Calcium and mitochondrial dysregulation have been implicated in neuronal cell death for several neurodegenerative diseases. These diseases share a common trait in that elevated calcium levels and reactive oxygen species (ROS) production can lead to necrosis and apoptosis. Since there are no therapies currently approved by the FDA to prevent neurodegeneration by these mechanisms, we investigated the use of small organic compounds which could modulate calcium movement and ROS production in neurons. By mimicking ischemic conditions, we will evaluate novel compounds and their ability to act as neuroprotective agents against oxygen and glucose deprivation in a cell-based model. Two classes of compounds will be used: the TZDs as mitoNEET ligands and polycyclic cage amines (PCUs) as VGCC blockers. Specifically, we are interested in focusing on calcium movement via voltage gated calcium channels (VGCCs) and ROS production through mitoNEET.
To mimic stroke conditions, we developed an ischemia model using a hypoxia chamber to deprive mixed cortical cells of oxygen and glucose. After this deprivation, reperfusion injury was initiated by replacing the media with glucose and oxygen. Cell death was assessed after a 6 hour incubation using an LDH assay to detect membrane disruption. The mitoNEET ligand NL-1 and the VGCC ligand NGP1-01 were both shown to be protective following reperfusion related injury. This suggests that they would be useful pharmacological compounds to treat the reperfusion injury found in stroke.