| 1. |
- Berglind, Fredrik, et al.
(författare)
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Neuronal activity dynamics in the dentate gyrus during early epileptogenesis
- 2023
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Ingår i: Epilepsy Research. - 0920-1211. ; 194
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Tidskriftsartikel (refereegranskat)abstract
- Epileptogenesis is a complex process involving a multitude of changes at the molecular, cellular and network level. Previous studies have identified several key alterations contributing to epileptogenesis and the development of hyper-excitability in different animal models, but only a few have focused on the early stages of this process. For post status epilepticus (SE) temporal lobe epilepsy in particular, understanding network dynamics during the early phases might be crucial for developing accurate preventive treatments to block the development of chronic spontaneous seizures. In this study, we used a viral vector mediated approach to examine activity of neurons in the dentate gyrus of the hippocampus during early epileptogenesis. We find that while granule cells are active 8 h after SE and then gradually decrease their activity, Calretinin-positive mossy cells and Neuropeptide Y-positive GABAergic interneurons in the hilus show a delayed activation pattern starting at 24 and peaking at 48 h after SE. These data suggest that indirect inhibition of granule cells by mossy cells through recruitment of local GABAergic interneurons could be an important mechanisms of excitability control during early epileptogenesis, and contribute to our understanding of the complex role of these cells in normal and pathological conditions.
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| 2. |
- 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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| 3. |
- Melin, Esbjörn
(författare)
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Advancing gene therapy for epilepsy. Translational pre-clinical studies with neuropeptide Y and glial cell-line derived neurotrophic factor.
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Epilepsy is a neurological disorder, affecting approximately 1% of the population. The high rate of drug-resistance in epilepsy in general (30%), and temporal lobe epilepsy (TLE) in particular, pose a serious clinical problem. Thus, novel treatments for drug-resistant epilepsy is highly warranted. Gene therapy has been suggested to be a promising approach to target drug-resistant focal epilepsy since it offers the opportunity of delivering therapeutic agents directly into the seizure focus, thereby possibly being more effective in suppressing seizures and causing less adverse effects than conventional anti-seizure drugs. Two endogenous proteins that have been shown to be able to modulate seizures when delivered by gene therapy are neuropeptide Y (NPY) through its interaction with the Y2 receptor and glial cell-line derived neurotrophic factor (GDNF). In this thesis, the seizure supressing potential of these two theraputic strategies was investigated in an animal model of TLE. In the case of combinatorial NPY and Y2 receptor, overexpression was achived via adeno-associated viral (AAV) vector mediated in-vivo gene therapy. GDNF levels were increased by ex-vivo gene therapy via encapsulated cell biodelivery (ECB). The efficacy studies were performed in a manner that is suggested to increase the translational value of the results. Thus, both strategies were evaluated by continous video-EEG monitoring in the intrahippocampal kainic acid (KA) rat model of post status epilepticus spontanous recurrent seizures (SRSs), which is considered to share pathopysiology with human TLE. Moreover, the treatments were individualized by MRI to target the hippocampal seizure focus, ipsilateral to the injection of KA.The results indicate that both combinatorial NPY and Y2 receptor overexpression and ECB of GDNF were capable of reducing the frequency of SRSs when administered unilaterally in the seizure focus, with a responder rate of 31.3% respective 50%. Moreover, AAV derived overexpression of the NPY and Y2 receptor moduated SRS clustering patterns by increasing the latency between individual SRSs, but also between SRS clusters. These findings further strengthes the translational potential for these gene therapy strategies of treating TLE.Finally, the insights from the work with the model contributed to an attemt at harmonizing experimental procedures and standardising data collection within the field of pre-clinical epilepsy research. The implementation of common data elements (CDEs) might serve as support for future multicenter studies, which would improve reproducibility and hopefully enhance translation of preclinical findings to the clinic.
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| 4. |
- Melin, Esbjörn, et al.
(författare)
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Disease Modification by Combinatorial Single Vector Gene Therapy : A Preclinical Translational Study in Epilepsy
- 2019
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Ingår i: Molecular Therapy - Methods and Clinical Development. - : Elsevier BV. - 2329-0501. ; 15, s. 179-193
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Tidskriftsartikel (refereegranskat)abstract
- Gene therapy has been suggested as a plausible novel approach to achieve seizure control in patients with focal epilepsy that do not adequately respond to pharmacological treatment. We investigated the seizure-suppressant potential of combinatorial neuropeptide Y and Y2 receptor single vector gene therapy based on adeno-associated virus serotype 1 (AAV1) in rats. First, a dose-response study in the systemic kainate-induced acute seizure model was performed, whereby the 1012 genomic particles (gp)/mL titer of the vector was selected as an optimal concentration. Second, an efficacy study was performed in the intrahippocampal kainate chronic model of spontaneous recurrent seizures (SRSs), designed to reflect a likely clinical scenario, with magnetic resonance image (MRI)-guided focal unilateral administration of the vector in the hippocampus during the chronic stage of the disease. The efficacy study demonstrated a favorable outcome of the gene therapy, with a 31% responder rate (more than 50% reduction in SRS frequency) and 13% seizure-freedom rate, whereas no such effects were observed in the control animals. The inter-SRS and SRS cluster intervals were also significantly prolonged in the treated group compared to controls. In addition, the SRS duration was significantly reduced in the treated group but not in the controls. This study establishes the SRS-suppressant ability of the single vector combinatorial neuropeptide Y/Y2 receptor gene therapy in a clinically relevant chronic model of epilepsy.
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| 5. |
- Melin, Åsa
(författare)
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Olika vägar till enhetlig skola? : En studie av grundskolans etablering på kommunal nivå, 1950-1968
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The importance of the local community for the development of the school system during the 19th century has been touched upon by several researchers. However, interest in the changes to the school system in Sweden during the 1950s and 1960s has largely focused on developments at the national level. The picture has mostly been that the state, the formulating arena, set the rules and the municipalities, the realization arena, implemented nationally decided welfare policy. Here the interest is different; by focusing on municipal conditions and local interests, the implementation of political reforms, specifically the nine-year compulsory school, can be nuanced.By a case study comparing two municipalities in the county of Värmland, Storfors and Arvika, with different local conditions and traditions of education, this study aims to investigate and analyse the establishment of the nine-year compulsory school at the local level, thereby making local interests and the importance of local conditions visible for the establishment of the compulsory school.The processes in the two municipalities were affected by the state formulation arena's decisions but, as previous research has shown, there was a high degree of variation in how the school system was shaped locally. The same applies to local decision-making. It too was influenced and shaped based on local conditions. From the analysis of the process in Storfors and Arvika, three main results can be discerned: 1) the establishment of the primary school at the local level was largely about initiating and completing processes sideways, within and between municipalities, not only vertical processes between state and municipality. 2) The local tradition, which can also be called the local culture or the social mechanisms, influenced the processes in the two municipalities, and 3) the process in the local realization arena was largely driven by what we would call civil servants.
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| 6. |
- Nanobashvili, Avtandil, et al.
(författare)
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Unilateral ex vivo gene therapy by GDNF in epileptic rats
- 2019
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Ingår i: Gene Therapy. - : Springer Science and Business Media LLC. - 0969-7128 .- 1476-5462. ; 26:3-4, s. 65-74
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Tidskriftsartikel (refereegranskat)abstract
- Temporal lobe epilepsy (TLE) is the most common type of epilepsy in adults. This neurological disorder is characterized by focal seizures originating in the temporal lobe, often with secondary generalization. A variety of pharmacological treatments exist for patients suffering from focal seizures, but systemically administered drugs offer only symptomatic relief and frequently cause unwanted side effects. Moreover, available drugs are ineffective in one third of the epilepsy patients. Thus, developing more targeted and effective treatment strategies for focal seizures, originating from, e.g., the temporal lobe, is highly warranted. In order to deliver potential anti-epileptic agents directly into the seizure focus we used encapsulated cell biodelivery (ECB), a specific type of ex vivo gene therapy. Specifically, we asked whether unilateral delivery of glial cell line-derived neurotrophic factor (GDNF), exclusively into the epileptic focus, would suppress already established spontaneous recurrent seizures (SRS) in rats. Our results show that GDNF delivered by ECB devices unilaterally into the seizure focus in the hippocampus effectively decreases the number of SRS in epileptic rats. Thus, our study demonstrates that focal unilateral delivery of neurotrophic factors, such as GDNF, using ex vivo gene therapy based on ECB devices could be an effective anti-epileptic strategy providing a bases for the development of a novel, alternative, treatment for focal epilepsies.
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| 7. |
- Nikitidou, Litsa, et al.
(författare)
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Translational approach for gene therapy in epilepsy: Model system and unilateral overexpression of neuropeptide Y and Y2 receptors.
- 2016
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 86:nov 19, s. 52-61
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Tidskriftsartikel (refereegranskat)abstract
- Although novel treatment strategies based on the gene therapy approach for epilepsy has been encouraging, there is still a gap in demonstrating a proof-of-concept in a clinically relevant animal model and study design. In the present study, a conceptually novel framework reflecting a plausible clinical trial for gene therapy of temporal lobe epilepsy was explored: We investigated (i) whether the post intrahippocampal kainate-induced status epilepticus (SE) model of chronic epilepsy in rats could be clinically relevant; and (ii) whether a translationally designed neuropeptide Y (NPY)/Y2 receptor-based gene therapy approach targeting only the seizure-generating focus unilaterally can decrease seizure frequency in this chronic model of epilepsy. Our data suggest that the intrahippocampal kainate model resembles the disease development of human chronic mesial temporal lobe epilepsy (mTLE): (i) spontaneous seizures originate in the sclerotic hippocampus; (ii) only a part of the animals develops chronic epilepsy; (iii) animals show largely variable seizure frequency that (iv) tends to progressively increase over time. Despite significant hippocampal degeneration caused by kainate injection, the use of MRI allowed targeting the recombinant adeno-associated viral (rAAV) vectors encoding NPY and Y2 receptor genes to the remaining dorsal and ventral hippocampal areas ipsilateral to the kainate injection. Continuous video-EEG monitoring demonstrated not only prevention of the progressive increase in seizure frequency in rAAV-NPY/Y2 treated animals as compared to the controls, but even 45% decrease of seizure frequency in 80% of the epileptic animals. This translationally designed study in a clinically relevant model of epilepsy suggests that simultaneous overexpression of NPY and Y2 receptors unilaterally in the seizure focus is a relevant and promising approach that can be further validated in more extensive preclinical studies to develop a future treatment strategy for severe, often pharmacoresistant focal epilepsy cases that cannot be offered alternative therapeutic options.
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| 8. |
- Ramos-Moreno, Tania, et al.
(författare)
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Collagen VI : Role in synaptic transmission and seizure-related excitability
- 2024
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Ingår i: Experimental Neurology. - 0014-4886. ; 380
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Tidskriftsartikel (refereegranskat)abstract
- Collagen VI (Col-VI) is an extracellular matrix protein primarily known for its bridging role in connective tissues that has been suggested to play a neuroprotective role. In the present study we report increased mRNA and protein expression of Col-VI in the hippocampus and cortex at a late stage of epileptogenesis in a post-status epilepticus (SE) model of epilepsy and in brain tissue from patients with epilepsy. We further present a novel finding that exposure of mouse hippocampal slices to Col-VI augments paired-pulse facilitation in Schaffer collateral-CA1 excitatory synapses indicating decreased release probability of glutamate. In line with this finding, lack of Col-VI expression in the knock-out mice show paired-pulse depression in these synapses, suggesting increased release probability of glutamate. In addition, we observed dynamic changes in Col-VI blood plasma levels in rats after Kainate-induced SE, and increased levels of Col-VI mRNA and protein in autopsy or postmortem brain of humans suffering from epilepsy. Thus, our data indicate that elevated levels of ColVI following seizures leads to attenuated glutamatergic transmission, ultimately resulting in less overall network excitability. Presumably, increased Col-VI may act as part of endogenous compensatory mechanism against enhanced excitability during epileptogenic processes in the hippocampus, and could be further investigated as a potential functional biomarker of epileptogenesis, and/or a novel target for therapeutic intervention.
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| 9. |
- Szczygieł, Julia Alicja, et al.
(författare)
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Gene Therapy Vector Encoding Neuropeptide Y and Its Receptor Y2 for Future Treatment of Epilepsy : Preclinical Data in Rats
- 2020
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Ingår i: Frontiers in Molecular Neuroscience. - : Frontiers Media SA. - 1662-5099. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Gene therapy to treat pharmacoresistant temporal lobe epilepsy in humans is now being developed using an AAV vector (CG01) that encodes the combination of neuropeptide Y and its antiepileptic receptor Y2. With this in mind, the present study aimed to provide important preclinical data on the effects of CG01 on the duration of transgene expression, cellular tropism, and potential side effects on body weight and cognitive function. The CG01 vector was administered unilaterally into the dorsal and ventral hippocampus of adult male rats and expression of both transgenes was found to remain elevated without a sign of decline at 6 months post-injection. CG01 appeared to mediate expression selectively in hippocampal neurons, without expression in astrocytes or oligodendrocytes. No effects were seen on body weight as well as on short- or long-term memory as revealed by testing in the Y-maze or Morris water maze tests. Thus these data show that unilateral CG01 vector treatment as future gene therapy in pharmacoresistant temporal lobe epilepsy patients should result in stable and long-term expression predominantly in neurons and be well tolerated without side effects on body weight and cognitive function.
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