Astrocytic endothelin-1 and cerebral hypoperfusion in multiple sclerosis

Multiple sclerosis is a chronic inflammatory and neurodegenerative disorder of the central nervous system characterized by inflammatory demyelinating lesions and progressive axonal degeneration. The underlying pathophysiology of the progressive axonal degeneration is not completely understood, but there is increasing evidence that axonal mitochondrial energy failure is involved in this process. Decreased levels of N-acetylaspartate (NAA) are found in the cerebral normal-appearing white matter (NAWM) in MS patients, which is considered as a marker for axonal mitochondrial activity. Furthermore, the cerebral blood flow (CBF) seems also to be globally impaired in the NAWM. In animal models, decreased CBF leads to mitochondrial energy failure and axonal degeneration. An increased cytokine-induced astrocytic endothelin-1 (ET-1) production seems to be involved in the reduction of the CBF, as a study with a single 62.5 mg dose of bosentan (ET-1 receptor antagonist) in MS patients restored CBF to levels similar to healthy controls. In this thesis, we wanted to explore the underlying mechanisms for astrocytic ET-1 upregulation in MS, as well as to find drugs that can suppress this upregulation. We found that simvastatin and resveratrol were able to reduce the ET-1 expression in vitro, however these effects cannot be achieved in humans when pharmacologically tolerated doses are used. The effect of fluoxetine on the ET-1 production was rather modest and probably not sufficient enough to be clinically relevant. A 4-
weeks trial with bosentan was set up in MS patients, to explore if prolonged restoration of the CBF could improve axonal
itochondrial metabolism. This trial showed no effect on the CBF and NAA-levels, probably because of the mild disease courses and minimal local inflammatory activity. It seems plausible that only MS patients with decreased CBF benefit from therapies suppressing
astrocytic ET-1 production or blocking its effect, but further clinical trials are necessary.

Publication year:2020