Structural and functional rejuvenation of the aged brain by an approved anti-asthmatic drug.
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.
Institute of Molecular Regenerative Medicine, Paracelsus Medical University, 5020 Salzburg, Austria.|Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, 5020 Salzburg, Austria.
Julia
J
Marschallinger
Institute of Biochemistry, Emil Fischer Center, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany.
Iris
I
Schäffner
Institute of Molecular Regenerative Medicine, Paracelsus Medical University, 5020 Salzburg, Austria.|Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, 5020 Salzburg, Austria.
Barbara
B
Klein
Institute of Molecular Regenerative Medicine, Paracelsus Medical University, 5020 Salzburg, Austria.|Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, 5020 Salzburg, Austria.
Renate
R
Gelfert
Institute of Molecular Regenerative Medicine, Paracelsus Medical University, 5020 Salzburg, Austria.|Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, 5020 Salzburg, Austria.
Francisco J
FJ
Rivera
Institute of Molecular Regenerative Medicine, Paracelsus Medical University, 5020 Salzburg, Austria.|Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, 5020 Salzburg, Austria.
Sebastian
S
Illes
Institute of Molecular Regenerative Medicine, Paracelsus Medical University, 5020 Salzburg, Austria.|Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, 5020 Salzburg, Austria.|Center for Spinal Cord Injuries, BG Trauma Center Murnau, 82418 Murnau am Staffelsee, Germany.
Lukas
L
Grassner
Institute of Molecular Regenerative Medicine, Paracelsus Medical University, 5020 Salzburg, Austria.|Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, 5020 Salzburg, Austria.
Maximilian
M
Janssen
Institute of Molecular Regenerative Medicine, Paracelsus Medical University, 5020 Salzburg, Austria.|Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, 5020 Salzburg, Austria.|Institute of Experimental Neuroregeneration, Paracelsus Medical University, 5020 Salzburg, Austria.
Peter
P
Rotheneichner
Department of Pharmacology and Toxicology, Institute of Pharmacy and CMBI, Leopold-Franzens-University of Innsbruck, 6020 Innsbruck, Austria.
Claudia
C
Schmuckermair
Department of Neuropathology, University Hospital Erlangen, 91054 Erlangen, Germany.
Roland
R
Coras
Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, Italy.
Marta
M
Boccazzi
Pharmidex, London W1S 1RR, UK.
Mansoor
M
Chishty
Department for Paediatrics, Institute for Inborn Errors of Metabolism, Paracelsus Medical University, 5020 Salzburg, Austria.
Florian B
FB
Lagler
Croatian Institute for Brain Research, University of Zagreb School of Medicine, 10000 Zagreb, Croatia.
Marija
M
Renic
Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, 5020 Salzburg, Austria.|Institute of Tendon and Bone Regeneration, Paracelsus Medical University, 5020 Salzburg, Austria.
Hans-Christian
HC
Bauer
Department of Pharmacology and Toxicology, Institute of Pharmacy and CMBI, Leopold-Franzens-University of Innsbruck, 6020 Innsbruck, Austria.
Nicolas
N
Singewald
Department of Neuropathology, University Hospital Erlangen, 91054 Erlangen, Germany.
Ingmar
I
Blümcke
Department of Neurology, University Hospital Regensburg, 93053 Regensburg, Germany.
Ulrich
U
Bogdahn
Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, 5020 Salzburg, Austria.|Institute of Experimental Neuroregeneration, Paracelsus Medical University, 5020 Salzburg, Austria.
Sebastien
S
Couillard-Despres
Institute of Biochemistry, Emil Fischer Center, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany.
D Chichung
DC
Lie
Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, Italy.
Maria P
MP
Abbracchio
Institute of Molecular Regenerative Medicine, Paracelsus Medical University, 5020 Salzburg, Austria.|Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, 5020 Salzburg, Austria.
Ludwig
L
Aigner
D000328:Adult; D000367:Age Factors; D000375:Aging / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage*; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D003071:Cognition; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D018782:Maze Learning; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D018077:Receptors, Leukotriene / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
D018927:Anti-Asthmatic Agents; D018077:Receptors, Leukotriene