Pre-clinical in-vivo and in-vitro investigations to discover new anti-epileptogenic drugs and their cellular targets

点击翻译按钮获取中文摘要

For my PhD research I propose to work on the discovery of new antiepileptogenic substances and to contribute to our understanding of how they work. For patients with epilepsy the uncertainty about when the next seizure will occur impairs their quality of life more than the seizure itself. It is therefore desirable to not only lower seizure frequency, but to achieve seizure freedom. As epilepsy is not curable today this can unfortunately often only be reached through life-long medication with anti-seizure drugs. Thus, it is crucial to develop anti-epileptogenic drugs (AEDs) that permanently reduce the cerebral excitability instead of only controlling seizures. However, such drugs are not yet available. Amongst others, this is due to the insufficient output of preclinical research of new antiepileptogenic substances. As antiepileptogenesis is a fascinating emerging field in neuroscience, I want to spent my PhD investigating such AEDs in preclinical research. Specifically, I propose to start with examining cellular components that potentially participate in epileptogenesis in order to unravel possible targets for new AEDs. I plan to do this in specimens obtained from patients with epilepsy by surgery or autopsy, as well as from animals with chronic epilepsy, for example induced by status epilepticus or kindling. Additionally, I intend to test the outcome of treatment with respective agents in such animal models. Therefore, I propose to perform randomized and blind tests in an animal model of chronic epilepsy by injection of different doses of potential AEDs, as well as of a control solution (e.g. physiological saline solution) at various time points prior, duringand after the induction of epilepsy. The outcome of a treatment with respective agents could be determined by observing the animals and their seizure frequency over a long period and by examination of isolated brain slices and singular cells, for example with electrophysiological measurements and patch clamp investigations. On one hand my goal is to find molecular biological components in cerebral cells suitable for targeting with AEDs. On the other hand, I aim to successfully prove the antiepileptogenic potential of agents targeting such structures in animal models so that they then can be used for clinical trials. Since epilepsy is a common neurological condition (over 1% of the population suffer from epilepsy), I believe that the development of antiepileptogenic medication is fundamental for the well-being of many people. As I already have research experience in diverse medical disciplines and am very enthusiastic about neuroscience and specifically epilepsy research, I am well-suited for undertaking a PhD at University of Oxford.