A deficiency in Vitamin B12 (B12) can lead to neurological symptoms that resemble those seen in multiple sclerosis (MS). However, the specific molecular reasons behind this similarity still need to be understood.
A new study by the scientists at Sanford Burnham Prebys, with collaborators elsewhere, explains a novel molecular link between vitamin B12 and MS in astrocytes – important non-neuronal glial cells in the brain. The study could offer new ways to improve the treatment of MS through CNS-B12 supplementation.
Scientists looked closely at how a medication called FTY720 or fingolimod (brand name Gilenya®) works on a molecular level. This medication affects a part of the body called sphingosine 1-phosphate (S1P) receptor. It helps control immune cells (T and B cells) that mistakenly attack the brains of people with multiple sclerosis (MS).
Scientists studied animals with a condition similar to multiple sclerosis (MS) and looked at the brains of people who had MS after they passed away. By physically and functionally controlling B12 communication pathways, specifically by increasing a B12 receptor called CD320 required to absorb and utilize required B12 when it is bound to TCN2, which distributes B12 throughout the body, including the central nervous system, scientists discovered that fingolimod suppresses neuroinflammation. Because of its known mechanism, fingolimod interactions inside astrocytes have recently been found. Crucially, human MS brains also showed this link.
The scientists found that dietary B12 restriction or lower levels of CD320 exacerbated the disease course in an animal model of multiple sclerosis (MS) and decreased the therapeutic efficacy of fingolimod. This was due to a mechanism whereby fingolimod hitches a ride by binding to the TCN2-B12 complex, facilitating the delivery of all to the astrocytes via interactions with CD320. Loss of any component of this process disrupts and exacerbates the disease.
These new findings show that fingolimod can restore the compromised astrocyte-B12 pathway in MS patients, and they also lend more support to the usage of B12 supplements, particularly when it comes to supplying the vitamin to brain astrocytes.
Scientists said, “It is possible that other S1P receptor modulators on the market, such as Mayzent®, Zeposia®, and Ponvory®, may access at least parts of this CNS mechanism. The study supports B12 supplementation with S1P receptor modulators to improve drug efficacy for this class of medicines.”
Senior study author Jerold Chun, M.D., Ph.D., professor and senior vice president of neuroscience drug discovery, said, “The study also opens new avenues on how the B12-TCN2-CD320 pathway is regulated by sphingolipids, specifically sphingosine, a naturally occurring and endogenous structural analog of fingolimod, toward improving future MS therapies.”
“It supports creating brain-targeted B12 formulations. In the future, this mechanism might also extend to novel treatments of other neuroinflammatory and neurodegenerative conditions.”
Journal Reference:
- Deepa Jonnalagadda, Yasuyuki Kihara, Aran Groves et al. FTY720 requires vitamin B12-TCN2-CD320 signaling in astrocytes to reduce disease in an animal model of multiple sclerosis. Cell Reports. DOI: 10.1016/j.celrep.2023.113545Â