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

Neurotherapeutics, 2020 · DOI: https://doi.org/10.1007/s13311-020-00836-3 · Published: February 18, 2020

Simple Explanation

This research investigates Montelukast, an anti-asthma drug, as a potential treatment for Dementia with Lewy Bodies (DLB). The study found elevated levels of a key enzyme involved in leukotriene production in DLB brains, suggesting a link between leukotrienes and the disease. The study used transgenic mice that overexpress human alpha-synuclein, a protein associated with DLB, to test Montelukast's effects. Treatment with Montelukast improved memory in these mice. Montelukast treatment modulated beclin-1 expression, a marker for autophagy, and reduced the alpha-synuclein load in the transgenic mice, suggesting a possible mechanism for its therapeutic effect.

Study Duration

6 weeks

Participants

Transgenic mice expressing human wild-type alpha-synuclein and wild-type litter mates

Evidence Level

Not specified

Key Findings

1
Expression of 5-lipoxygenase, the rate-limiting enzyme for leukotriene production, was found to be elevated in brains with DLB.
2
Treatment with Montelukast restored memory in cognitively deficient human alpha-synuclein overexpressing transgenic mice.
3
Montelukast treatment modulated beclin-1 expression, a marker for autophagy, and reduced the human alpha-synuclein load in the transgenic mice.

Research Summary

The study demonstrates that the leukotriene receptor antagonist Montelukast improves memory in a synucleopathy animal model of dementia. The underlying scientific rational is based on the finding that expression of 5-Lox is elevated in DLB brains suggesting that also leukotriene levels might be elevated in such brains. An unexpected and novel finding of the present work was that Montelukast treatment induced reduction in the alpha-synulcin load in the dentate gyrus.

Practical Implications

Potential Therapeutic Target

Leukotriene signaling may represent a potential drug target for DLB.

Drug Repurposing

Montelukast might be a promising drug candidate for future DLB therapy development.

Broader Applications

Montelukast might be a potential drug candidate not only in DLB but also in other synucleophaties.

Study Limitations

1
The mode of action of the Montelukast induced reduction in the alpha-synuclein load in the TG animals is unclear at present.
2
The possible effects of Montelukast on neuroinflammation and on microglia certainly require further in-depth analysis.
3
It is unknown, as the effects of leukotrienes and of leukotriene inhibition on autophagy are rather unexplored

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