Endotelin-1 involved in MS
Posted: Sun Nov 24, 2019 5:48 am
Endotelin-1 (ET-1) is a protein related to the vascular system.
Modulation of cytokine-induced astrocytic endothelin-1 production as a possible new approach to the treatment of multiple sclerosis.
https://www.frontiersin.org/articles/10 ... 1/abstract
Results and Conclusions:
ET-1 secretion by astrocytoma cells was only stimulated by the pro-inflammatory cytokines IL-1β and TNF-α. Fluoxetine, simvastatin and resveratrol significantly inhibited this IL-1β- and TNF-α-induced ET-1 production. Simvastatin and resveratrol significantly reduced ET-1 mRNA levels, indicating an effect at the level of transcription.
Fluoxetine significantly reduced endothelin converting enzyme-1 mRNA levels, suggesting and effect at the level of protein-processing. The required concentrations of simvastatin (> 0.1 µM) and resveratrol (> 10 µM) cannot be achieved in humans using pharmacologically accepted doses. Fluoxetine exerted a significant inhibitory effect on ET-1 secretion at a concentration of 5 µM, which is pharmacologically achievable in human brain, but the effect was modest (< 50% suppression) and probably not sufficient to obtain a clinically relevant ET-1 effect.
Our in vitro model can be a useful screening tool in the development of new drugs to suppress astrocytic ET-1 production. The effect of simvastatin was for the most part mediated via the mevalonate pathway, suggesting that this might be an interesting target for further drug development.
Modulation of cytokine-induced astrocytic endothelin-1 production as a possible new approach to the treatment of multiple sclerosis.
https://www.frontiersin.org/articles/10 ... 1/abstract
Results and Conclusions:
ET-1 secretion by astrocytoma cells was only stimulated by the pro-inflammatory cytokines IL-1β and TNF-α. Fluoxetine, simvastatin and resveratrol significantly inhibited this IL-1β- and TNF-α-induced ET-1 production. Simvastatin and resveratrol significantly reduced ET-1 mRNA levels, indicating an effect at the level of transcription.
Fluoxetine significantly reduced endothelin converting enzyme-1 mRNA levels, suggesting and effect at the level of protein-processing. The required concentrations of simvastatin (> 0.1 µM) and resveratrol (> 10 µM) cannot be achieved in humans using pharmacologically accepted doses. Fluoxetine exerted a significant inhibitory effect on ET-1 secretion at a concentration of 5 µM, which is pharmacologically achievable in human brain, but the effect was modest (< 50% suppression) and probably not sufficient to obtain a clinically relevant ET-1 effect.
Our in vitro model can be a useful screening tool in the development of new drugs to suppress astrocytic ET-1 production. The effect of simvastatin was for the most part mediated via the mevalonate pathway, suggesting that this might be an interesting target for further drug development.