Published on January 1, 2018 – LinkedIn

Treatment of multiple sclerosis (MS) needs to target not only focal inflammatory lesions but also the neurodegenerative component of the pathology. While several treatment modalities are available to suppress inflammation during the relapsing-remitting disease course, it still remains a medical and scientific challenge to develop a treatment for progressive MS. In consequence, there is an increasing interest in developing new drugs that will promote neuroprotection and/or myelin repair.

In a nice study by Y. Chen and R. Wang (Neuro-immunology Discovery Performance Unit, Shanghai, China), which was recently published in PLoS One, it was demonstrated that blocking of the Histamine Receptor 3 (Hrh3) promotes oligodendrocyte differentiation and remyelination. In vitro, applying primary rat oligodendrocyte cultures, Hrh3 knockdown led to an increase in the expression of myelin proteins, which was paralleled by an acceleration of differentiation on the morphological level. Treatment of cultured oligodendrocytes with the inverse agonist GSK247246 (GlaxoSmithKline, UK) promoted oligodendrocyte progenitor cell differentiation in a dose-dependent manner with nanomolar potency. In vivo treatment of mice with the inverse H3R agonist GSK247246 after acute cuprizone-induced demyelination demonstrated an acceleration of remyelination. H3R expression by oligodendrocytes was as well shown in post-mortem brain sections from patients with MS. Furthermore, a common Hrh3 SNP was found to be suggestively associated with susceptibility to MS. Collectively, their data suggest that blocking of the Histamine Receptor 3 might be a promising strategy to promote remyelination in MS patients.

It is worth to mention that in the acute cuprizone model, complete and fast remyelination follows after a 5-weeks intoxication period (i.e., called acute demyelination). It is important to notice that under such experimental paradigms, we cannot investigate the potency of a pharmaceutical compound to induce remyelination, but rather can assess the potency of drugs to accelerate remyelination.

Although it is principally possible that in MS patients remyelination fails because the repair process per se is too slow, I consider it more likely that the environment is not supportive for myelin repair, and therefore remyelination does not occur. As a conclusion, in the field of remyelination research, the translation from bench to bedside might be hampered because of the discrepancy between the reason of remyelination failure in MS patients and the high endogenous remyelination capacity in the applied animal model.

Of note, there are animal models/experimental setups available which show severely impaired endogenous remyelination capacity, for example the chronic cuprizone-model. If the cuprizone-intoxication period is prolonged till week 12 (i.e., chronic demyelination) endogenous remyelination is insufficient. Using this paradigm would allow us to study the induction rather than the acceleration of remyelination. It would now be interesting to see whether treatment of experimental mice after chronic cuprizone-induced demyelination with the inverse Hrh3 agonist GSK247246 as well promotes oligodendrocyte differentiation and, in consequence, remyelination.