The Leukotriene Receptor Antagonist Montelukast Reduces Alpha-Synuclein Load and Restores Memory in an Animal Model of Dementia with Lewy Bodies.
Acetates
/ pharmacology
Animals
Cyclopropanes
/ pharmacology
Disease Models, Animal
Female
Humans
Leukotriene Antagonists
/ pharmacology
Lewy Body Disease
/ drug therapy
Memory
/ drug effects
Memory Disorders
/ drug therapy
Mice
Mice, Transgenic
Quinolines
/ pharmacology
Receptors, Leukotriene
/ genetics
Sulfides
/ pharmacology
alpha-Synuclein
/ antagonists & inhibitors
Leukotrienes
Montelukast
alpha-synulcein
autophagy
cognition
dementia
neuroinflammation
Journal
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
ISSN: 1878-7479
Titre abrégé: Neurotherapeutics
Pays: United States
ID NLM: 101290381
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
pubmed:
20
2
2020
medline:
2
9
2021
entrez:
20
2
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32072462
doi: 10.1007/s13311-020-00836-3
pii: 10.1007/s13311-020-00836-3
pmc: PMC7609773
doi:
Substances chimiques
Acetates
0
Cyclopropanes
0
Leukotriene Antagonists
0
Quinolines
0
Receptors, Leukotriene
0
Sulfides
0
alpha-Synuclein
0
montelukast
MHM278SD3E
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1061-1074Subventions
Organisme : Medical Research Council
ID : G0400074
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0502157
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0900652
Pays : United Kingdom
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