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Intrasubthalamic cell transplants for epilepsy therapy: hopes and concerns Manuela Gernerta,b The mainstay of treatment of patients suffering from epilepsies involves antiepileptic drug therapy. However, about one-third of patients continue to have seizures or show intolerable adverse effects despite appropriate medication. Neuronal transplantation into key brain regions involved in seizure generation, propagation, or modulation is a promising alternative experimental approach to treat drug-resistant epilepsies. Especially for patients with multiple-epileptic foci, or without a clear focal onset, therapeutic manipulation of brain structures remote to the focus but significantly involved in seizure modulation may be a more advantageous strategy. Using animal experiments, we recently showed that the subthalamic nucleus (STN) may be an auspicious target region in this respect. The STN repeatedly showed up to be highly sensitive to changes in GABAergic transmission, which can be achieved by localized microinjection of GABA-elevating drugs or by grafting GABA-releasing cells.

However, there are many hurdles to overcome and questions to resolve before clinical translation of this approach appears realistic. This commentary discusses potential benefits as well as concerns associated with grafting of inhibitory cells into the STN. NeuroReport c 2013 Wolters Kluwer Health | Lippincott 24:1062–1066 Williams & Wilkins.

Background

porcine GABAergic cells have been grafted into the seizure focus in a few patients suffering from localizationrelated epilepsies showed encouraging anticonvulsant results [11].

Epilepsies are common chronic neurological diseases characterized by recurrent spontaneous seizures of central origin. The mainstay of treatment involves symptomatic suppression of seizures with systemically applied antiepileptic drugs, which often has to be continued throughout live. Pharmacotherapies for epilepsies are facing a two-fold challenge: first, unwanted side effects from systemic drug treatment are common, and second, about one-third of affected patients are considered resistant to currently available antiepileptic drugs. These pharmacoresistant patients continue to have seizures despite appropriate medication. In particular the localization-related epilepsies, such as temporal lobe epilepsy, in which seizures emanate from the limbic system, are characterized by difficult-to-treat types of seizures. For some pharmacoresistant patients, resection of the seizure focus may lead to control of seizures or even a cure. For many however, focus resection is not an option because of difficulties localizing the focus, the occurrence of a mirror focus in the contralateral hemisphere, the existence of multiple foci, unacceptable surgical risks, or expected unwanted postoperative adverse effects. Thus, there is considerable interest in developing promising alternative treatment approaches, among which cell transplantation into appropriate brain target regions is one of them [1–10]. Even so, grafting studies in epilepsies so far have almost exclusively been investigated in animal models, a pilot study in which fetal c 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins 0959-4965

NeuroReport 2013, 24:1062–1066 Keywords: basal ganglia, cell transplants, GABAergic precursors, grafts, seizures, substantia nigra pars reticulata, subthalamic nucleus a Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover and bCenter for Systems Neuroscience, Hannover, Germany

Correspondence to Manuela Gernert, PhD, BSc, MSc, Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Bu¨nteweg 17, 30559 Hannover, Germany Tel: + 49 511 9538527; fax: + 49 511 9538581; e-mail: [email protected] Received 30 August 2013 accepted 20 September 2013

Why choose the subthalamic nucleus as a target region for cell transplantation?

Apart from directly targeting the seizure focus and thereby being confronted with problems similar to those associated with focus resection, another promising strategy is to target cells into brain regions responsible for seizure propagation and remote modulation of seizure initiation [3]. In that regard, the basal ganglia have long been known from numerous animal studies to be part of a seizure-gating network (reviewed by Gale et al. [12]). Also, an increasing number of clinical studies support the concept of an inhibitory role of the basal ganglia in seizures (overview by Rektor et al. [13]). Most obviously in this respect, deep brain stimulation targeting the subthalamic nucleus (STN), a key basal ganglia structure (see below), is a clinically used therapeutic approach, which repeatedly proved anticonvulsant efficacy in some of the drug-resistant patients suffering from epilepsy [14,15]. For more than three decades, however, most animal studies investigating seizure modulation through the basal ganglia concentrated on the substantia nigra pars reticulata (SNr), a basal ganglia output structure, which inhibits downstream anticonvulsant zones within the DOI: 10.1097/WNR.0000000000000059

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dorsal midbrain, the pedunculopontine nucleus, and/or thalamic regions. Pharmacological inhibition or grafting of inhibitory cells into the SNr has been shown repeatedly not only to impede seizure propagation, but also to prevent initiation of different experimentally induced seizure types emanating from limbic structures [3,12], the latter probably through reciprocal connections with the limbic system. It is important to note that the SNr seems to have seizure-gating properties regardless of the exact localization of the seizure focus within the limbic system. This is why the SNr and its related structures are considered a common final pathway, a highly attractive feature with regard to putative clinical implementations. Although the SNr traditionally has been considered to be the key basal ganglia structure with respect to rather unspecific seizure-gating properties, experimental data using different seizure or epilepsy models indicated that a remarkable nonselective seizure modulation can also be achieved by other basal ganglia structures. In this respect the STN, which is composed of glutamatergic projection neurons, seems to be a strategically promising basal ganglia region [16–18]. The STN monosynaptically excites the ipsilateral SNr and influences nigral discharge pattern, thereby modulating the nigral inhibitory influence on downstream anticonvulsant zones. The STN also excites the internal part of the globus pallidus, which then may influence seizure circuits through the habenula or other limbic structures. In addition, it is highly interconnected with other basal ganglia regions such as the external part of the globus pallidus, from which it receives strong inhibitory, GABAergic input. GABA has a major role in modulating firing rate and pattern of STN neurons, and this is mediated mainly by postsynaptic GABAA receptors and to a lesser extent by presynaptic GABAB receptors. Apart from the basal ganglia, the STN influences the activity of numerous further brain regions including pedunculopontine neurons and additionally integrates input from many structures including cortical regions. Just as other basal ganglia regions, the STN shows a tripartite functional subdivision into a motor, limbic, and associative portion (reviewed by Hamani et al. [18]). Likely because of its widespread connectivity with other basal ganglia as well as cortical and limbic structures, the STN also seems to be relatively nonselective as to the seizure types it can influence. Thus, pharmacological inhibition of the STN by acute intrasubthalamic microinjection of the GABAA receptor agonist muscimol or the antiepileptic drug vigabatrin, which irreversibly inhibits degradation of GABA, revealed anticonvulsant effects on seizures originating in the forebrain such as generalized nonconvulsive seizures [19], flurothylinduced seizures [20], amygdala-kindled seizures [21], bicuculline-induced seizures [22], and pentylenetetrazol (PTZ, metrazole)-induced seizures [23]. As a logical consequence of the studies mentioned before, the question arose as to which structure, the SNr or the

STN, should be considered the more promising with regard to anticonvulsant efficacy in response to local inhibition. Both structures show seizure-outlasting plastic network changes in response to repeated seizure activity emanating from the limbic system and therefore are considered to be part of the epileptic network [24–26]. Until a study from our group published last year [23], there was no direct comparison available about the efficacy of localized inhibition of SNr and STN, respectively, on experimentally induced seizures. Indeed, the study by Bro¨er et al. [23] is the first to provide a direct comparison between systemic administration of a GABA-elevating antiepileptic drug and its targeted microinjection into different brain regions including anterior and posterior SNr and the STN on PTZ-induced seizures. It became evident that at least for PTZ-induced seizures the STN was a more promising target region than different SNr subregions. Furthermore, targeting the STN locally caused stronger anticonvulsant effects with fewer adverse effects than systemic application of the antiepileptic drug vigabatrin [23]. These are important findings not only relevant for future focal pharmacotherapy studies, but also for cell transplantation approaches. In this regard, it is highly important to note that targeting the STN, but not the SNr, is already clinically used to treat patients suffering from drug-resistant epilepsy. As mentioned before, anticonvulsant effects can be induced by high-frequency stimulation (HFS) of the STN in some patients with epilepsy [14,15]. Thus, targeting the STN seems to be a realistic goal also for other treatment approaches such as cell transplantation. Hopes and concerns

The first study showing anticonvulsant effects of cell transplantation into the STN in experimental epilepsy was performed recently by our group [27]. In this proof-of-principle study, immortalized GABAergic striatal rat cells were placed bilaterally into the STN and PTZ seizures were induced before and at several time points after grafting. Intrasubthalamic transplantation of GABAergic cells caused clear anticonvulsant effects. This effect was not seen after grafting of non-GABAergic control cells or when grafts were placed bilaterally outside the STN, emphasizing cell-specificity and site-specificity of the transplantation. Assuming that grafting of GABAergic cells into the STN results in an increased inhibition of the target region, Handreck et al. [27] suggested that the anticonvulsant efficacy induced by this approach is caused not only by indirect inhibition of the SNr, but also by reduced excitation of multiple other regions efferent to the STN. This may explain its potentially higher success over the SNr with regard to anticonvulsant efficacy in response to local inhibition. It can be anticipated that these findings will have an impact on future grafting studies in epilepsy models. However, there are several unresolved questions, one of which is

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that we do not know the exact mechanisms underlying the anticonvulsant effects caused by intrasubthalamic cell transplantation. Future research will likely contribute to a better understanding of those mechanisms. It is noteworthy that grafting of GABA-producing cells into the STN does not simply mimic microinjection of drugs, which increase GABAergic function into this target region. For example, Dybdal and Gale [22] observed a contralateral postural asymmetry caused by contralateral microinjection of muscimol into the STN of rats, whereas unilateral grafting of GABA-producing cells into the STN did not cause similar postural side effects [27]. Apart from a direct and rather nonphysiological inhibition of STN neurons by microinjection of inhibitory receptor agonists, a more physiological inhibition can be expected from intrasubthalamic grafting of GABAergic cells because the inhibition then is dependent on the strength of tonic inhibitory activity influencing STN neurons. This of course assumes a functional integration into the host neural circuitry through the establishment of synaptic contacts rather than a tonic nonsynaptic release of GABA. Although not directly compared, the study by Handreck et al. [27] indeed also indicated that bilateral grafting of an inhibitory cell line into the STN might be more promising than placing the same cell line bilaterally into the SNr. However, so far we are confronted with the same hurdles already known for grafting into the SNr. The observed anticonvulsant effects were only transient despite longterm survival of grafted cells and depending on the cell type used for transplantation, graft rejection or unwanted migration of cells may occur. Although not yet investigated, there is no indication of significant neurodegeneration of STN neurons in response to epileptic seizures, meaning that we add neurons to a rather intact brain structure. An integration of grafted cells into the host brain therefore may be hindered. Furthermore, it may be more likely that adaptive processes are induced in response to intrasubthalamic grafting. These include for example compensatory down-regulation of GABA-receptors within the STN in response to chronic exposure to GABA and/or an upregulation of NMDA receptors within the SNr, which in turn may lead to enhanced sensibility of SNr neurons to the remaining excitatory influence from the STN. Thus, what is the optimum grafting protocol for the STN to induce long-lasting anticonvulsant effects? How many cells have to survive grafting into the STN to reliably induce longterm anticonvulsant effects? How do we avoid downregulation of postsynaptic GABA receptors, if we have to? And how do we facilitate integration of grafted cells into the STN? It would be helpful to have further studies directly comparing grafting of a specific cell type into the STN and the SNr, respectively, in the same epilepsy or seizure model, as has been carried out in the above mentioned

pharmacological study by Bro¨er et al. [23]. However, it is conceivable that the most powerful anticonvulsant effects induced by grafting into the STN or SNr, respectively, will require either different cell types or completely different grafting protocols. Indeed, a direct comparison between STN and SNr may be hampered by many known as well as unknown factors. For example, one obvious factor may be the higher neuronal density within the STN compared with the SNr with its rather scattered neurons. One concern in this regard is that placing additional cells into a densely packed structure such as the STN may lower the survival rate and/or the network integration of grafted cells within the target region, especially when considered in light of the relatively low volume of the STN. In contrast, the smaller size of the STN compared with the SNr may be advantageous, because a targeted placement of a cell graft into one site within the STN is more likely to have a more widespread impact on this compact target region than grafting into one site of the larger SNr. This is more so as the dendritic field of a STN neuron almost covers the whole nucleus, at least in rodents. This may not necessarily be beneficial, because it would in turn cause a rather unspecific modulation of limbic, associative, and motor circuits of the STN. Hence, we do not yet know whether the compact structure of the STN with its small size and densely packed neurons is an advantage or a disadvantage with regard to successful cell transplantation into this target. A further disadvantage of the smaller volume of the STN also includes the inherent difficulty of placing all grafted cells within the boundaries of the STN. At least in our hands, the transplant typically extended into areas surrounding the STN, such as the zona incerta [27], which is located in close vicinity dorsal to the STN. The zona incerta is highly connected with numerous brain regions including key structures of seizure propagation and modulation. For example, similarly to the STN, it has monosynaptic glutamatergic connections to the SNr. An anticonvulsant effect mediated by the zona incerta nevertheless can be expected to be less relevant because of two reasons. First, the zona incerta has a complex chemoarchitecture and connectivity and is composed of diverse subsections [28], resulting in a rather inconsistent seizure modulation. Second, inhibitory cell grafts placed completely outside the STN, for instance within the zona incerta, did not raise seizure thresholds [27], emphasizing the site specificity of the observed anti-convulsant effects. Because of the much larger volume of the STN in humans, it should be easier to confine the complete transplant to the STN so that the hurdle of misplaced cells is probably less relevant with regard to clinical translation. Even more, it can be expected to be easier to select motor, limbic, or associative subregions for cell

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grafting. Thus, a specific subregional placement of cells within the STN may combine high efficacy with a lower risk of unwanted side effects such as involuntary movements. However, if this approach was to reach clinical application, there are numerous anatomical differences between the STN in rats and humans to be considered [18]. Apart from the volume differences (0.8 mm3 in rats vs. 240 mm3 in humans), the average number of neurons in the STN per hemisphere varies between the two species (B25 000 in rats vs. B560 000 in humans) [18,29]. The number of neurons per volume, that is the density, does not vary between rats and humans, but there are some differences in connectivity with other brain areas [18]. The species differences as well as further issues such as the chosen seizure or epilepsy model add to the difficulty that current preclinical testing may not always be sufficiently predictive for clinical efficacy. Although the acute seizure model used by Handreck et al. [27] has the advantages of being sensitive for GABAergic seizure modulations and to be a fast and nonlaborious screening method, clinically more relevant chronic epilepsy models with spontaneous, ideally drug-resistant, seizures should be used for more detailed investigations on the efficacy of cell grafting into the STN [30]. Apart from many unresolved questions and concerns associated with cell transplantation into the STN, this approach opens up a new avenue for future grafting studies because neurosurgically targeting the STN in humans is clinically established due to many years of experience with deep brain stimulation [14,15]. HFS of the STN aims to treat several neurologic disorders including pharmacoresistant epilepsies [14,15] and is suggested to be mediated by multiple mechanisms, one of which is the reversible suppression of subthalamic neural activity. Although an effective approach, seizure freedom is not obtained by HFS of the STN. But can knowledge from deep brain stimulation studies be directly transferred to grafting studies? The mechanisms and pathways mediating anticonvulsant effects by HFS of the STN or by inhibitory cell grafting, respectively, are somehow different [27]. It therefore remains to be evaluated whether more pronounced anticonvulsant effects or even seizure freedom can be obtained by grafting GABA-releasing cells into the STN.

2013 [31]. With regard to future clinical translation of cell transplantation therapies in epilepsies, we can benefit from plenty of clinical experience with this treatment approach from different other neurological diseases including stroke, Parkinson’s disease, Huntington’s disease, and multiple sclerosis [6,32–36]. Apart from the intended anticonvulsant effect, a beneficial influence on further features associated with severe epilepsies such as behavioral or psychiatric comorbidities is desirable. In this respect, Hunt et al. [37] could recently show that grafting of GABAergic progenitor cells into the hippocampus of epileptic mice not only reduced seizure frequency, but also restored behavioral deficits in spatial learning, hyperactivity, and the aggressive response to handling. It remains to be evaluated whether grafting of inhibitory cells into the STN is also able to restore epilepsy-associated behavioral deficits. In this regard, a wealth of data is available at least on the influence of HFS of the STN in animal models and in human patients [38], impressively confirming that the range of STN functions goes far behind motor functions.

Conclusion The STN occupies a key position not only to modulate basal ganglia output activity, but also to exert a widespread influence on seizure circuitry through numerous other brain regions. Even though the remarkable effects of intrasubthalamic cell transplantation experiments are promising, a considerably high number of concerns also can be formulated. Thus, it is a long way until this approach is clinically applicable, because up to now it seems we have more questions than answers and many hurdles to overcome. Nevertheless, the STN can be considered a highly promising target region for modulation of seizure circuits by cell grafting approaches and has the advantage of being clinically established for functional neurosurgery.

Acknowledgements Our studies on therapeutic manipulation of the subthalamic nucleus in epilepsy models are funded by the German Research Foundation (Ge1103/7). Conflicts of interest

There are no conflicts of interest. With regard to clinical applicability, grafting of cells from readily available sources is inevitable. These include patient-derived cells generated from pluripotent stem cells [4,5,10], or non-patient-derived cells such as humanized porcine GABAergic progenitor cells [11]. The latter approach is currently investigated by our group and first promising results showing anticonvulsant effects after grafting of porcine GABAergic progenitor cells into the STN of rats have been obtained and were presented during the XIIth International Symposium on Neural Transplantation held in Cardiff, Wales, UK in

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Intrasubthalamic cell transplants for epilepsy therapy: hopes and concerns.

The mainstay of treatment of patients suffering from epilepsies involves antiepileptic drug therapy. However, about one-third of patients continue to ...
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