Parkinson's disease (PD) is a debilitating, age-related neurodegenerative disorder that results from a loss of dopamine neurons in the substantia nigra. This neuronal death is believed to involve: 1) a loss of function in mitochondria;2) oxidative stress;and 3) aggregation of the presynaptic protein 1-synuclein. Current pharmaceutical treatments address the symptoms resulting from the loss of neurons, but they do not prevent the progression of the disease and the underlying continued neuronal death. Thus, there is a critical biomedical need to discover new treatments to slow the progression of PD and other age-related neurodegenerative disorders. Fruits such as blueberries, grapes, and black currants are an abundant source of a diverse class of biologically active, polyphenolic molecules called anthocyanins. These natural products (which exist in a glycosylated form) are potent antioxidants. Previous studies have shown that only the glycosylated anthocyanins are present in the brain after oral administration;however, the sugar moiety is rapidly hydrolyzed during digestion to give the anthocyanin aglycone (called anthocyanidin), and high oral doses must be given to observe any biological effects. In this study, we will address whether anthocyanins found in various botanical extracts and metabolically stable derivatives, where the sugar group cannot be hydrolyzed, are reasonable lead structures for drug discovery to promote neuron survival in Parkinson's disease. Our key data driving this effort is the identification of neuroprotective effects of anthocyanin-rich extracts (and two individual anthocyanins) in a primary cell culture model of PD. Additional in vivo studies in rats and pigs following administration of anthocyanin-rich extracts led to the identification of one of the same individual anthocyanins in the brain tissue. Also, we have developed a new synthetic method to replace the unstable glycosyl linkage of the anthocyanins with a stable, fluorinated methyl group. The collective expertise of the Colby group (synthesis of natural product derivatives), Rochet group (characterization of bioactivity of botanical extracts in cellular models of PD), and Ferruzzi/Janle group (analysis of polyphenol bioavailability in rat brain) places us in a strong position to develop and characterize anthocyanin derivatives with enhanced stability, brain bioavailability, and neuroprotective activity. Our central hypothesis is that metabolically stable semisynthetic anthocyanins will increase neuron viability when administered in low doses. Our studies are innovative, because the identification of lead structures from naturally occurring compounds that prevent neuronal death in PD models would be valuable in the development of new treatment strategies for this age-related, neurodegenerative disorder. Also, there are no efficient synthetic methods to replace the labile linkage in these molecules with fluorinated methyl groups. A metabolically stable and biologically active anthocyanin derivative would be a significant lead structure for use in drug development in age-related neurodegeneration.
Parkinson's disease disrupts the lives of an estimated 5 million people worldwide, and current therapies only temporarily relieve symptoms without slowing the underlying neurodegeneration. As our population continues to age, the financial burden associated with Parkinson's disease and other age-related neurodegenerative disorders will become more severe unless ways to prevent, delay, or treat these diseases are implemented. In this project we will seek to develop new molecules that may have value in drug discovery to decrease the risk of Parkinson's disease and other age-related neurodegenerative disorders in humans.
|Strathearn, Katherine E; Yousef, Gad G; Grace, Mary H et al. (2014) Neuroprotective effects of anthocyanin- and proanthocyanidin-rich extracts in cellular models of Parkinson?s disease. Brain Res 1555:60-77|
|Griggs, Amy M; Agim, Zeynep S; Mishra, Vartika R et al. (2014) 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is selectively toxic to primary dopaminergic neurons in vitro. Toxicol Sci 140:179-89|
|John, Jinu P; Colby, David A (2011) Synthesis of ?-halo-?,?-difluoromethyl ketones by a trifluoroacetate release/halogenation protocol. J Org Chem 76:9163-8|