Marschallinger J, Schäffner I, Klein B, Gelfert R, Rivera FJ, Illes S, Grassner L, Janssen M, Rotheneichner P, Schmuckermair C, Coras R, Boccazzi M, Chishty M, Lagler FB, Renic M, Bauer HC, Singewald N, Blümcke I, Bogdahn U, Couillard-Despres S, Lie DC, Abbracchio MP, Aigner L. Structural and functional rejuvenation of the aged brain by an approved anti-asthmatic drug. Nat Commun. 2015 Oct 27;6:8466. PubMed.
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Cedars-Sinai Medial Center
A short-term oral treatment of the anti-inflammatory drug montelukast was enough for significant cognitive improvement in naturally aged rats. Along with a reduction of neuroinflammation, the authors found that montelukast increased neurogenesis, improved blood-brain barrier (BBB) integrity, and improved cognition. Whether a reduction in inflammation directly contributed to these other improvements or whether these are independent effects of montelukast is unknown. However, the rejuvenating effects of montelukast are consistent with the recent line of parabiosis studies showing that young blood-borne factors can improve cognition, increase neurogenesis, and decrease microglia activation in aged mice (Villeda et al., 2011). In both cases, short-term treatment regimens are sufficient to see significant improvements in cognition and neurogenesis and decreases in inflammation. As with the blood studies, it is of interest to further investigate the dynamics and long-term effects of montelukast. For example, does montelukast turn on a switch in various brain cells, thus changing their phenotype and resulting in long-lasting cognitive effects? Or does cognitive improvement quickly decline when treatment is halted?
The authors focused on the hippocampal neural progenitors and neurons in this study, but the montelukast targets, CysLTR1 and GPR17, are also expressed in non-neuronal cells, suggesting other possible mechanisms by which brain rejuvenation occurs. Since glial cells, especially microglia and astrocytes, have been shown to directly contribute to cognitive decline it will be extremely interesting to understand the impact of montelukast on glial cells in the neurogenic niche and elsewhere throughout brain (Sierra et al., 2014; Miranda et al., 2012).
So far, anti-inflammatory drugs have met with limited success in clinical trials of various neurodegenerative diseases. However, this study exciting because i) montelukast is already a clinically approved drug and ii) it crosses the BBB.
This study has identified leukotriene receptors in the brain as a novel anti-aging target and hopefully future work will divulge whether this can slow symptoms of age-associated neurodegenerative diseases as well.
References:
Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, Stan TM, Fainberg N, Ding Z, Eggel A, Lucin KM, Czirr E, Park JS, Couillard-Després S, Aigner L, Li G, Peskind ER, Kaye JA, Quinn JF, Galasko DR, Xie XS, Rando TA, Wyss-Coray T. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 2011 Sep 1;477(7362):90-4. PubMed.
Sierra A, Beccari S, Diaz-Aparicio I, Encinas JM, Comeau S, Tremblay ME. Surveillance, Phagocytosis, and Inflammation: How Never-Resting Microglia Influence Adult Hippocampal Neurogenesis. Neural Plast. 2014;2014:610343. Epub 2014 Mar 19 PubMed.
Miranda CJ, Braun L, Jiang Y, Hester ME, Zhang L, Riolo M, Wang H, Rao M, Altura RA, Kaspar BK. Aging Brain Microenvironment Decreases Hippocampal Neurogenesis Through Wnt-Mediated Survivin Signaling. Aging Cell. 2012 Mar 8; PubMed.
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