Targeted drug microinfusions into the subthalamic nucleus as a strategy to treat epilepsies

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About 30% of patients suffering from epilepsies are considered pharmacoresistant and continue having seizures despite optimally applied antiepileptic drugs. Clinically applied alternatives to systemic pharmacotherapy are limited, for example the resection of the seizure-initiating focus by the occurrence of multifocal epilepsies or by unknown focus localization. The preclinical and clinical development of alternative treatment strategies, such as the intracerebral pharmacotherapy aiming to target key epileptic network regions remote to the seizure focus, is one of the most urgent current challenges in epilepsy therapy. Because the blood-brain-barrier is bypassed, higher local drug concentrations within the brain can be achieved without inducing systemic adverse effects. Using the antiepileptic drug vigabatrin, an irreversible GABA-transaminase inhibitor, the subthalamic nucleus (STN) proved to be the most promising target region for intracerebral drug microinfusion aiming to induce long-lasting anticonvulsant effects. This was first reported by our group in 2012 in a direct comparison of several putative target regions remote to the seizure focus. Additionally, the STN is highly attractive for its ability to modulate seizure initiation and propagation independent of the exact location of the epileptic focus within the limbic system. Aim of the planned research project is the further rational development of the intrasubthalamic pharmacotherapy of epilepsies. The anticonvulsant effectiveness will be compared to as yet unconvincing data provided by deep brain stimulation of the STN. New rational strategies for the targeted intrasubthalamic drug microinfusion will be comparably tested for the first time and developed in vivo using appropriate rat models. The aim is to overcome challenges elaborated in recent studies and, in the long term, to enable clinical translation of the most promising strategy. Mainly the following strategies will be directly compared with regard to anticonvulsant effectiveness, development of tolerance, diffusion range, GABA metabolism, and adverse effect profile during chronic microinfusion into the STN: (a) CPP-115 as a new GABA-transaminase inhibitor with much higher potency and at the same time less toxicity than vigabatrin, (b) valproate as a drug with mixed mechanisms of action, (c) the positive SK2/3 subtype-selective modulator CyPPA as a drug with rather restrictive points of effect within the brain. Innovative, chronically implantable microinfusion pumps will be used, which allow intermittent drug infusion and which are reprogrammable even after implantation. Finally, the most promising strategy will be investigated mechanistically by neuroimaging studies. I expect that the gained knowledge not only will be relevant for the development of intracerebral pharmacotherapies of epilepsies, but additionally will be important for the intracerebral pharmacotherapy of further neurological and neuropsychiatric diseases.