for the foot sole (Pressure Shoe), to avoid the Bed Rest Syndrome. A new method was developed by the Russian Space Medicine, the Foot Loading Imitator (Korvit System) and the cosmonaut-trousers (Treatment Suite Regent), used spastic paresis. The influence of the vibro tactile stimulation of the foot sole could be demonstrated with the functional MRI method, showing an increase of blood flow (BOLD Effect) in the sensomotoric areas, contra lateral and homo lateral, as well as in the thalamus, the frontal brain and the temporal lobe. Space neurology is not only a fascinating new and pioneering research field with a special fascination, but supplies a wide range of new possibilities in neurorehabilitation. 23
SEIZURES AND DEMENTIA AFTER STROKE. 1 2 1 Alla B. Guekht, N. V. Gulyaeva, E. I. Gusev ١ Russian State Medical University, Moscow ۲ Inst. of Higher Nervous Activity&Neurophysiol., RAS, Moscow Seizures and dementia after stroke (S) increase exponentially with aging of the population. About 10% of all S. patients experience seizures, from onset until several years later. Five percent are early-onset seizures (ES, within 7 days of S.) and another 5% are late-onset seizures (LS) (Hauser W.A. et al.,1993). Poststroke dementia occurs in up to one third of patients with clinically eloquent ischemic stroke after age 65 years (Pohjasvaara et al., 1997), and pre-existing dementia is present in 12-16% of S. patients. Pre-existing dementia was independently associated with the occurrence of LS, and ES were independent predictors of new-onset dementia within 3 years after S (Cordonnier C et al., 2005, 2007). Both conditions (dementia and seizures) share important risk factors, for example, hippocampal atrophy and atrial fibrillation. Besides, pre-existing vascular pathologies that may predispose to both seizures and new onset dementia could be white matter changes, silent infarcts or microbleeds. Though the mechanisms of seizures and dementia after S. are widely discussed in the literature, the mechanisms of interconnections between them are much less known. According to the results of our study, patients with ES have higher risk for ischemia-induced neurodegeneration, as CSF of patients with ES ( compared to matched stroke patents withour seizures) demonstrated higher ability to inhibit major cell deathrelated proteases (calpain and caspase-3). Several studies (Rao SC et al., 2009) indicated that most individuals with the comorbidity of epilepsy and dementia have complex partial seizures that may be adequately controlled by antiepileptic drugs. Still, the long-term effect of seizure activity on the neurodegenerative disorder is unknown. Prospective studies focused on interplay between dementia after S. and seizures (bearing in mind differences in mechanisms of ES and LS) are necessary; besides, this question is of importance for prevention and treatment of both conditions. 24
PRACTICAL PHARMACOLOGY IN NEUROREHABILITATION Volker Hömberg Meerbusch/Germany Two major facets of pharmacological treatment in neurorehabilitation have to be addressed: 1. It is of critical importance to avoid so called detrimental drugs defined as drugs known from animal experimental as well as from clinical catamnestic studies to interfere with brain plasticity after brain injury. 2. Drugs which eventually may have neuroprotective value or improve brain plasticity. Among the neuroprotective drugs only very few out of hundreds have been proven to be of some value. This is similarly true for the use of drugs affecting monaminergic pathways such as amphetamines, dopamine or amantadine. One of the best evidence-proven concepts is the use of antidepressive agents in patients after stroke with signs of depression. In these patients mood, rehabilitative outcome and life expectancy are improved by antidepressive therapy. 25
CEREBROLYSIN STABILIZES BLOOD-CSF AND BLOOD-BRAIN INTERFACES, AND REDUCES NEUROPATHOLOGY AND SENSORY-MOTOR MALFUNCTIONS, IN ADULT RATS AFTER TRAUMATIC BRAIN INJURY. Conrad E. Johanson 1, Sibilla Zimmermann- Meinzingen 2 and Hari S. Sharma 3. 1 Neurosurgery, Brown Medical School, Providence, Rhode Island, USA; 2 EBEWE Pharma, Unterach, Austria 3 Laboratory of Cerebrovascular Research, Institute of Surgical Sciences, University Hospital, Uppsala University, Uppsala, Sweden. Background: Traumatic brain injuries (TBI) badly damage both the blood-csf (choroid plexus) and bloodbrain barriers, leading to brain pathology/edema and multiple sensory-motor disturbances. The disrupted homeostasis following TBI may be prevented by timely administration of exogenous neurotrophic factors such as BDNF, IGF-1 or GDNF. A combination of neurotrophic factors may even enhance neurotrophic efficacy. Materials and Methods: We used a mixture of neurotrophins, i.e., cerebrolysin, to examine functional outcome and neuropathology in an adult rat TBI model. In anesthetized rats, TBI was produced by a longitudinal incision into the right parietal cortex. Test agent was administered into a lateral ventricle within an hour or less following TBI induction. Results: Cortical-injured animals not given cerebrolysin displayed ruptured CNS barrier systems, as evidenced by leakage of plasma protein into both CSF and brain; accordingly, the untreated rats (not given cerebrolysin) developed marked brain edema. Thus, five hr after TBI there were substantial sensory-motor dysfunctions as evaluated by grid walking and rota-rod tests. On the other hand, the intracerebroventricular injection of cerebrolysin (10 or 30 µl) either 5 min or 1 hr after TBI significantly reduced brain edema formation, as well as leakage of radioiodine and Evans blue tracers across the choroid plexus interface and the BBB. Consequently, there was less neuronal damage in the injured parietal cortex and the underlying sub-cortical regions. Consistently, the rats that received cerebrolysin within an hour or less of injury showed improved sensory-motor functions. However, when cerebrolysin was given 2 hr after TBI, the favourable histological and pharmacological effects were not observed. Conclusion: Our findings indicate that early intervention with cerebrolysin reduces the following: sensory/motor functional deficits, blood-csf and blood-brain barrier permeability, and brain pathology. Collectively, these observations point to possible therapeutic value of cerebrolysin in TBI disorders. Conclusions Aged rat CNS at 30 mo resembles NPH/AD. DG & SVZ are stressed by Aß burden and inflammation. The diminished spatial memory prompts potential CSF agent usage to stabilize neurogenesis. 26
IS VASCULAR COGNITIVE IMPAIRMENT A USEFUL CONCEPT? Amos Korczyn Sieratzki Chair of Neurology, Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel Epidemiological data have demonstrated that risk factors for vascular disease in general, and for stroke in particular, are largely identical to those of Alzheimer s disease (AD). Thus, hypertension, diabetes mellitus and elevated serum levels of cholesterol and homocysteine contribute to the occurrence of both diseases. The brain of elderly people accumulates amyloid, neurofibrillary tangles, as well as vascular lesions, large and small, cortical and deep. Blood vessels may manifest lipohyalinosis and result in leucoaraiosis. Cognitive decline in old age results from this cumulative burden. The clinical distinction between vascular dementia and AD is clinically impossible in most cases, is confusing and counterproductive. Most elderly patients with dementia do not have a monolithic pathologic disorder (e.g. AD or vascular dementia) but rather a combination of both. This overlap is supported by imaging evidence as well as by neurochemical markers. Unfortunately, mixed dementia, the most common cause of dementia, is not yet defined clinically or pathologically. Public health measures should be taken to lower the impact of the risk factors responsible for these diseases (such as hypertension, hyperlipidemia, hyperhomocysteinemia, and smoking). Attention to these risk factors by drugs and lifestyle is important in reducing the incidence and prevalence of dementia. 27
VAGAL NERVE STIMULATION IN PATIENTS WITH EPILEPSY AND OTHER NEUROLOGICAL DISORDERS. Robert Kuba Masaryk University, First Department of Neurology, St. Anne's Hospital, Brno, Czech Republic Vagal nerve stimulation (VNS) is a non-pharmacological treatment for epilepsy. Literature generated in recent years has shown that VNS is a safe, tolerable and effective adjunctive therapy for patients with refractory epilepsy. The clear pathophysiological mechanism of its action remains unknown. The majority of vagal nerve fibres are visceral afferents, which are widely distributed throughout the central nervous system. Some reports have suggested that VNS affects neurochemical signalling by modulation of GABA and norepinephrine. It is also suggested that VNS can provoke changes in cerebral blood flow (CBF) using SPECT and PET methodology. Various studies have proposed that CBF may be changed in various cortical and subcortical structures like thalamus, hippocampus, amygdala and cingulate gyrus after VNS, however the data remains conflicting. There are hundreds of papers describing the efficacy and tolerability of VNS in various types of epileptic seizures and epileptic syndromes, both in children and adults. VNS is chronic intermittent stimulation of the root of the vagal nerve, which probably causes the neurochemical changes in various part of the brain. Except for the long-term effect caused by chronic stimulation, patients can use the on demand magnetic extrastimualtion, which may, in some cases, abolish the seizures after their onset. Except for the effect of VNS on epilepsy, effect on mood and interictal behaviour in patients with epilepsy has been previously reported in the literature. The effect of VNS on depression is well known. There are some pilot data about the effectiveness of VNS in patients suffering from migraine, other types of headache and Alzheimer disease. 28
EMERGING NEUROTROPHIC FACTOR DRUGS IN A VIRTUAL UNIVERSE OF MEDICATION REGIMENS, REGULATION PARADOXES, AND E-SCAMS: THE CASE FOR LONGITUDINAL COMPARISONS OF INTERNET SEARCH RESULTS FOR CEREBROLYSIN TO FDA-APPROVED ALZHEIMER S DISEASE DRUGS. David W. Mulholland Faculty at University of British Columbia, Vancouver, Canada Community Neuro-Rehabilitation, Inc.Westminster West, VT, USA Overview: Studies indicate that patients and their loved ones use Internet search engines (ISEs) to discover information about medical diagnoses, treatment, and providers. Search engine results impact both patient demand for specific treatments as well as provider-patient relationships when consumers interject Internetderived drug information into conversations during office visits for chronic conditions. Internet direct-toconsumer advertisement encourages patients to move in two directions promptly: towards medical professionals to learn whether advertised drugs are more beneficial than ones now prescribed, and into cyberspace, at least to drug company or medication brand websites. Once on the Internet, consumers have the option to use ISEs to locate additional information for their consideration. However, little is known about the impact of emerging drug therapy information on patient inquiries or demand during physician consultations when patients, families, or friends discover that data via the Internet. Purpose: This research explores the ease of consumer access to information from ISEs regarding alternative drug therapies. Specifically, it examines access to data on Cerebrolysin, not yet approved by the federal Food and Drug Administration (FDA), amid the American policy paradox of open consumer access to international Internet health care information as constrained by federal advertising regulation and by ISE algorithms. Problem Statement: Patients often seek Internet information to learn about the risks and benefits of current medications or potentials ones to ease symptoms. In regulated pharmaceutical markets, alternate therapy Internet searches traditionally yield additional approved medications that the patient is not currently using, but may be safe and more effective, if a prescriber agrees. Unregulated therapy information includes polar opposites. It may contain controversial or untested treatments that intrinsically pose no proven harm or may be illegal offers to sell medication without prescriptions, biased reports intended to sway consumers away from reliable regiments, or self-reports of personal experiences with traditional or untraditional methods that make unsolicited recommendations. However, information regarding emerging drug therapies in trial or under consideration for admission into a new national market bridges both categories. Such drugs may be currently unaccepted for regulated use, but not worthy of categorical association with untested treatments, folly, or illegal activities. How accessible to consumers is information about emerging market medications via common search engines? Do ISE results for common Alzheimer s disease drugs produce different results for comparable search terms? Do consumers, providers, and pharmaceutical companies need to communicate differently about emerging drug therapies in cyberspace than for current FDA-approved drugs? Methods: Patient health-seeking behavior was simulated by entering categorical, direct, and indirect terms regarding Cerebrolysin into Google and searching with default preferences. Inquiry was limited to Alzheimer s disease applications. The top twenty search engine results for Cerebrolysin alone and with other keyword queries individually (such as memory and Alzheimer ) were analyzed categorically to assess the range and frequencies of information providers, communication focus, peripheral advertisements, and 30
website idiosyncrasies. The process was repeated for five drugs recognized by the Alzheimer Association as commonly used therapies: Aricept, Razadyne, Namenda, Exelon, and Cognex. In addition, Google was used to search for Cerebrolysin among clinical trials and drug research results. Univariate analysis methods were used to characterize categorical results. Results: ISEs provided 360 websites for analysis when drug-specific names were included among search terms. Of these results, 15.0% were omitted since the results were irrelevant to the product or merely offers to sell the regulated drugs online or term papers about the drug. In addition, 22 result pages (6.1%) contained peripheral advertisements, which ranged from shortcut links to official drug websites to offers of caregiver respite or support services. Of the remaining 306 relevant websites, 104 results contained information aimed primarily at medical providers, while 202 targeted the general public, including patients, their families, or advocates. Blogs or forums comprised 13 (3.6%) and medical research papers accounted for 44 (12.2%) of the 360 websites results. However, the distribution of medical, research, and online drug sale offers website results varied greatly for Cerebrolysin in comparison to FDA-approved drug ISE results, regardless of search terms used in addition to drug name. The average FDA-approved AD drug results contained 20.0% websites for medical professionals compared to 73.3% for Cerebrolysin. Further, 43.3% of Cerebrolysin results conveyed medical research studies compared to an average of 6.0% for other drugs studies. Both Aricept and Cerebrolysin ISE results yielded 11.7% results that were offers to sell the drugs online compared to a range of 1.7-5.0% for the others. Significantly, Cerebrolysin ISE results containing symptom or disease name yielded higher percentages of medical professional and professional research information, plus fewer offers to sell, than the search term Cerebrolysin alone (180-650% more scientific community information provided). No FDA-approved drug yielded the same response pattern. Since patients and caregivers may be unaware of Cerebrolysin, the search was repeated using generic keyword search terms: new Alzheimer s drug, new Alzheimer s medication, new Alzheimer s treatment, Alzheimer clinical trials, and Alzheimer drug research. No results addressed Cerebrolysin when the term new was used. Alzheimer clinical trials and Alzheimer drug research queries resulted in Cerebrolysin appearing once and twice, respectively. In both cases, the website presenting Cerebrolysin was a discussion site alzforum.org. Notably, ISE results in this keyword approach routinely contained information about drugs not yet approved by the FDA. Overall, consumers searching for new or alternative drug treatments for Alzheimer s disease have a low probability of finding information about Cerebrolysin unless they already know Cerebrolysin by name. However, when they search Cerebrolysin directly, they likely find a higher percentage of scientific and medical information about the drug than for other common AD drugs, but more opportunity to purchase it online. Implications: In order foramerican consumers and providers to learn about evolving medications in markets beyond geographical borders, pharmaceutical companies may need to develop relationships with informational intermediaries to gain exposure and product interest. Strategic Internet communication may lead to broader international trials or joint ventures to bring worthwhile products to needy consumers. Further research is needed to compare multiple emerging AD products from within and outside regulated markets. 31
UNDERSTANDING NEUROPLASTICITY:POSITIVE AND NEGATIVE OUTCOMES Dafin Fior Mureşanu Department of Neurology, Faculty of Health Sciences, University of Medicine and Pharmacy Iuliu Haţieganu, Cluj-Napoca, Romania Endogenous defense activity (EDA) of the nervous system is a polychronic continuous process that simultaneously performs activities of neurotrophicity, neuroprotection, neuroplasticity and neurogenesis (basic biological processes). Neurorecovery is the positive outcome producing clinically relevant results, with immediate functional and late structural effects. Immediate and late effects generate three types of changes: restitution, substitution and compensation. All basic biological processes can be naturally activated endogenously or exogenously. In order to successfully compete with pathophysiological processes and support recovery, EDA effects might be enhanced by: pharmacological support, physical means, electromagnetic stimulation, psychological support, environmental stimulation, stem cell transplantation or any demonstrated combinations of these factors capable of improving patient condition. Altered regulation of any of the four components of EDA may generate pathological conditions. In addition, altered neuroplasticity in the form of both up-regulation and down-regulation generates pathologies. The presentation will focus also on some potential pathological outcomes of neuroplasticity. 32
NEUROPROTECTIVE POTENTIAL OF QUINONE REDUCTASE 2 Gregory F. Oxenkrug Tufts University/Tufts Medical Center Boston, MA, USA Quinone Reductase 2 (QR2) (EC 1.10.99.2) distinguishes itself from other detoxifying and antioxidant enzymes. Firstly, inhibition (but not activation) of QR2 up-regulates the expression of cellular antioxidant enzymes and cellular resistance to oxidative stress. QR2 may transform certain quinone substrates into more highly reactive compounds capable of causing cellular damage. QR2 knockdown K562 cells exhibit increased antioxidant and detoxification enzyme expression. Secondly, human QR2 protein was identified as the same protein as low affinity binding site for melatonin (melatonin type 3 receptor, MT3). 5- methoxycarbonylamino-n-acetyltryptamine (5-MCA-NAT); N-acetylserotonin (NAS), immediate melatonin precursor; and prazosin (but not other alpha-1-adrenoblockers) reveal the higher that melatonin selectivity towards MT3. 5-MCA-NAT, resveratrol (3,4,5-trihydroxyestilbene), and prazosin specifically bind with the deep active-site cleft of QR2. Literature data suggest QR2/MT3 involvement in pathogenesis of glaucoma and such components of metabolic syndrome as inflammation, hypertension, and dyslipidemia. Our data suggest that QR2/MT3 might contribute to pathogenesis of major depressive disorder, another component of metabolic syndrome. 5-MCA-NAT, NAS and melatonin exert antidepressant-like activity (decrease duration of immobility) in tailsuspension test while prazosin attenuated their effects. Down-regulation of phospholipase A2 - arachidonic acid prostaglandin - 5-lipoxygenase leukotriene cascade and of kynurenine pathway of tryptophan metabolism might mediate clinical effects of QR2/MT3 agonists. Inhibition of the rate-limiting enzyme of kynurenine pathway, indoleamine 2,3-dihydroxygenase, by resveratrol (and may be by other QR2/MT3 agonists) might contribute to their neuroprotective action since most (but one) products of tryptophan - kynurenine pathway are N-methyl-D-aspartate agonists. QR2/MT3 might be a new pharmacological target for neuroprotective intervention. 33
A RAT MODEL OF PARKINSON' S DISEASE FOR TESTING NEUROPROTECTIVE DRUGS EFFECTS OF CEREBROLYSIN Bogdan O. Popescu 1,2, Radu Stoica 1, Maria Tuineag 1, Dafin F. Muresanu 3 1 Laboratory of Molecular Medicine, ' Victor Babeş' National Institute of Pathology, Bucharest, Romania 2 Department of Neurology, University Hospital Bucharest, ' Carol Davila' University of Medicine and Pharmacy, Bucharest, Romania 3 Department of Neurology, ' Iuliu Haţieganu' University of Medicine and Pharmacy, Cluj- Napoca, Romania Rotenone (ROT), 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP) and paraquat are mitochondrial complex I inhibitors used in different experimental models to induce parkinsonism and degeneration of nigrostriatal pathways. Validation of these models is important for testing new molecules with neuroprotective properties in order to offer premises for translation of the results in new clinical trials. In our study, we investigated the effect of a continuous infusion with the neurotrophic drug Cerebrolysin (CERE, Ebewe, Austria) on motor activity and dopaminergic cell depletion in ROT-exposed adult Wistar rats. CERE is a peptide mixture with neurotrophic effects demonstrated in both experimental and clinical studies. The model we used involves the implantation of each animal with two subcutaneous osmotic Alzet mini-pumps, which provide a constant release rate. The first pump was used to deliver ROT or sham for 28 days, the second pump being used for the administration of sham or CERE, as pre- or post-treatment related to ROT. The animals were tested for motor behavior in the open field box, at three time points. ROT treated animals showed reduced activity, less lines crossed, rearing and head dipping, as compared to the sham group. CERE + ROT treatment significantly increased the total rearing number at 28 days, as compared to ROT only. The histological examination of the nigral neurons is under current investigation. These preliminary data suggest a potential for clinical improvement with CERE of ROT-treated rats. 34
INSULIN AND INSULIN-RECEPTOR DYSFUNCTION IN AN ALZHEIMER MODEL 1 2 3 4 5 Peter Riederer, J. Osmanovic, K. Plaschke, M.B.H. Youdim, E. Sofic, 1 2 S. Hoyer; M. Salkovic 1 Clinic for Psychiatry, Psychosomatic and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany 2 Department of Pharmacology, School of Medicine and Croatian Institute for Brain Research, University of Zagreb, Croatia 3 University of Heidelberg, Anesthesiology, Germany 4 Technion-Rappaport Family Faculty of Medicine, Haifa,Israel 5 University of Sarajevo, Department of Chemistry, Sarajevo There is a consistent epidemiological evidence for an association between diabetes type II and sporadic Alzheimer s dementia (sad). A disturbed glucose metabolism has long been associated with sad. More recent molecular biological studies examining the insulin/insulin receptor cascade give evidence for this hypothesis. Experimental studies using the rat icv streptocotozin (STZ) model demonstrate that short-term application of STZ shows cognitive decline already two weeks later while histological hallmarks of sad are verified months later. Is sad based on an insulin resistant brain state? As corticosterone induced disturbance of the insulin/insulin receptor exerts similar results compared to STZ it is assumed that increased corticosterone/cortisol and noradrenaline due to chronic stress are metabolic parameters suitable to induce sad pathology. In line with increased environmental stress we have shown that oxidative stress (OS) parameters are significantly enhanced in the STZ-model. By blocking the production of radicals via M30 and HLA-20 we could demonstrate improvement of cognitive properties in such rats thus giving evidence for OS as part of the pathological cascade that underlies cognitive decline. 35