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Mevalonate Kinase Deficiency and Squalene Synthase Inhibitor (TAK-475): The Balance to Extinguish the Inflammation.
- Source :
-
Biomolecules [Biomolecules] 2021 Sep 30; Vol. 11 (10). Date of Electronic Publication: 2021 Sep 30. - Publication Year :
- 2021
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Abstract
- Mevalonate Kinase Deficiency (MKD) is a rare inborn disease belonging to the family of periodic fever syndromes. The MKD phenotype is characterized by systemic inflammation involving multiple organs, including the nervous system. Current anti-inflammatory approaches to MKD are only partially effective and do not act specifically on neural inflammation. According to the new emerging pharmacology trends, the repositioning of drugs from the indication for which they were originally intended to another one can make mechanistic-based medications easily available to treat rare diseases. According to this perspective, the squalene synthase inhibitor Lapaquistat (TAK-475), originally developed as a cholesterol-lowering drug, might find a new indication in MKD, by modulating the mevalonate cholesterol pathway, increasing the availability of anti-inflammatory isoprenoid intermediates. Using an in vitro model for MKD, we mimicked the blockade of the cholesterol pathway and evaluated the potential anti-inflammatory effect of Lapaquistat. The results obtained showed anti-inflammatory effects of Lapaquistat in association with a low blockade of the metabolic pathway, while this effect did not remain with a tighter blockade. On these bases, Lapaquistat could be configured as an effective treatment for MKD's mild forms, in which the residual enzymatic activity is only reduced and not almost completely absent as in the severe forms.
- Subjects :
- Alendronate pharmacology
Animals
Anti-Inflammatory Agents pharmacology
Apoptosis drug effects
Autophagy drug effects
Biosynthetic Pathways drug effects
Cell Death drug effects
Cell Shape drug effects
Farnesyl-Diphosphate Farnesyltransferase metabolism
Interleukin-6 metabolism
Lipopolysaccharides pharmacology
Macrophages drug effects
Macrophages metabolism
Macrophages ultrastructure
Mevalonic Acid metabolism
Mice
Mitochondria drug effects
Mitochondria pathology
Mitochondria ultrastructure
Oxazepines pharmacology
Piperidines pharmacology
RAW 264.7 Cells
Tumor Necrosis Factor-alpha metabolism
Farnesyl-Diphosphate Farnesyltransferase antagonists & inhibitors
Inflammation drug therapy
Inflammation enzymology
Mevalonate Kinase Deficiency enzymology
Oxazepines therapeutic use
Piperidines therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 2218-273X
- Volume :
- 11
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Biomolecules
- Publication Type :
- Academic Journal
- Accession number :
- 34680069
- Full Text :
- https://doi.org/10.3390/biom11101438