| 1. |
- Lapinlampi, Niina, et al.
(författare)
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Common data elements and data management : Remedy to cure underpowered preclinical studies
- 2017
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Ingår i: Epilepsy Research. - : Elsevier BV. - 0920-1211. ; 129, s. 87-90
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Tidskriftsartikel (refereegranskat)abstract
- Lack of translation of data obtained in preclinical trials to clinic has kindled researchers to develop new methodologies to increase the power and reproducibility of preclinical studies. One approach relates to harmonization of data collection and analysis, and has been used for a long time in clinical studies testing anti-seizure drugs. EPITARGET is a European Union FP7-funded research consortium composed of 18 partners from 9 countries. Its main research objective is to identify biomarkers and develop treatments for epileptogenesis. As the first step of harmonization of procedures between laboratories, EPITARGET established working groups for designing project-tailored common data elements (CDEs) and case report forms (CRFs) to be used in data collection and analysis. Eight major modules of CRFs were developed, presenting >1000 data points for each animal. EPITARGET presents the first single-project effort for harmonization of preclinical data collection and analysis in epilepsy research. EPITARGET is also anticipating the future challenges and requirements in a larger-scale preclinical harmonization of epilepsy studies, including training, data management expertise, cost, location, data safety and continuity of data repositories during and after funding period, and incentives motivating for the use of CDEs.
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| 2. |
- Mikroulis, Apostolos, et al.
(författare)
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Lipid mediator n-3 docosapentaenoic acid-derived protectin D1 enhances synaptic inhibition of hippocampal principal neurons by interaction with a G-protein-coupled receptor
- 2022
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Ingår i: FASEB Journal. - 0892-6638. ; 36:3
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Tidskriftsartikel (refereegranskat)abstract
- Epilepsy is a severe neurological disease manifested by spontaneous recurrent seizures due to abnormal hyper-synchronization of neuronal activity. Epilepsy affects about 1% of the population and up to 40% of patients experience seizures that are resistant to currently available drugs, thus highlighting an urgent need for novel treatments. In this regard, anti-inflammatory drugs emerged as potential therapeutic candidates. In particular, specific molecules apt to resolve the neuroinflammatory response occurring in acquired epilepsies have been proven to counteract seizures in experimental models, and humans. One candidate investigational molecule has been recently identified as the lipid mediator n-3 docosapentaenoic acid-derived protectin D1 (PD1n-3DPA) which significantly reduced seizures, cell loss, and cognitive deficit in a mouse model of acquired epilepsy. However, the mechanisms that mediate the PD1n-3DPA effect remain elusive. We here addressed whether PD1n-3DPA has direct effects on neuronal activity independent of its anti-inflammatory action. We incubated, therefore, hippocampal slices with PD1n-3DPA and investigated its effect on excitatory and inhibitory synaptic inputs to the CA1 pyramidal neurons. We demonstrate that inhibitory drive onto the perisomatic region of the pyramidal neurons is increased by PD1n-3DPA, and this effect is mediated by pertussis toxin-sensitive G-protein coupled receptors. Our data indicate that PD1n-3DPA acts directly on inhibitory transmission, most likely at the presynaptic site of inhibitory synapses as also supported by Xenopus oocytes and immunohistochemical experiments. Thus, in addition to its anti-inflammatory effects, PD1n-3DPA anti-seizure and neuroprotective effects may be mediated by its direct action on neuronal excitability by modulating their synaptic inputs.
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| 3. |
- Noe, Francesco M., et al.
(författare)
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Gene therapy of focal-onset epilepsy by adeno-associated virus vector-mediated overexpression of neuropeptide Y
- 2010
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Ingår i: Epilepsia. - : Wiley. - 0013-9580. ; 51, s. 96-96
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Tidskriftsartikel (refereegranskat)abstract
- P>Adeno-associated virus (AAV)-mediated neuropeptide Y (NPY) overexpression in areas of seizure onset or generalization may be effective for the treatment of pharmacoresistant seizures in focal onset epilepsy. NPY overexpression mediates anticonvulsant activity in various seizures models and antiepileptogenic effects in kindling. Side effects are limited thus suggesting that this therapeutic approach could be effective and relatively safe. For an expanded treatment of this topic see Jasper's basic mechanisms of the epilepsies. 4th ed. (Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, eds) published by Oxford University Press (available on the National Library of Medicine Bookshelf [NCBI] at http://www.ncbi.nlm.nih.gov/books).
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| 4. |
- Pitkänen, Asla, et al.
(författare)
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Advances in the development of biomarkers for epilepsy
- 2016
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Ingår i: Lancet Neurology. - 1474-4422. ; 15:8, s. 843-856
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Forskningsöversikt (refereegranskat)abstract
- Over 50 million people worldwide have epilepsy. In nearly 30% of these cases, epilepsy remains unsatisfactorily controlled despite the availability of over 20 antiepileptic drugs. Moreover, no treatments exist to prevent the development of epilepsy in those at risk, despite an increasing understanding of the underlying molecular and cellular pathways. One of the major factors that have impeded rapid progress in these areas is the complex and multifactorial nature of epilepsy, and its heterogeneity. Therefore, the vision of developing targeted treatments for epilepsy relies upon the development of biomarkers that allow individually tailored treatment. Biomarkers for epilepsy typically fall into two broad categories: diagnostic biomarkers, which provide information on the clinical status of, and potentially the sensitivity to, specific treatments, and prognostic biomarkers, which allow prediction of future clinical features, such as the speed of progression, severity of epilepsy, development of comorbidities, or prediction of remission or cure. Prognostic biomarkers are of particular importance because they could be used to identify which patients will develop epilepsy and which might benefit from preventive treatments. Biomarker research faces several challenges; however, biomarkers could substantially improve the management of people with epilepsy and could lead to prevention in the right person at the right time, rather than just symptomatic treatment.
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| 5. |
- Toft Sörensen, Andreas, et al.
(författare)
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NPY gene transfer in the hippocampus attenuates synaptic plasticity and learning.
- 2008
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Ingår i: Hippocampus. - : Wiley. - 1050-9631 .- 1098-1063. ; 18:6, s. 564-574
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Tidskriftsartikel (refereegranskat)abstract
- Recombinant adeno-associated viral (rAAV) vector-induced neuropeptide Y (NPY) overexpression in the hippocampus exerts powerful antiepileptic and antiepileptogenic effects in rats. Such gene therapy approach could be a valuable alternative for developing new antiepileptic treatment strategies. Future clinical progress, however, requires more detailed evaluation of possible side effects of this treatment. Until now it has been unknown whether rAAV vector-based NPY overexpression in the hippocampus alters normal synaptic transmission and plasticity, which could disturb learning and memory processing. Here we show, by electrophysiological recordings in CA1 of the hippocampal formation of rats, that hippocampal NPY gene transfer into the intact brain does not affect basal synaptic transmission, but slightly alters short-term synaptic plasticity, most likely via NPY Y2 receptor-mediated mechanisms. In addition, transgene NPY seems to be released during high frequency neuronal activity, leading to decreased glutamate release in excitatory synapses. Importantly, memory consolidation appears to be affected by the treatment. We found that long-term potentiation (LTP) in the CA1 area is partially impaired and animals have a slower rate of hippocampal-based spatial discrimination learning. These data provide the first evidence that rAAV-based gene therapy using NPY exerts relative limited effect on synaptic plasticity and learning in the hippocampus, and therefore this approach could be considered as a viable alternative for epilepsy treatment. (c) 2008 Wiley-Liss, Inc.
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