Identification of novel botanical derived NRF2 activating agents with potential against Alzheimer’s disease from Malagasy plants

About This Grant

The incidence of Alzheimer’s disease (AD) in the USA is expected to increase from 7.2 million to 13.8 million by 2060, highlighting the urgent need to discover new treatments. Madagascar is known for its unique plant biota and hosts about 12,000 plant species, of which 80% are endemic. Malagasy flora has provided clinically used bioactive compounds such as the anticancer drug vincristine. Madagascar is now among the top priority conservation sites in the world since the forest is deteriorating due to urban expansion, pollution, bushfires, and poverty. The overall goals of this proposal are (1) to assist in conserving the unique plants of Madagascar by developing a model program for bioprospection and conservation, (2) to identify plants from Madagascar that contain phytochemicals that can be used against Alzheimer’s disease (AD), and (3) to promote scientific training and capacity development in the island. This project will focus on three main objectives involving medicinal plant inventory and conservation, exploration/discovery, and training and capacity building. Plants have been used in traditional medicines for central nervous system (CNS)-related conditions and many are known to produce antioxidant compounds. We aim to perform an ethnobotanical survey and develop conservation approaches for plants that are being used in traditional medicine for brain-related diseases including dementia and contain neuroprotective constituents from among the rich biodiversity of flora in Madagascar. Oxidative stress can impair the functions and activities of the CNS and has been shown to contribute to the onset and progression of many neurodegenerative conditions including AD. Our previous studies have shown that that activation of NRF2, which is an antioxidant regulatory transcription factor, elicits neuroprotection both in vitro and in vivo, can attenuate decreases in dendritic arborization and synaptic density, reduces oxidative stress, and improves mitochondrial function in hippocampal neurons isolated from AD mice as well as in the brains of AD mice treated with NRF2 activators. These data suggest that identification of NRF2-activating compounds could be a useful approach to discovering novel AD therapeutic compounds. Based on the structures of previously isolated bioactive compounds and their plant families of origin, we hypothesize that plant species with a high level of endemicity from the Malagasy flora will produce many previously unknown NRF2-activating compounds. The project will assist aging populations developing AD diseases by not only identifying and standardizing plants that have already been used in traditional medicine but also discovering new chemical scaffolds for discovering AD drugs.