In laboratory experiments, a chemical compound found in the shell of the cashew nut promotes the repair of myelin, a team from Vanderbilt University Medical Center reports today in the Proceedings of the National Academy of Sciences.
Myelin is a protective sheath surrounding nerves. Damage to this covering – demyelination – is a hallmark of multiple sclerosis and related diseases of the central nervous system.
“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,” said the paper’s senior author, Subramaniam Sriram, MBBS, William C. Weaver III Professor of Neurology and chief of the Division of Neuroimmunology.
Previous work led by Sriram showed that a protein called interleukin 33, or IL-33, induced myelin formation.
IL-33 is, among other things, an immune response regulator, and multiple sclerosis is an autoimmune disorder.
The cashew shell compound is called anacardic acid.
Sriram and team grew interested in it because it’s known to inhibit an enzyme involved in gene expression called histone acetyltransferase, or HAT, and the team had discovered that whatever inhibits HAT induces production of IL-33.
The report includes a range of new findings that point to potential therapeutic use of anacardic acid for demyelinating diseases:
- In vitro, the addition of the compound to rat cells most responsible for myelination – oligodendrocyte precursor cells, or OPCs – spurred induction of IL-33 and rapidly increased the expression of myelin genes and proteins, including dose-dependent increases in myelin basic protein.
- In two animal models of demyelination, treatment with the compound increased the relative presence of
- IL-33-expressing OPCs and led to reduced paralysis.
- In an animal model of demyelination treated with the compound, dissection and electron microscopy showed dose-dependent increases in myelination.
“These are striking results that clearly urge further study of anarcardic acid for demyelinating diseases,” Sriram said.
Other research :
Background: Currently there are no approved agents which are available to repair demyelinating lesions. Axons devoid of myelin ultimately become atrophic and die leading to permanent neurologic deficits.
Design/Methods: Oligodendrocyte cultures were prepared from 6 day old rat pups. Purified populations of oligodendrocyte precursor cells (OPC) were cultured with AA and the expression of MBP, PLP and MOG was examined. We also examined the efficacy of AA in inducing Sox10 and Purα known transcription elements which regulate myelin gene expression. We used the Cuprizone model of gliotoxic demyelination to examine the effect of AA in promoting remyelination.
Results: AA enhanced the expression of MBP over that seen in controls in OPC using both western blot and qRT-PCR assays. In addition, using q RT-PCR there was a > 3 fold increase in mRNA for Mbp, Plp and Mog along with increase in mRNA expression of the transcriptional elements Purα and Sox 10 which regulate MBP expression by AA suggesting a rapid induction of myelin genes. AA also induced IL-33, a known trophic factor for axons. When AA was given to animals fed with cuprizone, AA treated mice showed a 18% increase in expression of MBP over vehicle treated controls (p,<0.01 AA versus vehicle).
Conclusions: Our studies show that AA a naturally occurring small molecule is able to induce myelin genes and promote remyelination in vivo. Induction of myelin genes appeared to be mediated as a direct effect on OPC and indirectly through the activation IL-33. Since the cashew fruit and nuts from which AA is isolated has been used as a nutrient and a diet supplement it is unlikely to be toxic and will form a basis for its use as a novel therapeutic agent to promote remyelination.
Disclosure: Dr. Natarajan has nothing to disclose. Dr. Rose has nothing to disclose. Dr. Sriram has received research support from EMD Serono.
reference link : https://n.neurology.org/content/92/15_Supplement/P3.2-066
More information: Åsa Ljunggren-Rose el al., “Anacardic acid induces IL-33 and promotes remyelination in CNS,” PNAS (2020). www.pnas.org/cgi/doi/10.1073/pnas.2006566117
