Abstracts

This is a Late-Breaking abstract.

Rationale: Targeted intracerebral drug delivery is an attractive experimental approach for the treatment of drug-resistant epilepsies. In this regard, the subthalamic nucleus (STN) represents a focus-independent target involved in the modulation and propagation of seizure activity. Indeed, acute and chronic inhibition of the STN has been shown to produce anticonvulsant effects. This effect has, however, been observed to be lost over time as tolerance develops with chronic, continuous intracerebral pharmacotherapy. We therefore investigated the anticonvulsant effects of chronic discontinuous intrasubthalamic convection-enhanced delivery of vigabatrin in an acute rat seizure model with particular focus on long-lasting anticonvulsant effects and circumventing the development of tolerance.

Methods: Timed intravenous pentylenetetrazol (PTZ) seizure threshold testing was conducted in adult, female Wistar-Unilever rats once before and three times after implantation of a subcutaneous mini drug pump connected to cannulas bilaterally targeting the STN. The drug pumps were programmed to infuse artificial cerebrospinal fluid (vehicle control) or the antiseizure medication vigabatrin either twice daily (0.4 µg BID; 1 hr on, 11 hr off) or once weekly (2.5 µg QW, 5 µg QW; 1 hr on, 167 hr off) for the three-week testing period. A behavioral test battery (Irwin screen, hyperexcitability test, ladder rung walking test) was conducted before each PTZ seizure threshold determination to evaluate putative adverse effects.

Results: Intracerebral vigabatrin was generally well tolerated with the main adverse effect observed being reduced bodyweight. Preliminary results indicate that discontinuous intrasubthalamic vigabatrin can maintain an anticonvulsant effect over the three-week test period with responder rates of upwards of 80% observed. Tolerance could not, however, be completely avoided in some animals.

Conclusions: Results confirm the STN as an effective target for intracerebral drug delivery in the treatment of epilepsy. Our data demonstrate that the extent of tolerance development after intrasubthalamic convection-enhanced vigabatrin delivery varies depending on application regime. Substances with varying mechanisms of actions may need to be considered to fully overcome the development of tolerance during long term treatment.

Funding: This work was supported by a grant (GE 1103/9-1, project number 390074275) from the German Research Foundation (Deutsche Forschungsgemeinschaft).