In a new study by researchers at Vanderbilt University Medical Center, a chemical compound known as anacardic acid – found in the shell of cashew nuts – promotes the repair of myelin in animal models of multiple sclerosis (MS).
The internet of the human body
Our nervous system is often analogized with the internet. Why? The internet functions because of connectivity, and so does the human body. Just as one online user in America might communicate with another across the world in Japan, the human body is continuously transmitting information from one part of our body to another almost instantaneously.
Information moves around the internet via fiber optic cables, or sometimes by satellite. In the human body, information travels as electrical impulses via nerves; long fibers that are coated in a fatty insulating sheath known as myelin. The myelin sheath is critical to meeting the "need for speed" of the human nervous system. It contains breaks known as the nodes of Ranvier which enable electrical impulses to effectively "jump" across the nerve fiber. The speed of signal transmission in a myelinated nerve can reach up to 150 m/s, competing with the speed of an ar plane.1 In the central nervous system (CNS), myelin is produced by cells known as oligodendrocytes, whereas in the peripheral nervous system, it is produced by Schwann cells.
The importance of the myelin sheath can be observed in pathologies through which it is damaged or destroyed. The autoimmune condition MS is a key example, where myelin and oligodendrocytes are destroyed as part of an abnormal immune response in the CNS. Destroying the myelin leaves the nerve fiber susceptible to damage and "short-circuiting" of electrical signals occurs. Patients with MS can present with a variety of symptoms, including blurred vision, sensory impairments, problems with controlling movement and issues with bodily functions. MS is not a fatal condition, but it is often debilitating for patients and in most cases, eventually becomes degenerative, with each new bout of symptoms more severe than the last. As such, clinicians and research scientists are pursuing research to explore whether the myelin sheath is repairable or can regenerate.
A role for IL-33 in the CNS?
Natural recovery of the myelin sheath can and does occur – either by the body stimulating oligodendrocytes in the region of nerve damage or recruiting them from further away. Nonetheless, this process is slow and often incomplete, preventing full recovery of nerve function. Can scientists manipulate oligodendrocyte progenitor cells (OPCs) to encourage remyelination?
Subramaniam Sriram, professor of neurology and chief of the Division of Neuroimmunology at the Vanderbilt University Medical Centeris trying to find an answer. In 2016, Sriram published a paper in PLoS One in which he and colleagues examined the impact of adding an immunostimulant known as polyinosinic:polycytidylic acid (poly-IC), an agonist of a receptor known as toll-like receptor 3 (TLR3), and interleukin 33 (IL-33), a cytokine which is induced by poly-IC, to experimental models of CNS demyelination and in vitro OPC cultures.2
In the mouse model, recruitment of OPC and repair of myelin was decreased in IL-33 knock-out mice, which implied a neuro-reparative role for IL-33. As such, the scientists hypothesized that the inflammatory signals induced via TLR3 agonists and the subsequent induction of IL-33 could directly affect the recruitment and maturation of OPCs, promoting remyelination.
They decided to further analyze this by adding poly-IC and IL-33 to OPCs in vitro to explore the impact on OPC maturation and myelin-related genes. Poly-IC and IL-33 were found to induce transcription of myelin genes and the differentiation of OPC to mature myelin-forming cells.
Collectively, the studies suggested that poly-IC and IL-33 play a role in myelin repair, and as the authors state in the paper, are "attractive therapeutic agents for use as remyelinating agents in human demyelinating disease."
However, the exact mechanism behind poly-ICs’ activation of myelin genes could not be conclusively determined. In the discussion, the authors write: "Although both IL-33 and poly-IC, induce the activation of myelin genes, it is not clear if the induction of myelin genes by poly-IC is mediated exclusively by the induction of IL-33. We cannot exclude the existence of other pathways following activation of TLR3 which can positively regulate myelin gene expression and myelin repair."
Nutty for myelin
Fast-forward to 2020. Sriram and colleagues at Vanderbilt have published a new study in the Proceedings of the National Academy of Sciences.3 It's an extension of the 2016 work, and focuses on the proposed mechanism that poly-IC induces OPC maturation via IL-33 induction. Taking this hypothesis and running with it, the team decided to screen for small molecules which induce IL-33 expression. An attractive compound came from an unlikely source – cashew nuts.
The compound, known as anacardic acid, is found in the shell of cashew nuts, and was of interest to Sriram and team because it is known to inhibit histone acetyl transferase (HAT). Inhibitors of this enzyme are known to cause an induction of IL-33.
Anacardic acid became the study’s focus, and the impact of its application was explored both in animal models of disease – whereby myelin loss was experimentally induced – and in OPC cell culture.
Looking first at the in vitro study, the team confirmed that application of anacardic acid produces an increase in IL-33. When focusing on the expression of myelin basic protein (MBP) – a hydrophilic protein that has a central role in the organization of myelin sheath structure – they identified that administration of anacardic acid increased expression levels of MBP, as measured by Western blot. An increased expression of transcription factors such as Sp1, Sox10, and Purα that bind to the promoter region of the Mbp gene were also found compared to controls.
For in vivo analysis, Sriram and colleagues adopted two experimental animal models: cuprizone-induced demyelination and experimental autoimmune encephalomyelitis (EAE), the most commonly used model for human MS. Exploring the impact of anacardic acid across the two models, they found that dose-dependent treatment produced an increase in the presence of IL-33. Functional analysis also demonstrated a reduction in clinical paralysis when compared to the application of a vehicle control. This data was coupled with dissection microscopy performed on spinal cord segments in the EAE model, which revealed an increase in myelination when compared to the vehicle control. Dose-dependent increases in myelination were observed in the cuprizone model as quantified by electron microscopy of the corpus callosum of animals across the treatment and control group.
In the paper, the scientists explain their choice of methods for each model: "Our studies demonstrating remyelination using electron microscopy was performed in the cuprizone model, since the location of demyelination in this model, and unlike that with EAE, occurs in anatomically determined sites, allowing for comparison between treatment groups."
Discussing the research in a press release, Sriram said: "We see this as an exciting finding, suggesting a new avenue in the search for therapies to correct the ravages of MS and other demyelinating diseases."
He believes the work "urges" further study of anacardic acid for demyelinating diseases. In addition to exploring novel therapeutic avenues for MS, the scientists have also added to the body of literature examining the role of IL-33 in the CNS. Previous studies identified in the paper have proposed a role for IL-33 in transcriptional regulation, but this has not included myelin genes.
1. Purves et al. Neuroscience. Sunderland (MA): Sinauer Associates; 2001. Increased Conduction Velocity as a Result of Myelination. https://www.ncbi.nlm.nih.gov/books/NBK10921/. Accessed August 18 2020.
2. Natarajan C, Yao SY, Sriram S. TLR3 Agonist Poly-IC Induces IL-33 and Promotes Myelin Repair. PLoS One. 2016;11(3):e0152163. DOI:10.1371/journal.pone.0152163.
3. Ljunggren-Rose et al. Anacardic acid induces IL-33 and promotes remyelination in CNS. Proceedings of the National Academy of Sciences. 2020. DOI: 10.1073/pnas.2006566117