Circadian Clock to Regulate Drug-Dosing Schedule

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Researchers from University of Pennsylvania revealed circadian clock involved in regulating the permeability of the blood–brain barrier

The principle of study was emerged from effectiveness of antiepileptic drug in a fruit fly seizure model, which has potential to improve drug-dosing schedules. According to the study, 40 to 50% of genes in the body are linked to the circadian clock. They respond to the circadian rhythm and change activity in a cyclic manner around the clock. The results of the study was published in in a paper named ‘Circadian Clock in the Blood-Brain Barrier Regulates Xenobiotic Efflux,’ which was published on March 8, 2018 in journal Cell. Researchers stated that circadian mechanism resides in the perineurial glia of the BBB.

The team used a dye to demonstrate transmission of 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. During night, magnesium passes through the junctions to decrease its concentration in cells that form the tight barrier, therefore allowing substances to permeate the brain. “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, PhD, a professor of Neuroscience in the Perelman School of Medicine at the University of Pennsylvania and a Howard Hughes Medical Institute investigator.

As a part of study, mutant flies prone to seizures were administered with anti-epileptic phenytoin to examine effect of drugs. 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. Findings of the study suggest that timings of drug delivery that act in the brain should consider when the barrier is open as well as other cyclical aspects of neuron physiology.

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