Eliciting the Hormetic Effect: The Importance of Plant Alkaloids for Treatment of Inflammation
Eliciting the Hormetic Effect: The Importance of Plant Alkaloids for Treatment of Inflammation
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In a story that is legendary in the annals of medicine, the 18th century English botanist William Withering learned from “old Mother Hutton,” a folk herbalist, that a concoction including foxglove (Digitalis purpurea), the garden flower, could be used to treat dropsy. Withering’s investigation into the active ingredient in the herbal formulation led to the discovery of digoxin, a plant alkaloid still used as a treatment for congestive heart failure, as dropsy is now known.
Though the existence of an actual old Mother Hutton has been called into question, Withering’s isolation of digoxin from a folk remedy highlights the importance of plant alkaloids in medicine for thousands of years. In addition to digoxin, the long list of plant-based alkaloids of pharmacological interest includes morphine used for pain, colchicine for gout, ephedrine for low blood pressure, paclitaxel for cancer and quinine for malaria.
Today, plant alkaloids are attracting notice1 as novel therapies for conditions involving inflammation, such as metabolic syndrome and autoimmune disease and even for aging, which are often characterized by chronic, low-grade over-activation of the immune system.2 In the case of metabolic syndrome and autoimmune disease, science is also finding that, because of their specificity, plant-derived therapies sometimes have fewer serious side effects than conventional treatments.
The phenomenon of hormesis
Though plant alkaloids, which are thought to be produced by plants under duress to defend against insects, microorganisms and herbivorous animals, can be toxic in large doses, they can also be therapeutic in low doses, a phenomenon known as hormesis.3 Similarly, toxic phytochemicals found in many foods exert a favorable hormetic effect in the small amounts in which they are consumed: for instance, the sulforaphanes in broccoli, the catechins in green tea or the allicins in garlic.
As a result of the insight into the inner workings of the cell enabled by the genomics age, science now knows that hormesis kicks the molecular machinery of the cell into protective gear. While too much of a toxic substance can damage the body, an optimal amount activates potent repair and maintenance programs in the cell that have evolved over billions of years to promote survival under challenging environmental conditions.
In healthy people, the immune system mounts an inflammatory response to an infection that lasts only as long as it is needed to vanquish the invading foes. Drugs that stimulate hormesis are of interest in the treatment of metabolic syndrome, autoimmune diseases and aging because of their potential to regulate the immune system. But in people with these conditions, the immune system becomes jammed in the “on” position, leading to chronic, low-grade inflammation.
By subjecting the body to a mild stress, drugs derived from plant alkaloids trigger a favorable response that helps restore balance to a dysfunctional immune system.
The need for novel treatments
The need for new anti-inflammatory drugs is critical due to the growing incidences of autoimmune disease, as well as to a rapidly aging worldwide population.
According to one study,4 a fifth of the adult population of Western countries now suffers from metabolic syndrome, a cluster of symptoms associated with chronic, low-grade inflammation that increases the risks of developing Type 2 diabetes, heart disease, stroke and other “lifestyle” diseases. The symptoms of metabolic syndrome include high blood pressure, high triglyceride levels, elevated fasting blood sugar and reduced high-density lipoprotein or “good” cholesterol.
Also on the increase are autoimmune diseases, a family of more than 80 chronic, often debilitating and in some cases life-threatening diseases that occur when the immune system launches an inflammatory response that attacks the body instead of defending it. Some of the most common autoimmune diseases are insulin dependent diabetes, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus.
Finally, aging of the population is calling attention to the phenomenon of inflamm-aging,5 a chronic, progressive increase in inflammation that occurs over time as the human body ages. While average lifespan has increased by approximately 30 years since 1900, old age is often blighted by multiple degenerative diseases in which inflammation is the common denominator, including Alzheimer’s, arthritis, cancer, cardiovascular disease, diabetes and sarcopenia.
While drugs exist to treat the symptoms of these conditions, the limited options for treatment of the underlying inflammation highlights the need for safe, effective new therapies. In some cases, the answer has been to revisit plant-derived compounds that have been used for hundreds of years to treat inflammatory conditions with the goal of developing novel synthetic versions of their pharmacologically active ingredients.
Harnessing the benefits of plant alkaloids
When used as anti-inflammatories, plant alkaloids prompt the machinery of the cell to shift into maintenance and repair mode, which has the effect of putting the brakes on runaway inflammatory responses that can damage tissues, organs and joints.
One new drug that is attracting notice is MYMD-1, an alkaloid derived from the tobacco plant that is being studied for treatment of autoimmune diseases such as multiple sclerosis5 and autoimmune thyroiditis.6 MYMD-1 works by inhibiting the production of tumor necrosis factor alpha (TNF-α), an inflammatory cytokine or immune cell signaling protein, that is responsible for inducing and maintaining the inflammatory process.
Because TNF-α is located at the head of the cascade of molecular signals that induces inflammation, MYMD-1 addresses autoimmune disease by cutting off inflammation at its source, rather than by treating its symptoms. Another potential therapeutic application of MYMD-1 is as a modulator of the pro-inflammatory response and impaired immune functioning underlying age-related diseases associated with inflamm-aging.
Another drug being developed as an anti-aging therapy is the diabetes drug, metformin, which was originally derived from the plant alkaloid isoamylene guanidine found in goat’s rue, which has been used as a folk remedy for hundreds of years. Though its common name derives from the fact that it is toxic to goats and other animals, in the low doses in which it is being studied as an anti-aging drug, it exhibits a hormetic effect.
Metformin is the subject of the landmark TAME (Targeting Aging with Metformin) trial,7 which will be the first FDA-sanctioned clinical trial to provide proof-of-concept that aging is a modifiable condition that can be treated just as medicine treats other diseases. If successful, the trial will open the door to new anti-aging therapies with the ability to treat many age-related degenerative diseases at once, instead of treating each separately.
Scientists who study plant alkaloids believe it evolved to allow primitive organisms to respond to the toxic substances, environmental challenges, lack of food and other stressors to which they were constantly exposed under the harsh conditions in which life evolved. Though billions of years have since elapsed, the genetic mechanisms that allowed these organisms to cope with these challenges have been passed down through evolution, or conserved, in our genes.
Today, science is taking advantage of the hormetic response elicited by plant alkaloids to develop safe, effective drugs based on time-tested herbal remedies that, because they target the underlying inflammation rather than symptoms, offer new hope to the millions suffering from pro-inflammatory diseases and conditions.
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8. Kulkarni AS, Gubbi S, Barzilai N. Benefits of metformin in attenuating the hallmarks of aging. Cell Metab. 2020;32(1):15–30. doi:10.1016/j.cmet.2020.04.001
About the author
Dr Adam Kaplin is the chief scientific officer of MyMD Pharmaceuticals, a clinical-stage pharmaceutical company focused on the development of drug products that represent a transformation in the targeting of aging and age-related diseases; autoimmune diseases; and chronic pain, anxiety and sleep disorders. As a neuropsychiatrist in Baltimore, he cares for patients with central nervous system neuroinflammatory diseases, such as multiple sclerosis (MS) and related MS-spectrum diseases. Before joining MyMD Pharmaceuticals, he was the principal psychiatric consultant to the Johns Hopkins Multiple Sclerosis Center of Excellence and the clinical director of the Johns Hopkins Psychiatric Esketamine Clinic.