Californian 'Holy Herb' a Potential Treatment for Alzheimer's?

Batya Swift Yasgur, MA, LSW

February 25, 2019

An extract of yerba santa (Eriodictyon californicum), a native Californian medicinal plant, has been shown to have neuroprotective properties and may be a promising new compound in the treatment of Alzheimer disease (AD), new research suggests.

Investigators used a panel of phenotypic screening assays that mimic the toxicities seen in the aging brain to test an array of extracts from plants with identifiable pharmacologic uses.

Analysis of an extract from the yerba santa herb — the name is Spanish for "holy herb" — identified the flavanone sterubin as the active component of the plant. Sterubin was found to have neuroprotective and anti-inflammatory effects.

"We found that yerba santa extract was one of the most potent from the library of plant extracts we analyzed, primarily due to the flavonoid sterubin, which had not previously been studied in the context of neuroprotection," senior author Pamela Maher, PhD, senior staff scientist, Salk Institute, La Jolla, California, told Medscape Medical News.

"We hope that sterubin might decrease age-related changes in the brain, as well as perhaps other tissues, and this might lead to slowing the development of AD, since old age is the major risk factor for the disease," she said.

The study was published online February 20 in Redox Biology.

Urgent Need for New Treatments

Recent research into the treatment of disease has typically utilized a paradigm that identifies drug candidates with high selectivity and affinity for a specific molecular target, the authors write.

This approach, however, has "not produced the successes that were initially expected, especially with respect to complex neurodegenerative diseases such as AD," they state.

Prior to the development of target-based agents, drugs were discovered "by evaluating chemicals against observable characteristics or phenotypes in biological systems, such as cells or animals" — a method known as phenotypic screening.

"There are no drugs for the treatment of AD or other age-related neurodegenerative disease, indicating that new approaches to identifying drug candidates are sorely needed," Maher said.

The researchers used a panel of phenotypic screening assays that screened for observable characteristics rather than a specific target.

The panel was developed "as an alternative approach to identifying potential drug candidates for AD, since the focus of most drug discovery for AD has been a specific target, the amyloid pathway, and drugs directed against this target have all failed in clinical trials," said Maher.

"Since natural products are the original source of many drugs now in the clinic, we decided to start this screen with a library of plant extracts," she said.

400 Plants Screened

The phenotypic screening approach combined multiple assays to enable "the identification of potent, disease-modifying compounds for preclinical testing in animal models of neurodegenerative diseases," the authors explain.

These assays generally involve primary neurons, neuronlike cell lines, or microglial lines that have been subjected to toxic insults that have been observed in the aging brain in general and, to a larger extent, in AD.

The researchers used these assays to screen a commercial library of 400 different plant extracts and previously uncharacterized neuroprotective flavonoids.

The generality of the toxicity pathway in oxytosis and its mechanistic association with aging and AD made it a good assay to quickly and simply screen the various extracts.

They initially tested all plant extracts in the oxytosis assay in HT22 mouse hippocampal nerve cells.

Those that were found to be positive in this assay were then screened in several additional assays that assessed for protection against energy depletion in HT22 hippocampal nerve cells; intracellular amyloid toxicity in MC65 human nerve cells; inhibition of inflammation medicated by microglial activation using BV-2 mouse microglial cells; and differentiation of rat PC12 cells, the authors recount.

They explain that these assays "reflect multiple, age-associated neurotoxicity/survival pathways directly relevant to AD, such as increased oxidative stress and glutathione (GSH) depletion, reduced energy metabolism, accumulation of misfolded, aggregated proteins, loss of neurotrophic support, and inflammation."

The particular models were chosen to provide an approach that was replicable, cost-effective, and time-effective.

Neuroprotective Properties

Of the 400 plant extracts, the researchers identified nine that provided significant protection from glutamate at the degree of dilution used.

When these extracts were further analyzed for neurotrophic activity (PC12 differentiation) and anti-inflammatory activity (BV-2 cells), as well as direct toxicity, two extracts, called "C" and "G," were identified. These were highly protective in the oxytosis assay and showed strong anti-inflammatory and neurotrophic activity.

Moreover, these extracts demonstrated <10% cell growth inhibition at the protective doses.

Yerba santa was the source of "C" and was of "significant local interest," because it is a shrub native to California.

The researchers applied a further set of methods to ascertain which particular chemicals in "C" were biologically active and identified two flavonoids, homoeriodictyol and sterubin. Of these, sterubin was found to be the more active compound.

Because the first step of oxytosis involves loss of major endogenous intracellular GSH, which is an antioxidant, the researchers investigated whether sterubin could preserve GSH levels.

They found that sterubin increased GSH levels in a dose-dependent manner in control cells and also maintained the levels of GSH in cells treated with glutamate to induce oxytosis.

Moreover, sterubin provided "excellent" dose-dependent protection against two inducers of ferroptosis, a cell death pathway closely related — if not identical — to oxytosis.

Ferroptosis is an iron-dependent form of cell death, and iron chelators offer protection from oxytosis. The researchers therefore investigated whether sterubin can chelate iron, which might contribute to its antioxidant properties.

A ferrozine assay found that sterubin was indeed an effective iron chelator, even at a 1:1 ratio of flavonoid to iron.

Other assays found that sterubin altered the level of transcription factors responsible for upregulating GSH in HT22 cells and also exerted an anti-inflammatory effect on BV-2 microglial cells.

Sterubin was additionally found to strongly reduce, in a dose-dependent manner, the production of proinflammatory cytokines, including nitric oxide, interleukin-6, interleukin-11β, inducible nitric oxide synthase, and cyclooxygenase-2.

Yerba santa has long been known to have medicinal properties. Historically, it has been used by Native Californian tribes to treat a variety of ailments, including respiratory conditions, fever, bruises, infections, and pain, the authors observe.

"Thus, its anti-inflammatory properties are well-documented, consistent with the potent anti-inflammatory effects of sterubin in our in vitro assay," they comment.

Not only is sterubin anti-inflammatory, but it is also effective against multiple inducers of cell death that activate distinct cell death pathways, they add.

Innovative Approach

Commenting on the study for Medscape Medical News, Gregory Cole, PhD, interim director, Mary S. Eastern Alzheimer Center, and professor, Departments of Neurology and Medicine, University of California, Los Angeles, said that the "phenotypic screening approach developed by Maher and colleagues is conceptually innovative in attempting to find a predictive panel of in vitro toxicity assay to screen and identify protective candidate compounds with the potential to mitigate aging and age-related diseases."

This is important because "aging is a notoriously complex and multifactorial process, and in most species, there is no evidence for a single pathway controlling it," he said.

Moreover, "in complex tissues like the brain, there are select populations of neurons that are more vulnerable to aging per se, populations vulnerable to specific age-related diseases, and also populations that are more resilient," Cole added.

Thus, the assay "screens for what this group [of investigators] calls 'gero-protectors' that confer a resilient phenotype," he said.

"One caveat with all of these natural polyphenols is their propensity to high rates of intestinal glucuronidation and first-pass metabolism, but the advantage is that this also limits toxic dosing. That these natural-product protective polyphenols can be readily advanced to clinical trials adds to the potential impact of this report," he added.

Maher said that in the future, the team hopes to test sterubin in animal models of AD.

Specifically, "we have an animal model of accelerated aging that develops the behavioral characteristics of AD — memory loss — but also other changes associated with aging in general, and we are very interested in seeing if sterubin would be effective against any or all of these changes," she said.

The research was supported by the National Institutes of Health, the Edward N. and Della Thome Memorial Foundation, and the Paul F. Glenn Center for Aging Research at the Salk Institute. No relevant financial relationships of authors were listed in the study. Cole reports having a UCLA/VA patent on a curcumin formulation licensed to Verdure Biosciences and a medical food patent with DHA/fisetin through UCLA, also licensed by UCLA.

Redox Biol. Published online February 20, 2019. Full text

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