The Value of Herbarium Collections to the Discovery of Novel Treatments for Alzheimer’s Disease, a Case Made With the Genus Eriodictyon

Abstract

Plants, in particular those with a history in traditional medicine, hold enormous potential as sources of new therapies for dementias such as Alzheimer's disease (AD). The largest collections of plants can be found in herbaria all over the world, but the value of these collections to AD drug discovery has been significantly neglected. As a proof of principle, we investigated the neuroprotective activity of herbarium specimens of Eriodictyon (yerba santa), a genus with a long history of usage by the indigenous tribes in California to treat respiratory and age-related complications. Dichloromethane extracts were prepared from leaves of 14 Eriodictyon taxa preserved in the SD Herbarium located at the San Diego Natural History Museum. The extracts were tested for neuroprotection in nerve cells against oxytosis and ferroptosis and for anti-inflammatory activity in brain microglial cells exposed to bacterial lipopolysaccharide. In parallel, the levels of the flavanones sterubin, eriodictyol and homoeriodictyol were measured by mass spectrometry. Several Eriodictyon species presented strong neuroprotective and antiinflammatory activities. The protective properties of the extracts correlated with the amount of sterubin, but not with eriodictyol or homoeriodictyol, indicating that sterubin is the major active compound in these species. The occurrence of eriodictyol and homoeriodictyol may be predictive of the phylogenetic relationship between members in the genus Eriodictyon. The data offer insight into the traditional use of yerba santa across indigenous tribes in California, while demonstrating the value of herbarium collections for the discovery of novel therapeutic compounds for the treatment of neurodegenerative diseases.

The Regulatory Effects and the Signaling Pathways of Natural Bioactive Compounds on Ferroptosis

“…Yerba santa is a plant that has been brewed into a tea and used as a bitter flavoring additive to foods historically by Native Americans [ 126 ]. Previous studies have demonstrated that sterubin extracted from Yerba santa exhibited strong neuroprotective properties and held notable potential as a neuroprotectant [ 127 , 128 ]. Recently, scientists found that sterubin is an effective iron chelator, which could inhibit ferroptosis in a dose-dependent way through increasing GSH, decreasing ROS levels and activating Nrf2/ATF4 signaling pathway in glutamate-treated HT22 cells [ 129 ].…”

The search for anti‐oxytotic/ferroptotic compounds in the plant world

“…Because our focus is on oxytosis/ferroptosis, we use a phenotypic screening assay that exposes cultured nerve cells to chemical inducers of oxytosis/ferroptosis (glutamate, erastin and RSL3) (Maher et al, 2020). We have shown that this assay is not only good at identifying natural inhibitors of oxytosis/ferroptosis but can also be used to screen extracts from plants with ethnopharmacological value and identify the underlying active agents (Currais, Chiruta, et al, 2014; Fischer et al, 2019; Maher, Fischer, et al, 2020). The assay also has the advantages of being simple, quick, of relatively low cost and high throughput, which significantly minimizes the unnecessary killing of animals.…”

“…Various methods to screen plant extracts and identify biologically active compounds have been used. A step-wise approach to identifying novel anti-oxytotic/ferroptotic neuroprotective compounds from plants is described below based on our own experience in successfully developing AD drug candidates as well as on the published literature (Atanasov et al, 2015;Azmir et al, 2013;Currais et al, 2018Currais et al, , 2019Currais, Chiruta, et al, 2014;Currais, Prior, et al, 2014;Fischer et al, 2019;Maher, Fischer, et al, 2020) (Figure 3) (for more details, please see an excellent review from Atanasov et al, 2015).…”

“…Another alternative is to work in collaboration with qualified entities such as research groups or botanists that have access to the plants of interest. We have recently shown that herbarium collections are also an excellent source of plants and that extracts can be prepared from small amounts of specimen material in a non-invasive manner (Maher, Fischer, et al, 2020). For initial screening purposes, the amount required for most assays is, in fact, minimal.…”

Development and Application of a Chemical Probe Based on a Neuroprotective Flavonoid Hybrid for Target Identification Using Activity-Based Protein Profiling

“…Natural products have been used in traditional medicine and are gaining increased attention for their potential as neuroprotectants interfering with disease progression. − The well-established antioxidant features of natural products, i.e., their radical scavenging abilities, are important for neuroprotection induced by oxidative stress . However, polyphenols as plant secondary metabolites have also shown to be neuroprotective by activating several intracellular pathways in addition to their antioxidative features .…”