Scientists Isolate Circadian Clock that Regulates Drug-Dosing Schedule
They say there’s a time for everything—though you might not know it from looking at a pill-bottle label. Most say how many pills to take, but not when to take them.
Now, researchers at the University of Pennsylvania have uncovered the circadian clock involved in regulating 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.
Between 40 and 50% of all genes in the body appear to be linked to the circadian clock in their activity. And the study sheds light on several genes that respond to the circadian rhythm and change their activity in a cyclic manner around the clock. Hundreds of genes get involved, with 3,186 genes in the liver alone showing this daily pattern.
One very interesting finding of the study is the presence of two time periods, just before dawn and dusk, when particularly large shifts in gene activity take place. This is when significant changes in our activity level, alertness and mood can occur. This is also when the metabolic activity of
our body changes.“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,” Amita Sehgal, PhD, a professor of Neuroscience in the Perelman School of Medicine at the University of Pennsylvania and a Howard Hughes Medical Institute investigator said. “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.”
The investigating team used a dye to demonstrate how clock signals are transmitted 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.
In order 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 anti-epileptic 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 timing the delivery of drugs that act in the brain should consider when the barrier is open as well as other cyclical aspects of neuron physiology. One relevant line of research is to identify the drugs most likely to be targeted by the mechanism that drives a rhythm in BBB permeability
