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Nat Commun. 2015 Oct 27;6:8466. doi: 10.1038/ncomms9466.

Structural and functional rejuvenation of the aged brain by an approved anti-asthmatic drug.

Author information

1
Institute of Molecular Regenerative Medicine, Paracelsus Medical University, 5020 Salzburg, Austria.
2
Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, 5020 Salzburg, Austria.
3
Institute of Biochemistry, Emil Fischer Center, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany.
4
Center for Spinal Cord Injuries, BG Trauma Center Murnau, 82418 Murnau am Staffelsee, Germany.
5
Institute of Experimental Neuroregeneration, Paracelsus Medical University, 5020 Salzburg, Austria.
6
Department of Pharmacology and Toxicology, Institute of Pharmacy and CMBI, Leopold-Franzens-University of Innsbruck, 6020 Innsbruck, Austria.
7
Department of Neuropathology, University Hospital Erlangen, 91054 Erlangen, Germany.
8
Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, Italy.
9
Pharmidex, London W1S 1RR, UK.
10
Department for Paediatrics, Institute for Inborn Errors of Metabolism, Paracelsus Medical University, 5020 Salzburg, Austria.
11
Croatian Institute for Brain Research, University of Zagreb School of Medicine, 10000 Zagreb, Croatia.
12
Institute of Tendon and Bone Regeneration, Paracelsus Medical University, 5020 Salzburg, Austria.
13
Department of Neurology, University Hospital Regensburg, 93053 Regensburg, Germany.

Abstract

As human life expectancy has improved rapidly in industrialized societies, age-related cognitive impairment presents an increasing challenge. Targeting histopathological processes that correlate with age-related cognitive declines, such as neuroinflammation, low levels of neurogenesis, disrupted blood-brain barrier and altered neuronal activity, might lead to structural and functional rejuvenation of the aged brain. Here we show that a 6-week treatment of young (4 months) and old (20 months) rats with montelukast, a marketed anti-asthmatic drug antagonizing leukotriene receptors, reduces neuroinflammation, elevates hippocampal neurogenesis and improves learning and memory in old animals. By using gene knockdown and knockout approaches, we demonstrate that the effect is mediated through inhibition of the GPR17 receptor. This work illustrates that inhibition of leukotriene receptor signalling might represent a safe and druggable target to restore cognitive functions in old individuals and paves the way for future clinical translation of leukotriene receptor inhibition for the treatment of dementias.

PMID:
26506265
PMCID:
PMC4639806
DOI:
10.1038/ncomms9466
[Indexed for MEDLINE]
Free PMC Article

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