Contribution of Levodopa to Brain Iron Accumulation

PROJECT SUMMARY/ABSTRACT The antiparkinson drug levodopa (L-DOPA) is the current standard of treatment for Parkinson’s Disease (PD) and can be used as either a monotherapy or in combination with monoamine oxidase-B (MAO-B) inhibitors, such as selegiline to ameliorate dopamine depletion. Despite L-DOPA’s recognition as the gold standard for PD management, our group has recently made a fundamental observation of iron accumulation in the substantia nigra (SN) of PD patients following L-DOPA but not selegiline administration. These findings indicate that the type of antiparkinson drug may be correlated with nigral iron increase. Evidence suggests that nigral iron accumulation is increased in PD patients, decreasing dopamine thus exacerbating the progression of neurodegeneration. Though, it remains unclear whether increased iron in the SN is from PD itself or from L- DOPA treatment. My objective for this proposal is to demonstrate that L-DOPA exposure alters the iron status through direct effects on dysregulation at the BBB (Aim 1) and/or through altering the molecular and cellular profile in the SN (Aim 2). Aim 1 of this project will elucidate how L-DOPA exposure will cause an increase in iron transport from the blood-brain barrier (BBB) to the brain in an in vitro BBB model. I will measure iron transport in endothelial cells after drug administration. Aim 2 will examine how L-DOPA delivered orally will impact the molecular, histological landscape, and iron metabolism in the ventral midbrain. Furthermore, Aim 2 will take a unique perspective to study how iron deficiency alters brain iron and exacerbate the severity of iron accumulation in a rat model by examining brain iron levels and immunohistological staining expressions. PD patients have a high prevalence of an anemic diagnosis, however, there is minimal research regarding the effects of L-DOPA and anemia on brain iron homeostasis. This research project will deepen our understanding of how antiparkinson treatments such as L-DOPA and selegiline impact iron homeostasis with the hopes of identifying iron-based mechanisms from the treatment. Importantly, advances in iron supplements will provide novel therapeutic targets to improve our standard of care for PD patients The proposed training plan is sponsored by Dr. James Connor. The overall goal of the training plan is to provide the fellowship applicant with a solid foundation for a successful career as a researcher and enhance techniques for translational studies. The goals included in the training plan are 1.) Gain experience and competence in various techniques integrating iron biology and neuroscience, 2.) collaborate with other research scientists to learn and complement my knowledge, 3.) develop hypothesis-driven research, 4.) conduct translational research, and 5.) effectively present data in a manuscript.