Discovering novel natural products from the Chilean medicinal flora of La Araucanía with neuroprotective activity for the treatment of aging-related cognitive impairment

• Grant number: 24/13124-4
• Support Opportunities: Regular Research Grants
• Start date: April 01, 2025
• End date: March 31, 2027
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Alexander Henning Ulrich
• Grantee: Alexander Henning Ulrich
• Principal researcher abroad: Cristian Fabian Paz Robles
• Institution abroad: Universidad de La Frontera (UFRO), Chile
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Alexandre Hiroaki Kihara ; Antonio Camins Espuny ; Roberto De Pasquale ; Robson Coutinho Silva ; Talita Glaser
• Associated scholarship(s): 25/07141-6 - Evaluation of natural products from the Chilean medicinal flora of La Araucanía on hippocampal neuronal activity - possible underlying mechanism of neuroprotection, BP.TT

Abstract

The current global sociodemographic scenario is characterized by an increase in life expectancy and an increasingly aging population. Chile and Brazil have an aging population in increasing leading to an increase in the prevalence of age-related diseases Alzheimer's (AD) and Parkinson's disease (PD) are the leading cause of disability and these disorders are expected to significantly increase within the next decades. Natural product plays a crucial role in drug development, with countless combinations of molecular structures opening new possibilities for the treatment of diseases. The market for natural neurodegenerative palliative compounds is increasing worldwide, the Araucanía Region in Chile is the place where the Mapuche People leave. This originary people of center-south of Chile and Argentina has a great knowledge of medicinal plants, which we will explore in a preliminary screening for neuroprotective activities. For that reason, we propose to isolate natural compounds from medicinal plants like Drimys winteri, Drimys andina, Austrocedrus chilensis, Cryptocarya alba, Leptocarpha rivularis, Lithraea caustica, Podanthus mitique, alkaloids of Aristotelia chilensis and Lobelia, followed by the purification and structure determination of the bioactive compounds. The compounds will be subjected to a preliminary screening based on cell survival and the modulation of intracellular calcium fluxes evoked by nicotinic acetylcholine and ATP-activated purinergic receptors as well as of which inflammatory pathways including the nuclear factor kapa b(NF-kB), and the Nrf2 transcription factor that plays a critical role in the oxidative stress stabilization. The most activate compounds will be further studied using oocyte-voltage clamp for their effects on nicotinic acetylcholine receptors (nAChRs) and their activities on P2Y2 and P2X7 receptors in calcium-imaging experiments. Furthermore, active compounds will be investigated regarding with mouse hippocampal slice electrophysiology to evaluate their impact on neuronal excitability, basal synaptic transmission, and synaptic plasticity. Our hypothesis is that the anti-inflammatory properties of these active compounds will: a) enhance hippocampal function by increasing synaptic plasticity, as measured by the induction of long-term potentiation, and b) reduce basal excitatory transmission and neuronal excitability of pyramidal cells, thereby mitigating the excitotoxicity associated with aging that can lead to oxidative stress. This proposal gather the results from the project CONICYT-FAPESP 2018/08426-0 (Indolic alkaloids, by-products of Maqui (Aristotelia chilensis) processing as food additives in the treatment of Alzheimer's disease) with pure compounds from Aristotelia chilensis and Drimys winteri having shown inhibition of nAChR and anti-inflammatory activities. Further, the therapeutic potential of a natural compound as drug target depends on the identification of which pathways are altered. In view that, we will perform a proteomic analysis followed by bioinformatic analysis to determine the efficacy of the molecules tested. This project will not only characterize neuroprotective activities of Chilean natural products with possible therapeutic applications in aging related neurodegeneration, but also promote interdisciplinary research of between Brazilian and Chilean research group and create collaborative links with scientists from Spain and Germany. (AU)