Zusammenfassung
Die Multiple Sklerose (MS) wurde bisher als entzündlich-demyelinisierende Erkrankung des zentralen Nervensystems betrachtet, bei der die Störung der elektrischen Erregungsleitung in zentralen Neuronen und die damit verbundene, schubförmig auftretende neurologische Symptomatik durch den Abbau der Myelinscheide bedingt ist. Doch die im Verlauf typischerweise auftretende Akkumulation dauerhafter klinisch-neurologischer Defizite kann allein durch de- und remyelinisierende Prozesse nicht zufrieden stellend erklärt werden. Sie wird heute vielmehr als Folge einer axonalen/neuronalen Degeneration betrachtet, die abhängig vom Stadium der Erkrankung verschiedene Ursachen haben kann: 1. Neuronen und deren Axone werden während der akuten Entzündung durch infiltrierende Lymphozyten und Makrophagen sowie aktivierte Gliazellen entweder durch direkten Zell-Zell-Kontakt oder die Freisetzung verschiedener Mediatoren (NO, Glutamat) geschädigt; 2. durch Schädigung der die Myelinscheide bildenden Oligodendrozyten kommt es indirekt durch einen fehlenden trophischen Einfluss auf das Axon zur axonalen Degeneration; 3. durch eine veränderte Verteilung und Expression verschiedener Ionenkanäle und Transporter kommt es im demyelinisierten Axon zu einer lokal gesteigerten elektrischen Aktivität und einer intrazellulären Kalziumakkumulation mit nachfolgender mitochondrialer Dysfunktion und neuronalem Zelltod.
Das neuroprotektive Potenzial einer pharmakologische Modulation dieser Ionenkanäle und Transporter mit zum Teil bereits zugelassenen Substanzen ist zum einen tierexperimentell bereits gut belegt und zum anderen nun auch Gegenstand erster klinischer Studien.
Summary
Multiple sclerosis (MS) has traditionally been regarded as an inflammatory demyelinating disorder of the CNS in which clinical symptoms result from axon conduction block caused by myelin degradation. However, typical accumulation of permanent neurological deficits during the clinical course of MS cannot be explained solely by de- and remyelinating processes. It is considered to be rather due to neuronal degeneration, for which several reasons could be identified depending on the state of the disease. First, neurons and their axons can be damaged by infiltrating lymphocytes and macrophages either directly by cell-to-cell contact or by the release of harmful mediators such as nitric oxide or glutamate. Second, indirect injury to neurons and axons may occur through the loss of trophic support by neighbouring oligodendrocytes due to destruction of both the myelin sheath and the oligodendrocyte itself. Third, redistribution of certain voltage- and ligand-gated ion channels and transporters along naked demyelinated axons restores axonal conduction but also leads to excessive spatially restricted electrical activity of the axonal membrane, intracellular calcium accumulation, impairment of mitochondrial function, and subsequent neuronal degeneration. The neuroprotective potential of pharmacological modulation of these channels and transporters using already approved drugs has been demonstrated in several animal studies, is the subject of current clinical trials and will be the topic of this review.
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Meuth, S., Melzer, N., Kleinschnitz, C. et al. Multiple Sklerose – eine Kanalopathie?. Nervenarzt 80, 422–429 (2009). https://doi.org/10.1007/s00115-008-2599-7
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DOI: https://doi.org/10.1007/s00115-008-2599-7
Schlüsselwörter
- Multiple Sklerose
- Experimentelle autoimmune Enzephalomyelitis
- Neurodegeneration
- Ionenkanäle
- Transporter
- Klinische Studien