Secrets of Herbal Antidepressant Synthesis Are Uncovered
The historical use of the herb St. John's Wort (known botanically as Hypericum perforatum) as a medicinal compound is well documented, and includes its recommended use as a diuretic, wound-healing herb, treatment for menstrual pain, and as a cure for snakebites by Greek physicians of the first century.1
More modern applications of St. John's Wort have included its adoption for the treatment of psychiatric conditions such as depression. You may recall the Daily Express headline that proclaimed St. John's Wort as "good at lifting depression as drugs like Prozac" back in 2008. The story was based on a published meta-analysis of 29 studies that compared the effect of the plant Hypericum perforatum to placebos and anti-depressants in treating people with depression. A more recent study published in 2016 concluded that both St. John's Wort extract and selective serotonin reuptake inhibitors (SSRIs) are effective in treating mild-to-moderate depression, but that St John's Wort extract is a "safer" option than SSRIs.
Despite its long-standing use in both traditional and modern medicine, our understanding of how one of the key active metabolites in St. John's Wort, hypericin, is produced, is incomplete. Hypericin is synthesized and stored in the dark glands of St. John's Wort, but the precise mechanisms and processes involved in synthesis remain to be clarified.
A new collaboration by scientists from German and Canadian research institutes has shed light on such matters by discovering some of the key genes that are proposed as being involved in the development of the plant's dark glands, in addition to the biosynthesis of hypericin. Their findings are published in the Plant Biotechnology Journal.2
Previous research in this space had focused primarily on the leaves of St. John's Wort as a model organ for the study of hypericin biosynthesis. However, the research team in this study, led by Paride Rizzo from the Leibniz Institute of Plant Genetics and Crop Plant Research (IPK) in Gatersleben, adopted a different approach. They focused on the glands of St. John's Wort, stating in the paper that "Understanding which genes are involved in dark gland development and hypericin biosynthesis is important for the development of new Hypericum extracts that are highly demanded for medical applications."
The scientists phenotyped 93 Hypericum-accessions and discovered a polymorphism which resulted in glanded and glandless phenotypes in the placental tissue of the sample. Focusing on the placental tissue, they then identified two transcription factors whose expression was "strictly synchronized" with the differentiation of the dark glands.
Utilizing a variety of techniques including microscopy, transcriptomics and metabolomics, they characterized the development of the dark glands within the placental tissue. "To reveal genes involved in dark gland development and the synthesis of hypericin as well as other metabolites correlated with DGs, mRNAs were isolated from placentas of three glandless (H06‐1369, H06‐1489 and H06‐3251) and three glanded lines (HyPR‐05, HyPR‐09 and H06‐1988) at predifferentiation (FB25), differentiation (FB45) and postdifferentiation stages (FB75)," the authors say in the publication. They continue: "462 DEGs were identified, which occur in glanded comparisons, but not in glandless comparisons, and therefore are potentially related to DG development."
After demonstrating the utility of placental tissue as a new model organ for studying the dark glands, the scientists hope to build on this knowledge to advance modern medicine. "The candidates reported in this study, when combined with an efficient transformation pipeline, could be used to completely shut down or, alternatively, hyperactivate dark glands. The production of new genotypes containing high levels of hypericin or of hypericin‐free cultivars would be highly valuable for research on depression, cancer and Alzheimer's disease where these types of Hypericum extracts are already in high demand."
1. Klemow et al. (2011) Medical Attributes of St. John’s Wort (Hypericum perforatum). Herbal Medicine: Biomolecular and Clinical Aspects. Chapter 11. Available from: https://www.ncbi.nlm.nih.gov/books/NBK92750/.
2. Rizzo et al. (2019) Discovery of key regulators of dark gland development and hypericin biosynthesis in St. John's Wort (Hypericum perforatum). Plant Biotechnol J. DOI: https://doi.org/10.1111/pbi.13141