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The Leukotriene Receptor Antagonist Montelukast Reduces Alpha-Synuclein Load and Restores Memory in an Animal Model of Dementia with Lewy Bodies.
- Source :
-
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics [Neurotherapeutics] 2020 Jul; Vol. 17 (3), pp. 1061-1074. - Publication Year :
- 2020
-
Abstract
- Dementia with Lewy bodies (DLB) represents a huge medical need as it accounts for up to 30% of all dementia cases, and there is no cure available. The underyling spectrum of pathology is complex and creates a challenge for targeted molecular therapies. We here tested the hypothesis that leukotrienes are involved in the pathology of DLB and that blocking leukotrienes through Montelukast, a leukotriene receptor antagonist and approved anti-asthmatic drug, might alleviate pathology and restore cognitive functions. Expression of 5-lipoxygenase, the rate-limiting enzyme for leukotriene production, was indeed elevated in brains with DLB. Treatment of cognitively deficient human alpha-synuclein overexpressing transgenic mice with Montelukast restored memory. Montelukast treatment resulted in modulation of beclin-1 expression, a marker for autophagy, and in a reduction in the human alpha-synulcein load in the transgenic mice. Reducing the protein aggregation load in neurodegenerative diseases might be a novel model of action of Montelukast. Moreover, this work presents leukotriene signaling as a potential drug target for DLB and shows that Montelukast might be a promising drug candidate for future DLB therapy development.
- Subjects :
- Acetates pharmacology
Animals
Cyclopropanes pharmacology
Disease Models, Animal
Female
Humans
Leukotriene Antagonists pharmacology
Lewy Body Disease genetics
Lewy Body Disease metabolism
Memory physiology
Memory Disorders drug therapy
Memory Disorders genetics
Memory Disorders metabolism
Mice
Mice, Transgenic
Quinolines pharmacology
Sulfides pharmacology
alpha-Synuclein genetics
alpha-Synuclein metabolism
Acetates therapeutic use
Cyclopropanes therapeutic use
Leukotriene Antagonists therapeutic use
Lewy Body Disease drug therapy
Memory drug effects
Quinolines therapeutic use
Receptors, Leukotriene genetics
Receptors, Leukotriene metabolism
Sulfides therapeutic use
alpha-Synuclein antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1878-7479
- Volume :
- 17
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 32072462
- Full Text :
- https://doi.org/10.1007/s13311-020-00836-3