This Millipede’s Secretions Could Help Target Brain Disorders, Scientists Say

BLACKBURG, Va. — Scientists exploring millipede defensive secretions in the forests of Virginia have discovered 18 previously unknown natural compounds, some of which interact with brain receptors linked to neurological diseases. One of these molecules, found in the species Andrognathus corticarius, binds to sigma-1 receptors, proteins that are emerging targets for treating conditions like Alzheimer’s, depression, and chronic pain. While the biological activity was modest, researchers say these complex molecules could inform future drug development efforts.

Millipedes in the species Andrognathus corticarius produce a cocktail of defensive chemicals that trigger freezing behavior in ants and include a compound that interacts with specialized brain proteins called sigma-1 receptors. These receptors are potential targets for treating a range of neurological disorders, and the discovery adds to the growing catalog of naturally occurring molecules that might one day be leveraged in drug development.

Scientists at Virginia Tech and the National Cancer Institute identified two previously unknown classes of molecules, which they’ve named andrognathines and andrognathanols. Many widely used medications, including treatments for neurological disorders, have been derived from natural compounds produced by plants, animals, and microbes.

Unlocking the Ancient Chemistry of Millipedes

Repugnatorial glands, the organs millipedes use to release defensive secretions, evolved over 385 million years ago, but researchers are only beginning to uncover the complexity of the chemicals these glands produce. Most millipede species generate relatively simple toxic compounds, but A. corticarius produces molecules with three-dimensional structures that rival those found in modern pharmaceuticals.

Emily Mevers and her team at Virginia Tech spent years collecting these millipedes from rotting logs across the southeastern United States. A. corticarius belongs to a rare group of millipedes that exhibit social behaviors such as forming aggregations of more than 100 individuals and caring for their eggs.

Chemical analyses revealed that each millipede contains, on average, 86 nanograms of the chemical mixture per defensive gland. Mature millipedes have over 100 ozopores (gland openings) running along their segmented bodies, allowing them to secrete the compounds when physically disturbed.

To explore the potential ecological role of these chemicals, researchers ran behavioral assays using Aphaenogaster ants, which share the same forest habitat. Individual ants were placed in arenas with filter paper treated with millipede extracts, and their behavior was tracked for 15 minutes using video analysis software.

Ants exposed to the chemical mixture spent significantly more time motionless than control groups exposed to untreated paper or solvent. While the ants did not avoid the treated areas or move more slowly overall, they experienced prolonged periods of freezing behavior, suggesting the compounds may serve a defensive function.

Brain Receptor Activity Shows Medical Potential

One of the newly discovered compounds, andrognathine A, demonstrated moderate activity against sigma-1 receptors, which are brain proteins involved in a range of neurological processes. Andrognathine A bound to these receptors with lower affinity than similar compounds identified in earlier millipede studies, while structurally more elaborate molecules in the group showed no activity against either sigma-1 or sigma-2 receptors.

Determining the precise molecular structures of these compounds required sophisticated analytical methods, including high-resolution mass spectrometry and nuclear magnetic resonance. Each compound also exists in multiple versions with different fatty acid side chains attached, producing dozens of unique molecular variants.

While none of the compounds exhibited strong activity, the fact that even a single molecule from A. corticarius bound to a brain receptor of pharmacological interest is noteworthy. The sigma-1 receptor has emerged in recent years as a target in research on neurodegenerative diseases, mood disorders, and chronic pain —conditions that remain difficult to treat effectively. Because sigma-1 is involved in regulating neural signaling, inflammation, and even cell survival, molecules that modulate its function are of high interest to drug developers.

Although the binding strength of andrognathine A was modest compared to other known compounds, its novel chemical structure could serve as a starting point for future medicinal chemistry efforts. Researchers note that many of today’s leading drugs began as naturally occurring molecules with only weak activity, later refined through structural modifications. The millipede-derived alkaloids may follow a similar path, provided further research uncovers more potent analogs or clarifies their biological effects in living systems.

Even in well-studied parts of the United States, nature continues to yield chemically rich organisms with potential relevance to human health. The intricate defensive molecules produced by a reclusive millipede under decaying logs may offer new leads for probing brain chemistry—and possibly for addressing neurological diseases in the long term.

Disclaimer: This research is in the early stages and does not suggest that millipede secretions are ready to treat human diseases. The compounds studied have shown limited activity in lab-based receptor tests and have not been tested in animals or humans. Any future medical applications would require extensive further research.