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Neurotherapeutics. 2020 Feb 18. doi: 10.1007/s13311-020-00836-3. [Epub ahead of print]

The Leukotriene Receptor Antagonist Montelukast Reduces Alpha-Synuclein Load and Restores Memory in an Animal Model of Dementia with Lewy Bodies.

Author information

1
Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria.
2
Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria.
3
Department of Neuroscience, School of Medicine, University of California San Diego, San Diego, USA.
4
QPS Austria GmbH, Neuropharmacology, Grambach, Austria.
5
Pharmidex, London, W1S 1RR, UK.
6
Department of Laboratory Medicine, Paracelsus Medical University, Salzburg, Austria.
7
Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
8
Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria. ludwig.aigner@pmu.ac.at.
9
Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria. ludwig.aigner@pmu.ac.at.
10
Austrian Cluster for Tissue Regeneration, Vienna, Austria. ludwig.aigner@pmu.ac.at.

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.

KEYWORDS:

Leukotrienes; Montelukast; alpha-synulcein; autophagy; cognition; dementia; neuroinflammation

PMID:
32072462
DOI:
10.1007/s13311-020-00836-3

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