Fig. 1.

Cascade of events potentially linking inflammatory activity to slowly progressive neurodegeneration in MS. Chronic inflammatory demyelination leads to redistribution of sodium channels along the denudated axolemma, resulting in sodium influx. Elevated intracellular sodium levels increase the work-load of the energy-dependent Na/K pump. Mitochondrial function is impaired in multiple sclerosis (mainly resulting from the oxidative stress associated with inflammatory activity) which causes insufficient energy supply to compensate this imbalance. Intracellular sodium levels rise, leading to accumulation of calcium, e.g. by reversal of the transmembrane Na/Ca exchanger and release from intracellular sources. Acidosis contributes to sodium and calcium influx through opening of acid-sensing ion channels. Calcium stacking induces protease and lipase activity, eventually ending with cellular breakdown. ATP: adenosine triphosphate, ASIC: acid-sensing ion channel, MS: multiple sclerosis