Seizure Suppression by GDNF Gene Therapy in Animal Models of Epilepsy

Experimental Epilepsy Group, Wallenberg Neuroscience Center, Lund University Hospital, Lund, Sweden.
Molecular Therapy (Impact Factor: 6.23). 07/2007; 15(6):1106-13. DOI: 10.1038/
Source: PubMed


Temporal lobe epilepsy patients remain refractory to available anti-epileptic drugs in 30% of cases, indicating a need for novel therapeutic strategies. In this context, glial cell line-derived neurotrophic factor (GDNF) emerges as a possible new agent for epilepsy treatment. However, a limited number of studies, use of different epilepsy models, and different methods of GDNF delivery preclude understanding of the mechanisms for the seizure-suppressant action of GDNF. Here we show that recombinant adeno-associated viral (rAAV) vector-based GDNF overexpression in the rat hippocampus suppresses seizures in two models of temporal lobe epilepsy. First, when rAAV-GDNF was injected before hippocampal kindling, the number of generalized seizures decreased, and the prolongation of behavioral convulsions in fully kindled animals was prevented. Second, injection of rAAV-GDNF after kindling increased the seizure induction threshold. Third, rAAV-GDNF decreased the frequency of generalized seizures during the self-sustained phase of status epilepticus. Our data demonstrate the complexity of mechanisms and the beneficial action of GDNF in epilepsy. Furthermore, we show that ectopic rAAV-mediated GDNF gene expression in the seizure focus is a feasible way to mitigate seizures and provides proof of principle that the neurotrophic factor-based gene therapy approach has the potential to be developed as alternative strategy for epilepsy treatment.

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Available from: Merab Kokaia, Mar 24, 2014
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    • "In that study, adequate numbers of donor cells for grafting in epilepsy were obtained by expanding MGE-derived NSCs in dishes as neurospheres. Transplanted cells differentiated into significant numbers of GABAergic interneurons and anticonvulsant neurotrophic factor GDNF-expressing astrocytes [49], which produced a sustained antiseizure effect over a prolonged period of time in a chronic TLE model. However, prior to clinical application of MGE-derived NSCs, developing additional cell grafting methods will be necessary for enhancing the production of graft-derived GABAergic neurons, the level of overall seizure suppression, and the cognitive performance. "
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    ABSTRACT: Cell transplantation has been suggested as an alternative therapy for temporal lobe epilepsy (TLE) because this can suppress spontaneous recurrent seizures in animal models. To evaluate the therapeutic potential of human neural stem/progenitor cells (huNSPCs) for treating TLE, we transplanted huNSPCs, derived from an aborted fetal telencephalon at 13 weeks of gestation and expanded in culture as neurospheres over a long time period, into the epileptic hippocampus of fully kindled and pilocarpine-treated adult rats exhibiting TLE. In vitro, huNSPCs not only produced all three central nervous system neural cell types, but also differentiated into ganglionic eminences-derived γ-aminobutyric acid (GABA)-ergic interneurons and released GABA in response to the depolarization induced by a high K+ medium. NSPC grafting reduced behavioral seizure duration, afterdischarge duration on electroencephalograms, and seizure stage in the kindling model, as well as the frequency and the duration of spontaneous recurrent motor seizures in pilocarpine-induced animals. However, NSPC grafting neither improved spatial learning or memory function in pilocarpine-treated animals. Following transplantation, grafted cells showed extensive migration around the injection site, robust engraftment, and long-term survival, along with differentiation into β-tubulin III+ neurons (∼34%), APC-CC1+ oligodendrocytes (∼28%), and GFAP+ astrocytes (∼8%). Furthermore, among donor-derived cells, ∼24% produced GABA. Additionally, to explain the effect of seizure suppression after NSPC grafting, we examined the anticonvulsant glial cell-derived neurotrophic factor (GDNF) levels in host hippocampal astrocytes and mossy fiber sprouting into the supragranular layer of the dentate gyrus in the epileptic brain. Grafted cells restored the expression of GDNF in host astrocytes but did not reverse the mossy fiber sprouting, eliminating the latter as potential mechanism. These results suggest that human fetal brain-derived NSPCs possess some therapeutic effect for TLE treatments although further studies to both increase the yield of NSPC grafts-derived functionally integrated GABAergic neurons and improve cognitive deficits are still needed.
    PLoS ONE 08/2014; 9(8):e104092. DOI:10.1371/journal.pone.0104092 · 3.23 Impact Factor
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    • "The method was described previously (Kanter-Schlifke et al., 2007; Sørensen et al., 2009). Animals were anesthetized by intraperitoneal (i.p.) injection of s-ketamine (80 mg/kg; Pfizer Inc., New York, NY) and xylazine (15 mg/kg; Sigma- Aldrich, St. Louis, MO), as well as a solution containing temgesic (0.06 mg/kg; Schering-Plough), rimadyl (5 mg/kg; Pfizer Aps), and baytril (10 mg/kg; Bayer HealthCare), and placed into a stereotaxic frame (Kopf Instruments). "
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    ABSTRACT: Neuropeptide Y (NPY) exerts anxiolytic- and antidepressant-like effects in rodents that appear to be mediated via Y1 receptors. Gene therapy using recombinant viral vectors to induce overexpression of NPY in the hippocampus or amygdala has previously been shown to confer anxiolytic-like effect in rodents. The present study explored an alternative and more specific approach: overexpression of Y1 receptors. Using a recombinant adeno-associated viral vector (rAAV) encoding the Y1 gene (rAAV-Y1), we, for the first time, induced overexpression of functional transgene Y1 receptors in the hippocampus of adult mice and tested the animals in anxiety- and depression-like behavior. Hippocampal Y1 receptors have been suggested to mediate seizure-promoting effect, so the effects of rAAV-induced Y1 receptor overexpression were also tested in kainate-induced seizures. Y1 receptor transgene overexpression was found to be associated with modest anxiolytic-like effect in the open field and elevated plus maze tests, but no effect was seen on depression-like behavior using the tail suspension and forced swim tests. However, the rAAV-Y1 vector modestly aggravated kainate-induced seizures. These data indicate that rAAV-induced overexpression of Y1 receptors in the hippocampus could confer anxiolytic-like effect accompanied by a moderate proconvulsant adverse effect. Further studies are clearly needed to determine whether Y1 gene therapy might have a future role in the treatment of anxiety disorders.
    Journal of Neuroscience Research 02/2012; 90(2):498-507. DOI:10.1002/jnr.22770 · 2.59 Impact Factor
    • "On the other hand, the transplanted cells could provide the epileptic brain with a number of trophic factors (Borlongan et al., 2004). It has been shown in the hippocampus of epileptic rats that trophic factors such as fibroblast growth factor 2 (FGF-2), brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) can reduce epileptogenesis (Eves et al., 2001; Kanter-Schlifke et al., 2007; Rao et al., 2006). Furthermore, growth factors that have been identified in hematopoiesis and angiogenesis – such as erythropoietin (EPO) and granulocyte colony-stimulating growth factor (G-CSF) – are currently being re-considered as therapeutic agents in a number of neurological diseases (Chu et al., 2008; Li et al., 2009a; Maurer et al., 2008; Minnerup et al., 2008). "
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    ABSTRACT: AimsEpilepsy affects 0.5–1% of the world's population, and approximately a third of these patients are refractory to current medication. Given their ability to proliferate, differentiate and regenerate tissues, stem cells could restore neural circuits lost during the course of the disease and reestablish the physiological excitability of neurons. This study verified the therapeutic potential of bone marrow mononuclear cells (BMMCs) on seizure control and cognitive impairment caused by experimentally induced epilepsy.Main methodsStatus epilepticus (SE) was induced by lithium–pilocarpine injection and controlled with diazepam 90 min after SE onset. Lithium–pilocarpine-treated rats were intravenously transplanted 22 days after SE with BMMCs obtained from enhanced green fluorescent protein (eGFP) transgenic C57BL/6 mice. Control epileptic animals were given an equivalent volume of saline or fibroblast injections. Animals were video-monitored for the presence of spontaneous recurrent seizures prior to and following the cell administration procedure. In addition, rats underwent cognitive evaluation using a Morris water maze.Key findingsOur data show that BMMCs reduced the frequency of seizures and improved the learning and long-term spatial memory impairments of epileptic rats. EGFP-positive cells were detected in the brains of transplanted animals by PCR analysis.SignificanceThe positive behavioral effects observed in our study indicate that BMMCs could represent a promising therapeutic option in the management of chronic temporal lobe epilepsy.
    Life sciences 06/2011; 89(7-8):229-234. DOI:10.1016/j.lfs.2011.06.006 · 2.70 Impact Factor
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