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Mevalonate Kinase Deficiency and Squalene Synthase Inhibitor (TAK-475): The Balance to Extinguish the Inflammation
- Source :
- Biomolecules, Volume 11, Issue 10, Biomolecules, Vol 11, Iss 1438, p 1438 (2021)
- Publication Year :
- 2021
- Publisher :
- MDPI AG, 2021.
-
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 :
- Lipopolysaccharides
Macrophage
Anti-Inflammatory Agents
Apoptosis
Drug repositioning
Inflammation
Mevalonate
Rare disease
Pharmacology
Systemic inflammation
Biochemistry
Mice
chemistry.chemical_compound
Piperidines
RAW 264.7 Cell
Mevalonate kinase deficiency
Alendronate
Cell Death
Biosynthetic Pathway
QR1-502
Mitochondria
Anti-Inflammatory Agent
Farnesyl-Diphosphate Farnesyltransferase
medicine.symptom
medicine.drug
Mevalonic Acid
Lipopolysaccharide
Microbiology
Article
NO
Piperidine
Animals
Autophagy
Biosynthetic Pathways
Cell Shape
Interleukin-6
Macrophages
Mevalonate Kinase Deficiency
Oxazepines
RAW 264.7 Cells
Tumor Necrosis Factor-alpha
medicine
Molecular Biology
Animal
Oxazepine
Cholesterol
business.industry
Apoptosi
medicine.disease
Blockade
Metabolic pathway
chemistry
business
Lapaquistat
Subjects
Details
- ISSN :
- 2218273X
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- Biomolecules
- Accession number :
- edsair.doi.dedup.....63e4fc7d3fcd910899a3042b330800b5