About 70 million people worldwide suffer traumatic brain injuries every year, and there are currently no approved drugs that can directly promote repair of damaged nerves and improve function. The research team of Chen Lingyi, a professor at the Tsinghua University Branch Hospital, discovered that the plant-derived compound "isoanacardin" can act on neurons and astrocytes at the same time, promote neurite repair, regulate oxidative stress, and provide a new research direction for the development of traumatic brain injury drugs. The research results were published in the internationally authoritative journal "Phytomedicine".
From plant screening, locking active compounds to analyzing the mechanism of action, the research process took more than 8 years. The team not only confirmed that isoanacardin has neurorepair effects, but also unraveled the mechanism by which it acts on two types of brain cells at the same time. One end acts on neurons, inhibiting S1PR3-related signals, allowing damaged neurites to re-grow; the other end acts on the NQO2 protein in astrocytes, reducing reactive oxygen species in the cytoplasm and mitochondria, improving the cellular environment required for nerve repair.
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Wang Yi, the first author of the paper and a doctoral student at the Tsinghua Branch Medical School, likens brain damage to a "broken nerve road." On the one hand, the road must be repaired to allow nerves to regrow; on the other hand, roadblocks and debris must be removed to reduce free radicals and oxidative stress. The team gradually verified from nerve cells, brain tissue slices and animal experiments. The results showed that allocardin can promote the re-growth of damaged neurites and improve the movement coordination of mice with traumatic brain injury. Brain tissue observations also showed that the repair of damaged areas in the treatment group was better.
Chen Lingyi said that when it was confirmed that isoanacardin has a nerve repair effect, the research was already eligible for publication, but the team still decided to continue to pursue it. "We must clarify what protein directly binds to isoanacardin." The team finally confirmed that isoanacardin can directly act on S1PR3 and NQO2, and also clarified the roles of the two in nerve repair. Chen Lingyi further emphasized that the discovery of this mechanism can serve as the basis for research on other nerve injuries and nerve inflammation in the future, including stroke and even "brain fog" caused by COVID-19. As long as nerve inflammation and repair needs are involved, further applications are possible.
In order to find candidate compounds that promote nerve repair, the team screened plant resources related to the Ku Yanzhuoyun Plant Conservation Center. The researchers tested more than 2,000 extracts made from nearly 900 kinds of plants one by one, and finally identified the active extract of Monstera oleracea. The researchers used about 1 kilogram of leaves for extraction, and then sent the active layer to Germany to isolate and identify single compounds, and finally found isoanacardin.
Li Jiawei, CEO of the Ku Yanzhuoyun Plant Conservation Center, said that this cooperation is the best research result of the drug bank so far. Other research is still continuing to develop, and the drug bank still has great research potential in the future. After the team found heteroanacardiin and analyzed the chemical structure, they turned to full chemical synthesis, which no longer required the continuous collection of plant materials. Wang Yi explained that currently, in cooperation with the Department of Chemistry at Tsinghua University, the laboratory has been able to complete the synthesis at the gram level and above, and produced analogues of different structures to compare the efficacy, laying the foundation for subsequent improvement and development.
Studies have shown that isoanacardin can be measured in the brain tissue of mice 15 minutes after nasal administration, showing the ability to enter the brain. Chen Lingyi said that nasal drug delivery has the characteristics of non-invasive and convenient use; if the subsequent new drug development, safety and clinical trials go well, nasal spray and other drug delivery methods can be evaluated in the future. Mild patients will have the opportunity to use it by themselves, and severe patients will have the opportunity to use intravenous drug administration.
Tsinghua University currently has a patent layout for related compounds. Wang Yi said that if we want to move forward to clinical trials, we still need to complete larger-scale drug manufacturing and toxicological testing. The team is also preparing for subsequent clinical trials of new drugs. The next step will be to apply for clinical trial-related consultation from the U.S. Food and Drug Administration (FDA).
