Induction of oligodendrocyte differentiation and in vitro myelination by inhibition of rho-associated kinase. Pedraza CE, Taylor C, Pereira A, Seng M, Tham CS, Izrael M, Webb M.
ASN Neuro. 2014;6(4). pii: 1759091414538134. doi: 10.1177/1759091414538134.
In inflammatory demyelinating diseases such as multiple sclerosis (MS), myelin degradation results in loss of axonal function and eventual axonal degeneration. Differentiation of resident oligodendrocyte precursor cells (OPCs) leading to remyelination of denuded axons occurs regularly in early stages of MS but halts as the pathology transitions into progressive MS. Pharmacological potentiation of endogenous OPC maturation and remyelination is now recognized as a promising therapeutic approach for MS. In this study, we analyzed the effects of modulating the Rho-A/Rho-associated kinase (ROCK) signaling pathway, by the use of selective inhibitors of ROCK, on the transformation of OPCs into mature, myelinating oligodendrocytes. Here we demonstrate, with the use of cellular cultures from rodent and human origin, that ROCK inhibition in OPCs results in a significant generation of branches and cell processes in early differentiation stages, followed by accelerated production of myelin protein as an indication of advanced maturation. Furthermore, inhibition of ROCK enhanced myelin formation in cocultures of human OPCs and neurons and remyelination in rat cerebellar tissue explants previously demyelinated with lysolecithin. Our findings indicate that by direct inhibition of this signaling molecule, the OPC differentiation program is activated resulting in morphological and functional cell maturation, myelin formation, and regeneration. Altogether, we show evidence of modulation of the Rho-A/ROCK signaling pathway as a viable target for the induction of remyelination in demyelinating pathologies.
The Rho pathway is involved in the changes in a the cell skeleton. In this study they report that inhibitors of ROCK can affect oligodendrocytes and promote remyelination. This would be a good think however this same pathway is involved in nerve growth cone formation and inhibition of this could limit nerve synapse formation and so stop the nerual plasticity that allows you to adapt to loss of nerve circuits. It could also stop white cells getting into the CNS as they could be involved in remodelling of cell structures in blood vessels as white cells move through the blood vessels. However this is all theoretical, I seem to remember trying some Rho kinase inhibitors in EAE.........about ten years ago.