Teriﬂunomide Promotes Oligodendroglial 8,9-Unsaturated Sterol Accumulation and CNS Remyelination

Neurol Neuroimmunol Neuroinﬂamm, 2021 · DOI: 10.1212/NXI.0000000000001091 · Published: November 1, 2021

Simple Explanation

This study investigates whether teriﬂunomide (TF), a drug used for multiple sclerosis (MS), can promote remyelination, the repair of the protective coating around nerve fibers. The researchers found that low concentrations of TF can help cells called oligodendrocytes mature, which is important for remyelination. This effect is linked to the accumulation of specific sterols (zymosterol) in these cells. In animal models, TF enhanced the regeneration of mature oligodendrocytes and increased remyelination in the spinal cord. This suggests that TF has a beneficial off-target effect that could be helpful for MS patients.

Study Duration

Not specified

Participants

Mice, Xenopus laevis tadpoles, and cell cultures

Evidence Level

Not specified

Key Findings

1
Teriﬂunomide (TF) promotes the diﬀerentiation of neonatal and adult mouse oligodendrocytes at nanomolar concentrations.
2
The effect of TF on oligodendrocyte differentiation was associated with an accumulation of the 8,9-unsaturated sterol zymosterol.
3
TF promoted remyelination in vivo both in Xenopus laevis and in mice.

Research Summary

The study demonstrates that teriﬂunomide (TF) enhances oligodendroglial diﬀerentiation in vitro at nanomolar concentrations, both on neonatal and adult puriﬁed OPCs in cultures, an eﬀect mediated by an accumulation of 8,9-unsaturated sterols. Following systemic administration, TF promoted remyelination in vivo across species in 2 noninﬂammatory models of demyelination. These results highlight a potential bystander eﬀect of the drug, independent from its action on the immune system.

Practical Implications

Potential Therapeutic Benefit

The promyelinating effect of TF could provide an additional benefit for patients with MS, beyond its known immunomodulatory effects.

Mechanism of Action

The study identifies the 8,9-unsaturated sterol pathway as a potential mechanism involved in the promyelinating effect of TF, reinforcing the idea that modulation of the cholesterol biosynthesis pathway is a promising therapeutic target.

Clinical Trial Reanalysis

Reanalysis of imaging data from previous clinical trials, focusing on markers sensitive to myelin content, could help differentiate the anti-inflammatory and remyelinating properties of TF.

Study Limitations

1
The study focused on noninflammatory animal models, questioning about its relevance in the human context.
2
The direct eﬀect of TF on oligodendrocyte was not maintained in the presence of interleukin-17 and interferon-γ.
3
Whether inhibiting DHODH in oligodendrocyte could result in an indirect eﬀect on cholesterol biogenesis cascade is a burning question that should be addressed in further research.

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