Abstracts

Rationale: Among different alternative treatment options, one promising approach to overcome pharmacoresistant epilepsy is to transplant GABA-producing cells into appropriate brain regions. Inhibition of the substantia nigra pars reticulata (SNr), a main basal ganglia output structure, has repeatedly been shown in experimental epilepsy to be a highly interesting target for modulation of different seizure types. Previous studies of our group could show clear but transient anticonvulsant effects after transplantation of fetal or genetically engineered GABA-producing cells into the SNr of rats. Our present studies aim to identify the most promising target region within the basal ganglia and the most promising cell type in order to achieve long-term anticonvulsant effects. Methods: Suitable target regions for neurotransplantation were assessed in rats using the pentylenetetrazole (PTZ, metrazol) seizure threshold test, which is particularly sensitive to GABA-potentiating manipulations. In order to mimic the effect of GABA-producing cells, we microinjected vigabatrin (10 ?g in 250 nl) bilaterally into the SNr or its excitatory input structure, the subthalamic nucleus (STN). Vigabatrin irreversibly inhibits the degradation of GABA, resulting in its elevation in the synaptic cleft. Before and at different time-points after microinjection, PTZ thresholds were determined with each animal serving as its own control. The anticonvulsant efficacy was compared to that of systemic application of vigabatrin (600 mg/kg and 1200 mg/kg). Targeting the above mentioned basal ganglia structures, different cell types (80,000 cells in 800 nl) were transplanted bilaterally: spherical aggregates and mature human model neurons of Ntera-2 cells as well as rat GABAergic precursor cells from the medial and lateral ganglionic eminence pretreated with growth factors. Prior to and 10 days, 5 and 12 weeks after transplantation, PTZ thresholds were determined to evaluate anticonvulsant effects.Results: Microinjection of vigabatrin into the STN and especially into the posterior SNr clearly proved that local increase of inhibition within these regions is at least as anticonvulsant as systemic administration. The advantages of the focal application were that fewer side effects occurred and the used dose was drastically lower. Preliminary transplantation data did not indicate robust anticonvulsant effects after grafting of spherical aggregates and mature Ntera-2 cells into the STN or anterior SNr. Results of GABAergic precursors will be presented at the Meeting.Conclusions: The STN as well as the posterior SNr are highly promising target regions for transplantation of GABA-producing cells. The lack of anticonvulsant efficacy of Ntera-2 cells supports previous data showing that increased inhibition of the SNr or STN is necessary to inhibit seizures. Differentiated Ntera-2 cells, however, comprise excitatory and inhibitory neural phenotypes.