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March 12, 2018

Circadian Clock in Blood–Brain Barrier May Decide Best Drug Dosing Times

A circadian mechanism that regulates the permeability of the blood–brain barrier has been found. The mechanism, which emerged from a study of an antiepileptic drug’s effectiveness in a fruit fly seizure model, points to possibilities for improving drug-dosing schedules. The mechanism may also be subject to manipulation. [Lab of Amita Sehgal, Ph.D./Perelman School of Medicine, University of Pennsylvania]

  • Keeping to a regular diurnal rhythm, the cell–cell junctions of the blood–brain barrier (BBB) tighten and loosen, tighten and loosen, on and on, admitting foreign substances such as drugs more readily during the night, but maintaining a more formidable barrier during the day. While scientists have long suspected as much, they have only recently isolated the circadian mechanism that regulates the BBB’s daily permeability.

    The mechanism, say its discoverers, could help clinicians time the administration of drugs that work only if they pass the BBB. In addition, the mechanism could be manipulated so that drugs could more easily pass the BBB at whatever times might be deemed most desirable.

    The scientists who discovered this circadian mechanism worked with fruit flies to study how they responded to an antiepileptic drug. Presenting their results in a paper (“A Circadian Clock in the Blood-Brain Barrier Regulates Xenobiotic Efflux”) that appeared March 8 in Cell, the scientists indicated that the circadian mechanism resides in the perineurial glia of the BBB. Efflux transporters, the article’s authors noted, are restricted to subperineurial glia (SPG).

    “We show that transmission of circadian signals across the layers requires cyclically expressed gap junctions,” wrote the article’s authors. “Specifically, during nighttime, gap junctions reduce intracellular magnesium ([Mg2+]i), a positive regulator of efflux, in SPG. Consistent with lower nighttime efflux, nighttime administration of the anti-epileptic phenytoin is more effective at treating a Drosophila seizure model.”

    There have been hints in past studies that the opening of the blood–brain barrier fluctuates over 24 hours, and now we see, for the first time, direct evidence that a local circadian clock exists in the barrier," said Amita Sehgal, Ph.D., the current study’s senior author and a professor of neuroscience in the Perelman School of Medicine at the University of Pennsylvania. "More importantly, we have identified a novel daily regulation that could have implications for the timing of taking medications targeted to the central nervous system."

    Using a dye, her team showed that transmitting clock signals across the BBB requires gap junctions, which are expressed cyclically. These are protein complexes organized into channels in cell membranes that allow ions and small molecules to pass between cells. Specifically, during the night, magnesium passes through the junctions to decrease its concentration in cells that form the tight barrier, therefore allowing substances to permeate the brain.

    To test if the cyclical permeability might also lead to a better outcome if brain drugs are administered at night, they gave mutant flies prone to seizures the antiepileptic drug phenytoin. While the incidence of seizures did not vary over the course of the day–night cycle, flies given the drug at night had a shorter time to recovery after seizures compared to flies given phenytoin during the day.

    Those findings suggest that when timing the delivery of drugs that act in the brain, when the barrier is open as well as other cyclical aspects of neuron physiology should be considered. A relevant line of research is to identify the drugs most likely to be targeted by the mechanism that drives a rhythm in BBB permeability.

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