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

• DOI: 10.1007/s13311-020-00836-3
• Publication Date: 2020-02-18T20:02:28Z
• Authors: Julia Marschallinger; Barbara Altendorfer; Edward Rockenstein; Miriam Holztrattner; Julia Garnweidner...; Nadine Pillichsha...; Iris Leister; Birgit Hutter-Paier; Katharina Strempfl; Michael S. Unger; Mansoor Chishty; Thomas Felder; Mary Johnson; Johannes Attems; Eliezer Masliah; Ludwig Aigner
• Keywords: Cyclopropanes; Lewy Body Disease; Receptors, Leukotriene; Memory Disorders; Mice, Transgenic; Acetates; Sulfides; 3. Good health; Disease Models, Animal; Mice; 03 medical and health sciences; 0302 clinical medicine; Memory; Quinolines; alpha-Synuclein; Animals; Humans; Leukotriene Antagonists; Original Article; Female

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.