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Coronal rat brain sections (Nissl stained or bisbenzimide fluorescence) showing the STN implanted with a cell suspension of GABA-producing cells overexpressing hGAD (isoform 67; Clone-4). Rectangles depict areas that are shown in higher magnification below, respectively. The section indicated as "Merged" shows a merged picture of the respective thionine and bisbenzimide staining given above. The hGAD-overexpressing cells shown here exemplarily were transplanted using either the glass microcapillary system (upper left) or the Hamilton syringe system (lower left and right). Rats were perfused at 10/11 days (10d), 3 weeks (not illustrated), or 5 weeks (5wk) after grafting. Note the more or less pronounced tissue reactions caused by grafting of the hGAD-overexpressing cells. Nevertheless, viable cells still were detected 5 weeks after transplantation. Scale bars: 500 µm on panels with lower magnification and 200 µm on panels with higher magnification. cp, cerebral peduncle.

Coronal rat brain sections (Nissl stained or bisbenzimide fluorescence) showing the STN implanted with a cell suspension of GABA-producing cells overexpressing hGAD (isoform 67; Clone-4). Rectangles depict areas that are shown in higher magnification below, respectively. The section indicated as "Merged" shows a merged picture of the respective thionine and bisbenzimide staining given above. The hGAD-overexpressing cells shown here exemplarily were transplanted using either the glass microcapillary system (upper left) or the Hamilton syringe system (lower left and right). Rats were perfused at 10/11 days (10d), 3 weeks (not illustrated), or 5 weeks (5wk) after grafting. Note the more or less pronounced tissue reactions caused by grafting of the hGAD-overexpressing cells. Nevertheless, viable cells still were detected 5 weeks after transplantation. Scale bars: 500 µm on panels with lower magnification and 200 µm on panels with higher magnification. cp, cerebral peduncle.

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Article
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Neural transplantation of GABA-producing cells into key structures within seizuresuppressing circuits holds promise for medication-resistant epileptic patients not eligible for resection of the epileptic focus. Especially the substantia nigra pars reticulata (SNr), a basal ganglia output structure, is well-known to modulate different seizure types....

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Context 1
... to (but clearly less pronounced than) previous findings after grafting into the SNr in amygdala- kindled rats (63), transplantation of the hGAD-overex- pressing cell line (Clone-4) caused tissue reactions within the host brain (Fig. 4). These tissue reactions appeared as cell accumulations, which were not restricted to the STN but additionally involved surrounding areas (Fig. 4). The tissue reactions caused by grafting of hGAD-over- expressing cells were characterized in detail previously (63). They involved infiltrating inflammatory cells and neuronal loss without ...
Context 2
... than) previous findings after grafting into the SNr in amygdala- kindled rats (63), transplantation of the hGAD-overex- pressing cell line (Clone-4) caused tissue reactions within the host brain (Fig. 4). These tissue reactions appeared as cell accumulations, which were not restricted to the STN but additionally involved surrounding areas (Fig. 4). The tissue reactions caused by grafting of hGAD-over- expressing cells were characterized in detail previously (63). They involved infiltrating inflammatory cells and neuronal loss without tumor formation (63). In this previ- ous study, no surviving Clone-4 cells were detected 4 to 8 weeks after transplantation. Using preincubation of ...
Context 3
... tumor formation (63). In this previ- ous study, no surviving Clone-4 cells were detected 4 to 8 weeks after transplantation. Using preincubation of the cells with bisbenzimide, we now show that even in rats showing a more pronounced tissue reaction, viable trans- planted cells could be observed within the STN at least up to 5 weeks after grafting (Fig. ...
Context 4
... in the present study the PTZ seizure threshold was raised by 27% and 52% (myoclonic twitch and clonus, respec- tively) at the same time point after grafting (10/11 days) of M213-2O cells bilaterally into the STN and compared to grafting of the control cell line 121-1I. Even unilater- ally localized M213-2O grafts within the STN still raised -4), and non-GABAergic cells (121-1I) localized bilaterally or unilaterally within the subthalamic nucleus (STN), or bilaterally outside the STN. Sample sizes are given within the bars. ...

Citations

... Genetic or transgenic mice such as Kv1.1 mutation which associates with human episodic ataxia type 1 and focal cortical epilepsy, and Stargazer (stg) transgenic mouse model of absence epilepsy have been applied to explore the therapeutic effects on epilepsy by transplantation of GABAergic interneurons into the brain (Baraban et al., 2009;Hammad et al., 2015). Pentylenetetrazole and picrotoxin rodent models are acute seizure models that can be used to evaluate the anticonvulsant effects of cell-based therapy (Handreck et al., 2014;de Gois da Silva et al., 2018). ...
Article
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Epilepsy is a common disabling chronic neurological disorder characterized by an enduring propensity for the generation of seizures that result from abnormal hypersynchronous firing of neurons in the brain. Over 20–30% of epilepsy patients fail to achieve seizure control or soon become resistant to currently available therapies. Prolonged seizures or uncontrolled chronic seizures would give rise to neuronal damage or death, astrocyte activation, reactive oxygen species production, and mitochondrial dysfunction. Stem cell therapy is potentially a promising novel therapeutic strategy for epilepsy. The regenerative properties of stem cell-based treatment provide an attractive approach for long-term seizure control, particularly in drug-resistant epilepsy. Embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), neural stem cells (NSCs), induced pluripotent stem cells (iPSCs), and adipose-derived regenerative cells (ADRCs) are capable of differentiating into specialized cell types has been applied for epilepsy treatment in preclinical animal research and clinical trials. In this review, we focused on the advances in stem cell therapy for epilepsies. The goals of stem cell transplantation, its mechanisms underlying graft effects, the types of grafts, and their therapeutic effects were discussed. The cell and animal models used for investigating stem cell technology in epilepsy treatment were summarized.
... Interneuron implantation has been shown to be beneficial in epilepsy as well. Implantation in TLE, absence epilepsy, and generalized epilepsy models in rodents was able to increase seizure threshold, reduce seizure frequency and duration, reduce network excitability, and improve behavioral deficits (270)(271)(272)(273). Implanting interneurons derived from human induced pluripotent stem cell (hiPSC) into the hippocampus of TLE rat model was able to reduce spontaneous seizures frequency after status epilepticus (274)(275)(276) which shows translational significance from rodents to humans. ...
Article
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There has been a major emphasis on defining the role of seizures in the causation of cognitive impairments like memory deficits in epilepsy. Here we focus on an alternative hypothesis behind these deficits, emphasizing the mechanisms of information processing underlying healthy cognition characterized as rate, temporal and population coding. We discuss the role of the underlying etiology of epilepsy in altering neural networks thereby leading to both the propensity for seizures and the associated cognitive impairments. In addition, we address potential treatments that can recover the network function in the context of a diseased brain, thereby improving both seizure and cognitive outcomes simultaneously. This review shows the importance of moving beyond seizures and approaching the deficits from a system-level perspective with the guidance of network neuroscience.
... Although not directly compared, a cell transplantation study also indicated that bilateral grafting of an inhibitory cell line into the STN might be more effective in raising seizure thresholds than placing the same cell line bilaterally into the SNr [233]. ...
... We currently investigate if discontinuous (intermittent) drug delivery will prevent the development of tolerance, similar to the observation after discontinuous transmeningeal muscimol delivery in rats [65]. Although not directly compared, a cell transplantation study also indicated that bilateral grafting of an inhibitory cell line into the STN might be more effective in raising seizure thresholds than placing the same cell line bilaterally into the SNr [233]. ...
Article
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Epilepsies are common chronic neurological diseases characterized by recurrent unprovoked seizures of central origin. The mainstay of treatment involves symptomatic suppression of seizures with systemically applied antiseizure drugs (ASDs). Systemic pharmacotherapies for epilepsies are facing two main challenges. First, adverse effects from (often lifelong) systemic drug treatment are common, and second, about one-third of patients with epilepsy have seizures refractory to systemic pharmacotherapy. Especially the drug resistance in epilepsies remains an unmet clinical need despite the recent introduction of new ASDs. Apart from other hypotheses, epilepsy-induced alterations of the blood-brain barrier (BBB) are thought to prevent ASDs from entering the brain parenchyma in necessary amounts, thereby being involved in causing drug-resistant epilepsy. Although an invasive procedure, bypassing the BBB by targeted intracranial drug delivery is an attractive approach to circumvent BBB-associated drug resistance mechanisms and to lower the risk of systemic and neurologic adverse effects. Additionally, it offers the possibility of reaching higher local drug concentrations in appropriate target regions while minimizing them in other brain or peripheral areas, as well as using otherwise toxic drugs not suitable for systemic administration. In our review, we give an overview of experimental and clinical studies conducted on direct intracranial drug delivery in epilepsies. We also discuss challenges associated with intracranial pharmacotherapy for epilepsies.
... Furthermore, it has been described that direct stimulation of the STN is able to suppress seizures in a variety of experimental models, such as absence seizures in genetically epileptic rats (Vercueil et al., 1998), and seizures induced with systemic kainate injections (Usui et al., 2005). Two studies have focused on transplantation of GABAergic cells in the STN in an acute seizure model (Handreck et al., 2014;Backofen-Wehrhahn et al., 2018) that show transient anticonvulsant effects can be observed for a few weeks. Remarkably though, even a unilateral graft into the STN significantly affected the seizure threshold (Handreck et al., 2014). ...
... Two studies have focused on transplantation of GABAergic cells in the STN in an acute seizure model (Handreck et al., 2014;Backofen-Wehrhahn et al., 2018) that show transient anticonvulsant effects can be observed for a few weeks. Remarkably though, even a unilateral graft into the STN significantly affected the seizure threshold (Handreck et al., 2014). Contrary to earlier discussed options lesioning of the entire STN was not as efficient as electrical stimulation in suppressing seizures (Vercueil et al., 1998) and could be associated with increased risks, as it was reported that upon unilateral lesioning of the STN excitatory glutamate receptors were upregulated in SNr ipsilateral to the lesion, which could result in an increased susceptibility to seizures (Price et al., 1993). ...
Article
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The most researched brain region in epilepsy research is the temporal lobe, and more specifically, the hippocampus. However, numerous other brain regions play a pivotal role in seizure circuitry and secondary generalization of epileptic activity: The substantia nigra pars reticulata (SNr) and its direct input structure, the subthalamic nucleus (STN), are considered seizure gating nuclei. There is ample evidence that direct inhibition of the SNr is capable of suppressing various seizure types in experimental models. Similarly, inhibition via its monosynaptic glutamatergic input, the STN, can decrease seizure susceptibility as well. This review will focus on therapeutic interventions such as electrical stimulation and targeted drug delivery to SNr and STN in human patients and experimental animal models of epilepsy, highlighting the opportunities for overcoming pharmacoresistance in epilepsy by investigating these promising target structures.
... Examination of epileptic tissue removed from TLE patients revealed a loss of interneurons that release inhibitory neurotransmitter GABA [72,73]. GABA-mediated inhibition has been repeatedly demonstrated to be weakened in TLE animal models [74] (Table 3). ...
Chapter
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Epilepsy is the fourth most common neurological condition characterized by recurrent unprovoked seizures. Chronic and recurrent seizures may give rise to cell necrosis, astrocyte activation, neuron death, reactive oxygen species (ROS) production, and mitochondria dysfunction. Recent studies have shown that cell-based therapy is a promising treatment option for epilepsy. Various stem cell types were used for treatment of epilepsy in basic and experimental researches. It is especially vital to gauge the efficacy of distinct donor cell types, such as the embryonic stem cells and induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs), hippocampal precursor cells, γ-aminobutyric acid-ergic progenitors, neural stem cells. The goal of this chapter is to evaluate the progress made hitherto in this area and to discuss the prospect for cell-based therapy for epilepsy.
... Targeting interneurons to a critical, common seizure network node or "choke point," 46 or to a neuromodulatory center that broadly projects to cortical areas, could prove an effective method for treating both focal and generalized forms of epilepsy. 21,36 Finally, the recipient background may influence the cellular development and circuit integration of transplanted interneurons. Epilepsies arise from numerous etiologies, including structural, genetic, infectious, immune, and met- abolic ones. ...
Article
Excitatory-inhibitory imbalance is central to epilepsy pathophysiology. Current surgical therapies for epilepsy, such as brain resection, laser ablation, and neurostimulation, target epileptic networks on macroscopic scales, without directly correcting the circuit-level aberrations responsible for seizures. The transplantation of inhibitory cortical interneurons represents a novel neurobiological method for modifying recipient neural circuits in a physiologically corrective manner. Transplanted immature interneurons have been found to disperse in the recipient brain parenchyma, where they develop elaborate structural morphologies, express histochemical markers of mature interneurons, and form functional inhibitory synapses onto recipient neurons. Transplanted interneurons also augment synaptic inhibition and alter recipient neural network synchrony, two physiological processes disrupted in various epilepsies. In rodent models of epilepsy, interneuron transplantation corrects recipient seizure phenotypes and associated behavioral abnormalities. As such, interneuron transplantation may represent a novel neurobiological approach to the surgical treatment of human epilepsy. Here, the authors describe the preclinical basis for applying interneuron transplantation to human epilepsy, discuss its potential clinical applications, and consider the translational hurdles to its development as a surgical therapy.
... Early models of mTLE revealed that while grafting hippocampal tissue from fetal rat brains into the adult epileptic animal was anticonvulsant, similar grafts into a non-epileptic hippocampus could be proconvulsant (Buzsaki et al., 1988). The decades following this work has demonstrated that replenishing the GABAergic neuron pool, in particular, can improve seizure phenotypes in commonly used rodent epilepsy models (Baraban et al., 2009;Calcagnotto et al., 2010;Cunningham et al., 2014;Hammad et al., 2015;Handreck et al., 2014;Hattiangady et al., 2008;Henderson et al., 2014;Hunt et al., 2013;Loscher et al., 1998;Maisano et al., 2012). The medial ganglionic eminence (MGE) contains GABAergic neuron progenitors that populate the forebrain during development. ...
Article
Despite the immense growth of new anti-seizure drugs (ASDs), approximately one-third of epilepsy patients remain resistant to current treatment options. Advancements in whole genome sequencing technology continues to identify an increasing number of epilepsy-associated genes at a rate that is outpacing the development of in vivo animal models. Patient-derived induced pluripotent stem cells (iPSCs) show promise in providing a platform for modeling genetic epilepsies, high throughput drug screening, and personalized medicine. This is largely due to the ease of collecting donor cells for iPSC reprogramming, and their ability to be maintained in vitro, while preserving the patient's genetic background. In this review, we summarize the current state of iPSC research in epilepsy and closely related syndromes, discuss the growing need for high-throughput drug screening (HTS), and review the use of stem cell technology for the purpose of autologous transplantation for epilepsy stem cell therapy. Although the use of iPSC technology, as it applies to ASD discovery, is in its infancy, we highlight the significant progress that has been made in phenotype and assay development to facilitate systematic HTS for personalized medicine. This article is part of the special issue entitled ‘New Epilepsy Therapies for the 21st Century – From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy’.
... However, considering the preponderance of interneuron pathologies in TLE, more recent studies have focused on transplanting GABAergic interneurons/progenitors into seizure foci. Preclinical studies in animal models of epilepsy have shown the efficacy of GABAergic interneuron/progenitor transplantation in ameliorating seizures (Löscher et al., 1998;Hattiangady et al., 2008;Baraban et al., 2009;Calcagnotto et al., 2010;Handreck et al., 2012;Maisano et al., 2012;Hunt et al., 2013;Cunningham et al., 2014;Hammad et al., 2014;Henderson et al., 2014; Table 1). Pioneering work by Löscher et al. (1998) revealed that transplanting rat fetal GABAergic neurons into the substania nigra (SN) led to a dramatic increase in afterdischarge thresholds and significant reductions in the severity of seizures. ...
... In 2012, Handreck et al. observed the anticonvulsant effects of GABA-producing cells implanted bilaterally/unilaterally into the subthalamic nucleus (STN) using a pentylenetetrazole (PTZ)-induced acute seizure model in adult rats. In addition, they observed that grafting into the STN caused more pronounced anticonvulsant effects than grafting into the SN (Handreck et al., 2012). In these two studies, GABA-producing cells were placed into sites that modulate seizures rather than the seizure focus. ...
... Third, the optimal site for interneuron transplantation must be determined, which is especially important when the seizure focus can not be clearly identified or there are multiple foci. As summarized above, seizure suppression has been observed following transplantation of interneurons to the seizure focus (Hunt et al., 2013;Henderson et al., 2014), but in addition, other brain regions such as SN or STN were shown to be effective sites for in modulating seizure activity in rat epilepsy models (Löscher et al., 1998;Handreck et al., 2012). Moreover, interneuron transplantation into part of epileptic brain region, providing limited innervation of the seizure focus, has also been found to reduce seizures or elevated seizure thresholds (Baraban et al., 2009;Calcagnotto et al., 2010;Hammad et al., 2014). ...
Article
Full-text available
Epilepsy is a severe neurological disease affecting more than 70 million people worldwide that is characterized by unpredictable and abnormal electrical discharges resulting in recurrent seizures. Although antiepileptic drugs (AEDs) are the mainstay of epilepsy treatment for seizure control, about one third of patients with epilepsy suffer from intractable seizures that are unresponsive to AEDs. Furthermore, the patients that respond to AEDs typically experience adverse systemic side effects, underscoring the urgent need to develop new therapies that target epileptic foci rather than more systemic interventions. Neurosurgical removal of affected brain tissues or implanting neurostimulator devices are effective options only for a fraction of patients with drug-refractory seizures, so it is imperative to develop treatments that are more generally applicable and restorative in nature. Considering the abnormalities of GABAergic inhibitory interneurons in epileptic brain tissues, one strategy with considerable promise is to restore normal circuit function by transplanting GABAergic interneurons/progenitors into the seizure focus. In this review, we focus on recent studies of cortical GABAergic interneuron transplantation to treat epilepsy and discuss critical issues in moving this promising experimental therapeutic treatment into clinic.
... This evidence has guided a straightforward concept that grafting of cells that release the inhibitory neurotransmitter GABA into the seizure focus would greatly restrain SRS . Indeed, grafting of GABA-soaked beads, immortalized GABA-ergic cells, cells engineered to produce GABA or fetal GABA-ergic cells into the epileptic foci produces anticonvulsant effects in a variety of animal models (Kokaia et al., 1994;Loscher et al., 1998;Gernert et al., 2002;Thompson, 2005;Castillo et al., 2006Castillo et al., , 2008Nolte et al., 2008;Handreck et al., 2014). However, anti-seizure effects were either modest or transient in most of these studies, presumably because of poor graft cell survival. ...
Article
Diminution in the number of gamma-amino butyric acid positive (GABA-ergic) interneurons and their axon terminals, and/or alterations in functional inhibition are conspicuous brain alterations believed to contribute to the persistence of seizures in acquired epilepsies such as temporal lobe epilepsy. This has steered a perception that replacement of lost GABA-ergic interneurons would improve inhibitory synaptic neurotransmission in the epileptic brain region and thereby reduce the occurrence of seizures. Indeed, studies using animal prototypes have reported that grafting of GABA-ergic progenitors derived from multiple sources into epileptic regions can reduce seizures. This review deliberates recent advances, limitations and challenges concerning the development of GABA-ergic cell therapy for epilepsy. The efficacy and limitations of grafts of primary GABA-ergic progenitors from the embryonic lateral ganglionic eminence and medial ganglionic eminence (MGE), neural stem/progenitor cells expanded from MGE, and MGE-like progenitors generated from human pluripotent stem cells for alleviating seizures and co-morbidities of epilepsy are conferred. Additional studies required for possible clinical application of GABA-ergic cell therapy for epilepsy are also summarized.
Article
Cell transplantation based therapy is a promising strategy for treating intractable epilepsies. Inhibition of the subthalamic nucleus (STN) or substantia nigra pars reticulata (SNr) is a powerful experimental approach for remote control of different partial seizure types, when targeting the seizure focus is not amenable. Here, we tested the hypothesis that grafting of embryonic/fetal neural precursor cells (NPCs) from various species (rat, human, pig) into STN or SNr of adult rats induces anticonvulsant effects. To rationally refine this approach, we included NPCs derived from the medial ganglionic eminence (MGE) and ventral mesencephalon (VM), both of which are able to develop a GABAergic phenotype. All VM- and MGE-derived cells showed intense migration behavior after grafting into adult rats, developed characteristics of inhibitory interneurons, and survived at least up to 4 months after transplantation. By using the intravenous pentylenetetrazole (PTZ) seizure threshold test in adult rats, transient anticonvulsant effects were observed after bilateral grafting of NPCs derived from human and porcine VM into STN, but not after SNr injection (site-specificity). In contrast, MGE-derived NPCs did not cause anticonvulsant effects after grafting into STN or SNr (cell-specificity). Neither induction of status epilepticus by lithium-pilocarpine to induce neuronal damage prior to the PTZ test nor pretreatment of MGE cells with retinoic acid and potassium chloride to increase differentiation into GABAergic neurons could enhance anticonvulsant effectiveness of MGE cells. This is the first proof-of-principle study showing anticonvulsant effects by bilateral xenotransplantation of NPCs into the STN. Our study highlights the value of VM-derived NPCs for interneuron-based cell grafting targeting the STN.