Development of P7C3-Class of Neuroprotective Molecules

Neurodegenerative diseases and disorders are physically, emotionally and financially devastating for patients and their families, and are also associated with great costs to caregivers and society. All of these neuropsychiatric conditions have in common neuronal cell death, for which there is currently no effective pharmacologic treatment. Here, I describe the development of the P7C3-series of neuroprotective compounds, which were originally discovered through an unbiased in-vivo screen for new chemicals with proneurogenic and/or neuroprotective properties. My dissertation work focused on evaluating the efficacy of these compounds in multiple models of neurodegeneration with respect to potency and efficacy of blocking neuronal cell death, as well as associated behavioral outcomes. I used multiple animal and cellular models of neuronal cell death, including Parkinson's disease, traumatic brain injury, and mice lacking expression of L-type calcium channels in the brain. I showed that the P7C3-series of compounds protect mature neurons outside of the hippocampus from otherwise overwhelming toxic insult, and that this protection is associated with preservation of normal neurological function. In these efforts, I also discovered a new function of the P7C3-series of compounds: preservation of normal axonal and mitochondrial integrity after injury. Together, these findings provide starting points for the development of new treatments for neurodegenerative disease, as well as tools to study the biology underlying these disorders.