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

约30%的癫痫患者被认为具有耐药性，尽管使用了最佳的抗癫痫药物，但仍持续发作。临床应用于全身药物治疗的替代方案是有限的，例如，由于多灶性癫痫的发生或由于未知的病灶定位而切除癫痫发作的病灶。替代治疗策略的临床前和临床开发，如针对远离癫痫发作焦点的关键癫痫网络区域的脑内药物治疗，是当前癫痫治疗中最紧迫的挑战之一。由于绕过了血脑屏障，可以在不引起全身不良反应的情况下，在脑内达到较高的局部药物浓度。使用抗癫痫药物vigabatrin（一种不可逆的gaba -转氨酶抑制剂），丘脑底核（STN）被证明是脑内微量注射药物以诱导持久抗惊厥作用最有希望的靶点区域。2012年，我们的研究小组首次报道了这一现象，对远离癫痫发作焦点的几个假定目标区域进行了直接比较。此外，STN非常有吸引力，因为它有能力调节癫痫发作的开始和传播，而不依赖于癫痫病灶在边缘系统中的确切位置。计划研究项目的目的是进一步合理发展下丘脑内药物治疗癫痫。抗惊厥效果将与STN的深部脑刺激提供的尚不令人信服的数据进行比较。我们将首次对靶向下丘脑内药物微输注的新策略进行可比性测试，并利用合适的大鼠模型在体内开发。其目的是克服最近研究中阐述的挑战，并从长远来看，使最有希望的策略的临床翻译成为可能。主要比较以下策略在慢性微量输注STN时的抗惊厥效果、耐受性发展、扩散范围、GABA代谢和不良反应概况：(a) CPP-115作为一种新的gaba -转氨酶抑制剂，具有比维加巴特林更高的效力，同时毒性更小；(b)丙戊酸盐作为一种具有混合作用机制的药物；(c) SK2/3亚型选择性阳性调节剂CyPPA作为一种在脑内具有相当限制性作用点的药物。将使用创新的长期植入式微输注泵，它允许间歇输注药物，即使在植入式微输注后也可重新编程。最后，最有希望的策略将通过神经影像学研究进行机械研究。我希望所获得的知识不仅与癫痫的脑内药物治疗的发展有关，而且对进一步的神经和神经精神疾病的脑内药物治疗也很重要。

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.