Two-step therapeutic screen for mitochondrial epilepsies

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DESCRIPTION (provided by applicant): The long-term goal of this translational research proposal is to develop novel therapeutic agents for the treatment of epilepsies associated with mitochondrial dysfunction. This proposal is intended to address an important NINDS intiative aimed at developing screening models and identifying candidate therapeutics for devastating neurological disorders. Epileptic seizures are the most common feature observed in children with inherited mitochondrial diseases. Work in this laboratory suggests an emerging role of mitochondrial dysfunction in seizure-induced brain injury as well as seizure susceptibility. Based on these studies, it is hypothesized that mitochondrial dysfunction is an attractive target for therapeutic intervention. The goal of this proposal is to develop and validate a two-step screening model to identify therapeutic agents that preferentially ameliorate mitochondrial dysfunction and would therefore benefit catastrophic childhood mitochondrial epilepsies. The model is based on a strain of mutant mice lacking mitochondrial manganese superoxide dismutase (MnSOD or Sod2), that develop frequent spontaneous seizures in postnatal life. The first screen (Specific Aim 1) will utilize rat brain mitochondria to select compounds that decrease mitochondrial oxidative stress. Selected compounds from this screen will be tested in a second in vivo model of Sod2-/- mice. The goal of the second therapeutic screen (Specific Aim 2) is to develop an in vivo model of mitochondrial dysfunction in B6D2F1 Sod2-/- mice. Model development will involve video monitoring, EEG recordings, mitochondrial enzymology, oxidative stress and survival analysis. The model will be validated with a series of lipophilic metalloporpyrin catalytic antioxidants designed to cross the blood-brain barrier. Together, the in vitro and in vivo approaches can be utilized sequentially to identify candidate therapeutic agents. This screening procedure will allow us to participate the the NINDS cooperative program designed to specifically develop candidate therapies for clinical development.