Abstracts

Rationale: Targeted delivery of antiepileptic drugs directly into brain regions involved in seizure modulation is a promising strategy to overcome pharmacoresistant epilepsies. In a previous study in rats, we could demonstrate strong anticonvulsant effects without severe adverse effects in response to acute bilateral microinjection of vigabatrin (VGB), an irreversible inhibitor of the GABA-degrading enzyme GABA-aminotransferase (GABA-T), into the subthalamic nucleus (STN). The STN is a key basal ganglia structure involved in remote control of seizures emanating from the limbic system. We now investigate, if chronic delivery of VGB into the STN of rats using implantable microinfusion pumps leads to long-lasting anticonvulsant effects in the pentylenetetrazole (PTZ) seizure threshold test. Methods: Chronic microinfusion of different doses of VGB (0.1, 1.0, 5.0, and 10-12 µg per day) over a period of 3 weeks bilaterally into the STN was conducted using implantable iPrecio® pumps (Data Science International). The anticonvulsant efficacy was assessed once weekly in the PTZ seizure threshold test. Immediately before, behavioral tests were carried out in the open field and rotarod to detect possible adverse effects of the treatment. Finally, neurochemistry was performed in post mortem tissue. Results: Chronic microinfusion of VGB bilaterally into the STN caused dose-dependent anticonvulsant effects on seizure thresholds with no effects using vehicle or low doses (0.1 and 1.0 µg) and clear anticonvulsant effects using high doses (5.0 and 10-12 µg). However, in part of the rats, the effect was lost after 3 weeks, indicating development of tolerance. This could be caused by feedback inhibition of the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD) in response to the high GABA levels. Indeed, the GAD activity was moderately reduced in the STN in those rats after chronic microinfusion of 10-12 µg VGB per day. GABA-T was dose-dependently inhibited by VGB infusion with complete inhibition after microinfusion of 5.0 and 10-12 µg VGB per day. Animals treated with 10-12 µg VGB per day showed significant body weight loss, a decrease in body temperature, and hypolocomotion and sedation during the infusion period. Animals receiving 5.0 µg VGB per day showed none of these adverse effects. Conclusions: Chronic microinfusion of 5.0 and 10-12 µg VGB per day bilaterally into the STN leads to clear anticonvulsant effects in rats. Some animals developed tolerance after 3 weeks of treatment, whereas other animals showed a stable increase in seizure threshold over the 3 weeks of infusion. In a next step, chronic microinfusion of VGB into the STN will be performed in a chronic epilepsy model (amygdala kindling). Acknowledgments: Vigabatrin was provided by Sanofi Deutschland GmbH. The study is supported by a grant (FOR 1103 / GE1103/7-2) from the German Research Foundation (Bonn, Germany). LG is supported by the Konrad-Adenauer-Stiftung e.V. (Sankt Augustin, Germany).