gms | German Medical Science

Introduction: Hallmarks of MS lesions are demyelination and axonal pathology, which occurs early after disease onset and is associated with disease progression and persistent disability. Demyelination, which leads to a loss of support by oligodendrocytes, increased energy demand of the axon and/ or increased impact of inflammatory mediators, is considered as the major cause for axonal damage and degeneration. Remyelination has been known as a mechanism of repair and axonal protection. Demyelination and remyelination cause a rearrangement of many transmembrane proteins, such as voltage gated potassium (K_V) channels, which might result in an increased vulnerability of the axon due to pH shifts and ion dysbalance.

Objectives: Remyelination is in the center of new MS therapies to resolve and improve disease symptoms. Although remyelination is known to be beneficial in the long term, it is not known, whether this is also the case for early remyelination.

Method: To shed light onto the interrelation between axons and the myelin sheath during de- and remyelination, we took advantage of a cohort of patients with early and late stage remyelinated lesions and assessed the density of acutely damaged and preserved axons. To investigate the relation of demyelination, remyelination and axonal damage in more detail, we employed the model of cuprizone-induced demyelination and performed tight time course experiments assessing the evolution of remyelination and acute axonal damage in the presence and absence of the acid sensing ion channel (ASIC) inhibitor amiloride and the K_V channel inhibitor 4-aminopyridine.

Results: We observed more damaged axons in late stage demyelinated MS lesions than in late stage remyelinated MS lesions. We found neither evidence for increased axonal vulnerability during early remyelination nor diminished numbers of damaged axons due to inhibition of ASICs or K_V channels during de- and remyelination in the absence of an adaptive immune response.

Conclusion: Remyelination seems to be axon protective in the short and long term. Furthermore, pH and K_V channel conductance appear not to be central mediators of axonal damage in the cuprizone mouse model.