title: Inhibition of leukotriene receptors boosts neural progenitor proliferation.
abstract: Neural stem and progenitor cells serve as a reservoir for new neurons in the adult brain throughout lifetime. One of the critical steps determining the net production of new neurons is neural progenitor proliferation, which needs to be tightly controlled. Since inflammation has detrimental effects on neurogenesis and the 5-lipoxygenase/leukotriene pathway is involved in inflammatory processes, we investigated the effects of leukotrienes and montelukast, a small molecule inhibitor of the leukotriene receptors CysLT(1)R and GPR17, on neural stem and progenitor cell proliferation. We demonstrate expression of the leukotriene receptor GPR17 by neural progenitors and by neural stem cells. Stimulation with excess amounts of leukotrienes did not affect progenitor proliferation, whereas blockade of GPR17 with montelukast strongly elevated neural stem and progenitor proliferation, while maintaining their differentiation fate and potential. This effect was associated with increased ERK1/2 phosphorylation suggesting an involvement of the EGF signaling cascade. Based on our results, montelukast and the inhibition of the 5-LOX pathway might be potent candidates for future therapies employing neurogenesis to promote structural and functional improvement in neurodegeneration, neuropsychiatric disease and ageing.
authors.affiliation: Institute of Molecular Regenerative Medicine, Paracelsus Medical University Salzburg, Salzburg, Austria.
authors.forename: Christophe
authors.initials: C
authors.lastname: Huber
authors.forename: Julia
authors.initials: J
authors.lastname: Marschallinger
authors.forename: Herbert
authors.initials: H
authors.lastname: Tempfer
authors.forename: Tanja
authors.initials: T
authors.lastname: Furtner
authors.forename: Sebastien
authors.initials: S
authors.lastname: Couillard-Despres
authors.forename: Hans-Christian
authors.initials: HC
authors.lastname: Bauer
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Rivera
authors.forename: Ludwig
authors.initials: L
authors.lastname: Aigner
mesh_terms: D000085:Acetates / Q000494:pharmacology; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D003521:Cyclopropanes; D005260:Female; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D015289:Leukotrienes / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism*; D055495:Neurogenesis; D010766:Phosphorylation; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D018077:Receptors, Leukotriene / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D013440:Sulfides
chemical_list: D000085:Acetates; D003521:Cyclopropanes; C514731:GPR17 protein, rat; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D011804:Quinolines; D043562:Receptors, G-Protein-Coupled; D018077:Receptors, Leukotriene; D013440:Sulfides; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C083169:leukotriene D4 receptor; C093875:montelukast