Britney Williams

2006 B.S., University of Louisiana at Lafayette, Lafayette, Louisiana

Mentor: Dr. Donard Dwyer

Brain deficit disorders affect a large percentage of the population, yet there are few drugs available for effective treatment. These disorders include neurodevelopmental conditions such as Rett Syndrome, Autism, and Schizophrenia, and neurodegenerative diseases, such as Alzheimer’s. Brain deficits may occur as a result of neurite retraction, impaired synaptogenesis, altered pruning, disturbed neuronal migration and/or differentiation, loss of neuronal survival, or decreased synaptic connectivity. Consequently, the goal of our research is to identify compounds that promote neurite outgrowth as a means of reversing or blocking the emergence of deficits in neurotransmission. These studies were inspired by the observation that olanzapine, a second generation antipsychotic drug, stimulates neurite outgrowth in PC12 (pheochromocytoma) cells. Using its structure as an initial prototype, we identified structurally similar compounds by screening commercially-available chemical inven tories. These compounds were then tested in biological assays for their ability to provide neuroprotection in cell viability assays and enhance neurite outgrowth. Several small molecules (m.w. < 550 daltons) stimulate neurite outgrowth in PC12 cells comparable to nerve growth factor. Currently, studies are underway to characterize their mechanism of action. Mechanistic studies of olanzapine suggested that the compounds might activate extracellular signal-regulated protein kinase (ERK) and Akt/protein kinase B (PKB) pathways to promote neuronal viability and neurite outgrowth. However, preliminary work indicates that alternative pathways may be involved, including DNA binding. Therefore, the aim of this project is to find compounds that promote neurite outgrowth and determine their mechanisms of action.