In the VP16/TLX assay, caffeine directly modulated TLX and counteracted its repressor activity with an IC50 value of 9 µM. We also observed an ability of caffeine to reverse TLX-mediated repression of various NRs. Considering that typical caffeine concentrations after coffee consumption or pharmacological caffeine intake peak at 10 mg/L (~ 50 µM) plasma levels and that brain penetration of caffeine is high , this unprecedented molecular activity of caffeine has potential biological relevance. Importantly, habitual caffeine intake has been correlated with reduced risk for Parkinson's Disease and Alzheimer's Disease . As TLX is an essential factor of neural maintenance and neurogenesis , a potential connection of these effects is obvious.