Stimulating brain drug delivery

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Science Translational Medicine  07 Oct 2020:
Vol. 12, Issue 564, eabe8119
DOI: 10.1126/scitranslmed.abe8119


Neural activity affects how the blood-brain barrier regulates influx and efflux of agents between the blood and the central nervous system.

It is commonly known that vascular function can affect neural activity; indeed, decreased brain perfusion impedes neural function. Conversely, neural activity can influence vascular function; for instance, neural activity induces blood flow changes, yielding the contrast mechanism of fMRI. A recent study by Pulido and colleagues has taken this story further, providing compelling evidence that neural activity can affect the function of the blood-brain barrier (BBB).

The BBB strongly restricts what molecules can transit between the body and the central nervous system (CNS). While serving this key protective function, it also prevents the delivery of therapeutic compounds to the CNS and regulates the clearance of toxic compounds and exogenous agents. Pulido and colleagues built on prior work that showed that neural activity could influence gene expression in brain vascular endothelium and performed genetic screening to identify which endothelial cell genes were up- or down-regulated following changes in neural activity. They used chemogenetic manipulations to drive neural activation or silencing and saw consistent changes in a population of BBB transporters and efflux pumps. They inferred that brain activation could yield net increased influx of molecules of the body past the BBB, whereas silencing would yield net efflux. Chemogenetic activation promoted increased selective delivery to the CNS of dyes that are known substrates for the transporters that showed up-regulation, but not for dyes that are not substrates of these transporters, and specifically so where there was more chemogenetic activation. Notably, they also showed that a similar pattern of genetic up-/down-regulation was seen with natural (whisker sensory) stimulation.

Although not directly assessed in this study, this might have implications for neurodegenerative disorders given that the efflux proteins affected by neural activation/silencing have been shown to affect clearance of molecules like Aβ, which is associated with Alzheimer’s disease. These results certainly need to be validated in relevant models of disease and therapeutic delivery, including large animals, and with more clinically translatable modes for neuromodulation. Meantime, the possible implications of these findings are quite stimulating for CNS drug delivery and neurodegenerative treatment, literally.

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