EPITARGET Kick-Off Meeting on 30-31 January 2014 in Lund
The whole EPITARGET Consortium kicked off the project at the end of January 2014. The meeting was hosted by the coordinating institution Lund University and was held in the historical Old Bishop's House in Lund, Sweden. Altogether 48 attendees met at this meeting, including numerous young investigators and members of the EPITARGET Scientific Advisory Board.
EPITARGET Satellite Workshop on 24 September 2014 at the AMC in Amsterdam
On 24 September 2014 an EPITARGET satellite workshop associated with the annual General Assembly Meeting was held in Amsterdam. The workshop was hosted by EPITARGET partner Academisch Medisch Centrum (AMC) and was held in the facilities of the AMC. The title of the workshop was Anti-epileptogenesis and disease modification: Clinical Targets and Pre-Clinical Models. Apart from speakers from within the Consortium and the SAB of EPITARGET, two guest speakers from outside the consortium were invited (Ype Elgersma, Erasmus MC and Roland Krause, University of Luxembourg).
2nd General Assembly Meeting in Amsterdam on 25-26 September 2014
The 2nd General Assembly and 3rd Steering Committee Meeting of EPITARGET took place in Amsterdam from 25 to 26 September. Attendance was excellent, with 49 scientists from all participating groups present. Presentations of the project progress by all workpackages alternated with breakout sessions, which were utilized for in-depth discussions of specific challenges encountered in the project. We are looking forward to the next EPITARGET meeting in Milan!
Brandt C, Töllner K, Klee R, Bröer S, Löscher W. Effective termination of status epilepticus by rational polypharmacy in the lithium pilocarpine model in rats: Window of opportunity to prevent epilepsy and prediction of epilepsy by biomarkers. Neurobiol Dis. 2014 Dec 27;75C:78-90.
In the pilocarpine model, which is widely used to study status epilepticus (SE) and epileptogenesis, SE duration is commonly restricted to 30-90 min by injection of anticonvulsants to reduce mortality, but SE typically recurs, thus forming a bias for studies on epilepsy prevention. When using a drug cocktail (diazepam, phenobarbital, scopolamine), SE could be completely and permanently terminated, which led to prevention of epilepsy when SE was interrupted after 60 min, whereas longer SE (90 and 120 min) induced epilepsy. By comparing rats that did and did not develop epilepsy after pilocarpine, we found that decrease in seizure threshold, behavioral hyperexcitability, and neurodegeneration in the dentate gyrus were associated with development of epilepsy.
Weissberg I, Veksler R, Kamintsky L, Saar-Ashkenazy R, Milikovsky DZ, Shelef I, Friedman A. Imaging Blood-Brain Barrier Dysfunction in Football Players. JAMA Neurol. 2014 Nov;71(11):1453-5.
To test the potential of imaging BBB integrity in human patients we established a new approach for a quantitative assessment of BBB permeability using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). We implemented the method in concussed American football players and were able to clearly divide all study participants (16 football players and 13 non-contact sports athletes) into an intact-BBB group and a pathological-BBB group, with the pathological-BBB group consisting almost exclusively of football players. Our findings indicate a clear association between football and increased risk of BBB pathology.
Friedman A, Bar-Klein G, Serlin Y, Parmet Y, Heinemann U, Kaufer D. Should losartan be administered following brain injury? Expert Rev Neurother. 2014 Dec;14(12):1365-75.
Having shown that losartan blocks TGF-b signaling in the brain and prevents epilepsy in BBB dysfunction models of epilepsy, we set out to evaluate the potential of such preventive treatments following brain injury in man. We highlight the challenges of designing clinical trials testing the efficacy of these therapies without the ability to diagnose patients at risk of developing epilepsy (or other complications) after brain injury. We stress that reliable diagnostics are a pre-requisite to clinically testing neuroprotective treatments, and elaborate on the potential of BBB imaging as a novel biomarker.
Schoknecht K, Prager O, Vazana U, Kamintsky L, Harhausen D, Zille M, Figge L, Chassidim Y, Schellenberger E, Kovács R, Heinemann U, Friedman A. Monitoring stroke progression: in vivo imaging of cortical perfusion, blood brain barrier permeability and cellular damage in the rat photothrombosis model. J Cereb Blood Flow Metab. 2014 Nov;34(11):1791-801.
In this study we set out to develop new imaging methods for studying BBB pathology in experimental rodents in vivo, allowing parallel imaging of BBB dysfunction and associated pathological mechanisms, including: free radical formation, cellular injury and cortical perfusion. We demonstrate the new approach in a rat model of BBB dysfunction following vascular occlusion, showing that BBB dysfunction propagates dynamically in the first hours after stroke and is associated with free radical formation and cellular injury.
Zucchini S, Marucci G, Paradiso B, Lanza G, Roncon P, Cifelli P, Ferracin M, Giulioni M, Michelucci R, Rubboli G, Simonato M. Identification of miRNAs differentially expressed in human epilepsy with or without granule cell pathology. PLoS One. 2014 Aug 22;9(8):e105521
The microRNAs (miRNAs) are non-coding RNAs that regulate expression of target mRNAs. miRNAs differentially expressed under pathological conditions may help identifying mechanisms underlying the disease and may represent biomarkers with prognostic value. Here, we examined the expression of more than 1000 miRNAs in the dentate granule cell layer of patients that underwent surgery for intractable temporal lobe epilepsy and were divided in two groups depending on the absence or presence of granule cell pathology (granule cell layer dispersion or bilamination). Twelve miRNAs were differentially expressed in the two groups, and one of these, miR487a, was confirmed to be expressed at highly differential levels in an extended cohort of patients. Bioinformatics searches and biological verification identified ANTXR1 as a possible target of miR487a. ANTXR1 may be directly implicated in granule cell dispersion because it is an adhesion molecule that favors cell spreading. Thus, miR487a could be the first identified element of a miRNA signature that may be useful for prognostic evaluation of post-surgical epilepsy and may drive mechanistic studies leading to the identification of therapeutic targets.
Simonato M, Brooks-Kayal AR , Engel J Jr., Galanopoulou AS, Jensen FE, Moshé SL, O’Brien TJ, Pitkanen A, Wilcox KS, French JA. The challenge and promise of epilepsy therapy development in animal models. Lancet Neurol. 2014 Sep;13(9):949-60.
Translating successful target or compound validation studies into clinically effective therapies for epilepsies is a major challenge, with potential for costly clinical trial failures. To date, availability of predictive animal models has led to development of many effective antiseizure therapies that are routinely used in clinical practice, demonstrating that translation has been very successful in the epilepsy field. There still are, however, several important unmet therapeutic needs: current therapies do not fully control seizures in a third of patients and produce significant side effects; no treatment can prevent development of epilepsy in at-risk patients; no specific treatment for epilepsy-associated comorbidities exists. The aim of this article was to redesign the current translational approaches to meet these demands.
van Vliet EA, Aronica E, Gorter JA. The role of the blood-brain barrier in temporal lobe epilepsy and pharmacoresistance. Neuroscience. 2014 Sep 26;277:455-73.
Leakage of blood components and upregulation of multidrug transporters has been observed in brain tissue of people with epilepsy as well as in experimental epilepsy models. This blood-brain barrier dysfunction has been associated with the development and progression of epilepsy (epileptogenesis) as well as the development of drug resistance. Therefore, the blood-brain barrier has received renewed interest during the last decade as a potential target to treat epilepsy or its progression. In this review we will discuss the role of the blood-brain barrier in epilepsy and drug resistance and summarize potential new therapies that may restore normal BBB function.
Kulbida R, Wang Y, Mandelkow EM, Schoch S, Becker AJ, van Loo KM. Molecular imaging reveals epileptogenic Ca2+-channel promoter activation in hippocampi of living mice. Brain Struct Funct. 2014 Jun 3. [Epub ahead of print]:
The expression of a bioluminescent reporter under control of the Calcium Channel promoter allows repetitive measurements of promoter activity in the same living mice. This approach allows more robust analyses and saves experimental animal lives. It also allows us to assess molecular cascades important in the development of epilepsy in living rodents over time.
Bar-Klein G, Cacheaux LP, Kamintsky L, Prager O, Weissberg I, Schoknecht K, Cheng P, Kim SY, Wood L, Heinemann U, Kaufer D, Friedman A. Losartan prevents acquired epilepsy via TGF-β signaling suppression. Ann Neurol. 2014 Jun;75(6):864-75.
The goal of this study was to test whether the development of post-traumatic epilepsy (PTE) may be prevented. As our earlier studies revealed the involvement of BBB damage and TGF-β signaling in the development of PTE, we hypothesized that blocking the TGF-β pathway may prevent the disease. Indeed, we found that losartan (Cozaar®, approved to treat high blood pressure) is able to inhibit TGF-β signaling in the brain and prevent the majority of epilepsy cases in the rodent blood-brain barrier (BBB) disruption models of PTE.