Researchers here note that leukotriene receptor antagonists appear to reduce inflammation and increase plasticity in the brains of rats. They pin down the receptor GPR17 as a protein of interest in this effect. While not directly addressing underlying damage and change that causes inflammation and loss of neural plasticity, it is possible that this type of approach may produce sufficient benefits in humans to merit development. The same arguments apply here as for other classes of therapy that improve tissue maintenance without doing much to reduce the molecular damage that drives aging, such as stem cell transplants. There are clearly meaningful benefits in that case, and so long as this sort of research and development doesn't result in the abandonment of attempts to repair damage and thus halt and reverse aging, it is worth pursuing.
Counteracting some, or ideally all, of such age-related changes might rejuvenate the brain and lead to preservation or even improvement of cognitive function in the elderly. The feasibility of such an approach was recently demonstrated by experiments exposing the aged brain to a young systemic environment, that is, young blood, through heterochronic parabiosis. The aged brain responded to young blood by reduced microglia activation, enhanced neurogenesis, and importantly, by improved cognition. Vice versa, old blood caused premature ageing of the young brain and led to impaired cognition. A proteomic approach identified eotaxin, a chemokine involved in asthma pathology, as one of the molecules that is elevated in ageing and that contributes to neuroinflammation, reduced neurogenesis and to impaired cognition. This triggered us to hypothesize that, aside from eotaxin, additional mechanisms that are originally related to peripheral inflammatory conditions such as asthma might act or even be present in the central nervous system (CNS), where they potentially modulate degenerative and regenerative events.
Leukotriene signalling is well studied in the field of asthma. Leukotrienes mediate inflammatory reactions associated with increased vascular permeability, and leukotriene receptor antagonists such as the drug montelukast have been successfully developed to treat asthmatic patients. The role of leukotrienes in the brain, in particular their contribution to degeneration and regeneration, is less clear and sometimes even controversial. Nevertheless, elevated levels of leukotrienes were reported in acute as well as chronic CNS lesions, and also in the aged brain, where they might mediate neuroinflammatory responses including microglia activation. Here, we demonstrate that montelukast reduces neuroinflammation, restores blood-brain barrier integrity and increases neurogenesis specifically in the brain of old rats, the latter being mediated through inhibition of the GPR17 receptor. Most importantly, montelukast treatment restores cognitive function in the old animals, paving the way for future clinical translation for the treatment of dementias.
The effect on neurogenesis was, like the anti-inflammatory activity, specific to old rats. Thus, montelukast might stimulate neural progenitor proliferation only in situations in which neurogenesis is compromised. Montelukast might liberate progenitors from age-associated inhibitory mechanisms, which most likely include elevated levels of leukotrienes. Obviously, the extrapolation of these results from normal ageing to neurodegenerative diseases is intriguing, and some of the beneficial effects of montelukast in animal models of neurodegeneration might well be attributed to enhanced neurogenesis. In general, a clear dissection between neurogenesis- and neuroinflammation-mediated effects on cognition is not straightforward as neurogenesis and neuroinflammation strongly influence each other. For example neural progenitors induce microglia proliferation and activation, and vice versa, microglia regulate adult hippocampal neurogenesis.