Myelin structures form an insulating sheath coating the axons that connect neurons, and are essential for proper electrical function of an axon, the conduction of nerve impulses along the axon structure. Dramatic loss of myelin, as occurs in conditions such as multiple sclerosis, results in severe symptoms and eventual death. A lesser degree of loss of myelin occurs more broadly with age throughout the population, and is thought to provide some contribution to declining cognitive function and conditions such as mild cognitive impairment. In this second case, how exactly the mechanisms cause myelin loss are less well understood. One can look at the state of the oligodendrocyte population responsible for maintaining myelin and see changes in size or changes in activity, but connections to specific molecular biochemistry is ever a challenge.
As researchers note in today's open access paper, there is no FDA-approved therapy to enhance remyelination. This isn't for lack of trying in the usual small molecule development space, where much of the work is focused on trying to find existing drugs and targets that have some modest beneficial effect and few enough side-effects to make it worth the effort. One of the small molecules tested in the paper here was in clinical trials for multiple sclerosis, the antihistamine clemastine, but prevalent inflammatory side-effects caused that line of development to be halted. The other, LL-341070, is in clinical trials for the treatment of depression.
The primary thrust of the paper is an examination of the way in which mild deymelination spurs a response from oligodendrocytes to repair the problem, and the threshold at which that response is insufficient. Drugs that boost oligodendrocyte activity might in principle be able to make a dent in demyelination conditions by shifting this threshold. Interestingly, even drugs and doses that have too small an effect to matter for multiple sclerosis, and have thus been discarded by the development community, could be useful in the treatment of age-related demyelination more generally. Though they are unlikely to be rigorously tested for this use in the present regulatory environment!
Demyelination is typically followed by a period of heightened new myelin formation known as remyelination, which can restore action potential propagation and prevent neurodegeneration. Remyelination is carried out primarily by newly formed oligodendrocytes differentiating from parenchymal and germinal zone derived oligodendrocyte precursor cells (OPCs) as well as - in some instances - by oligodendrocytes that survive the demyelinating injury. However, the endogenous remyelination response is often incomplete, resulting in chronic demyelination and limited functional recovery. Thus, understanding the drivers and limitations of endogenous remyelination and developing methods to enhance it are clinical imperatives for many demyelinating conditions. Despite substantial progress in identifying compounds that improve remyelination in recent years, there is still no FDA-approved remyelination therapy. Furthermore, independent of specific therapeutic strategies, we require a deeper understanding of fundamental aspects of therapeutic-induced remyelination, such as the dynamics and constraints of therapeutic action, and the magnitude and timing of remyelination required to recover neuronal function.
The afferent visual pathway is well-suited to investigate the relationship between myelin and neuronal function throughout de/remyelination. The circuits of primary visual cortex (V1) are sensitive to input spike precision and contain precise and reliable sensory-evoked activity, important for action potential transmission and visual coding. Moreover, perturbations in the timing of sensory-evoked activity in V1 have previously been observed in patients and animal models during de/remyelination. Here, we used longitudinal in vivo two-photon imaging of oligodendrocytes and high-density electrical recordings with single neuron resolution in V1 to study the dynamics of endogenous and therapeutic-induced neocortical remyelination and the relationship between remyelination and functional recovery. Demyelination was induced with cuprizone, and mice were treated with two remyelination drugs: a new thyroid hormone mimetic (thyromimetic), LL-341070, and a clinically validated therapeutic, clemastine.
Cuprizone treatment induced oligodendrocyte loss and a concomitant increase in visual response latency. This was followed by a rapid and robust endogenous remyelination response that was driven by recent oligodendrocyte loss. Endogenous remyelination was highly efficacious at mild demyelination levels, but when moderate or severe demyelination occurred quickly, endogenous remyelination failed to restore the oligodendrocyte population after seven weeks. Treatment with a high dose of LL-341070 substantially increased regenerative oligodendrogenesis during remyelination, acting more quickly and robustly than clemastine, and hastened neuron functional recovery. The therapeutic benefit of LL-341070 was loss-dependent, exclusively impacting remyelination after moderate or severe demyelination. Consequently, LL-341070 eliminated the endogenous remyelination deficit after seven weeks of remyelination, restoring oligodendrocyte numbers to original levels and myelin to levels comparable to those of age-matched healthy mice. However, full restoration of oligodendrocytes and myelin to these levels was not necessary to recover neuronal function.
View the full article at FightAging
