Life expectancy has increased dramatically in the last few decades, particularly in the most developed countries. And that’s a wonderful thing. But this increase has brought a number of new challenges in health and healthcare, specifically in age-related conditions, such as neurological conditions. One of the great challenges in medical research is, therefore, to find a way to keep up with the healthcare demands of an ageing population. So, whenever a new promising therapy emerges, it is always worth a shout out.
Age-associated diseases have a higher prevalence than ever and consequently, a huge social impact. The brain goes through a number of changes as it ages: our cognitive skills decay, while the risk of dementia and neurodegenerative diseases increases.
As it ages, the brain loses its ability to generate new cells, while the existing cells lose functional properties. The blood-brain barrier, the protective boundary that separates the blood from the extracellular fluid in the central nervous system, loses power and becomes less selective, allowing for more circulating (and potentially damaging) molecules to reach the brain. And the blood is an important factor in ageing: it has been shown that exposing the aged brain to young blood can reverse some of the age-associated changes; the opposite is also true – old blood can cause a premature ageing of a young brain.
One of the main driving forces of age-related neurological conditions is neuroinflammation. The aged brain produces increased levels of pro-inflammatory molecules and loses some ability to counterbalance these changes through anti-inflammatory mechanisms. Also, inflammatory mediators in the blood gain an easier access to the brain.
In theory, delaying or even reversing these neuroinflammatory changes could potentially rejuvenate the brain and help preserve or even improve cognitive functions in elderly people. And that is exactly what a European research group aimed at in a study recently published in Nature Communications.
This group of researchers from Austria, Germany, Italy and Croatia presented a new therapy that, according to their own words, can “functionally rejuvenate the aged but otherwise healthy brain”. And the therapeutic agent is probably surprising: it’s an anti-asthmatic drug named montelukast.
The authors had previously identified a molecule involved in asthma pathology as being elevated in ageing, contributing to neuroinflammation and cognitive impairment. This led them to the hypothesis that other mechanisms originally related to peripheral inflammatory conditions such as asthma might affect the central nervous system, potentially contributing to degenerative processes.
Leukotrienes are a group of molecules that mediate inflammatory reactions associated with increased vascular permeability. Increased levels of leukotrienes have been reported in a number of neurological conditions, as well as in the aged brain. Although their role is mostly unclear, it is believed that they may mediate inflammatory responses in the brain and blood vessels. The drug they used, montelukast, acts by blocking leukotriene activity, being highly successful in asthma.
According to their data, montelukast seems to be able to reduce the levels of inflammatory molecules in the brain, restore the blood-brain barrier’s integrity and increase neurogenesis in the brain of aged rats. As a consequence, montelukast treatment also restores cognitive function in the old animals.
Montelukast seems to be able to cross the blood-brain barrier and it had previously been shown to have a protective effects in animal models of neurodegenerative diseases, including Huntintgon’s and Alzheimer’s disease, as well as in induced loss of memory function, spinal cord and brain injuries and stroke, decreasing cognitive and structural deficits.
Here, they showed that this anti-asthma drug can reduce age-associated changes, improving learning and memory in old rats, reducing the inflammation-induced activation of glial cells in the brain, and restoring neurogenesis in the hippocampus of old rats most likely by targeting leukotriene actions in the brain.
It remains to be determined if a similar effect will be observed in humans, both in healthy aged humans and in the context of neurological and neurodegenerative diseases, but these results are promising.
References
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Kumar A, Prakash A, Pahwa D, & Mishra J (2012). Montelukast potentiates the protective effect of rofecoxib against kainic acid-induced cognitive dysfunction in rats. Pharmacology, biochemistry, and behavior, 103 (1), 43-52 PMID: 22878042
Lai J, Mei ZL, Wang H, Hu M, Long Y, Miao MX, Li N, & Hong H (2014). Montelukast rescues primary neurons against A?1-42-induced toxicity through inhibiting CysLT1R-mediated NF-?B signaling. Neurochemistry international, 75, 26-31 PMID: 24879954
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Saad MA, Abdelsalam RM, Kenawy SA, & Attia AS (2015). Montelukast, a cysteinyl leukotriene receptor-1 antagonist protects against hippocampal injury induced by transient global cerebral ischemia and reperfusion in rats. Neurochemical research, 40 (1), 139-50 PMID: 25403620
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 (2011). The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature, 477 (7362), 90-4 PMID: 21886162
Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher KI, Luo J, Smith LK, Bieri G, Lin K, Berdnik D, Wabl R, Udeochu J, Wheatley EG, Zou B, Simmons DA, Xie XS, Longo FM, & Wyss-Coray T (2014). Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nature medicine, 20 (6), 659-63 PMID: 24793238
Wang L, Du C, Lv J, Wei W, Cui Y, & Xie X (2011). Antiasthmatic drugs targeting the cysteinyl leukotriene receptor 1 alleviate central nervous system inflammatory cell infiltration and pathogenesis of experimental autoimmune encephalomyelitis. Journal of immunology (Baltimore, Md. : 1950), 187 (5), 2336-45 PMID: 21804021
Yu GL, Wei EQ, Zhang SH, Xu HM, Chu LS, Zhang WP, Zhang Q, Chen Z, Mei RH, & Zhao MH (2005). Montelukast, a cysteinyl leukotriene receptor-1 antagonist, dose- and time-dependently protects against focal cerebral ischemia in mice. Pharmacology, 73 (1), 31-40 PMID: 15452361
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