Cell: The first observation of the circadian rhythm of the blood-brain barrier

Release date: 2018-03-21

The blood brain barrier (BBB) ​​acts as a guard between the brain and other parts of the body. This barrier consists of a tight junction formed between cells on the inner wall of the blood vessel to prevent toxic substances and bacteria from invading the brain. But it can also stop many drugs used to treat brain diseases.

In a new study, Dr. Amita Sehgal, a professor of neuroscience at the University of Pennsylvania's Perelman School of Medicine, and his team described the permeability of the blood-brain barrier of Drosophila at night to be higher than during the day. In addition, her team found that this daily rhythm is controlled by the molecular clock in the supporting cells within this barrier, which affects how Drosophila mutants respond to epileptic drugs. The results of the study were published online in the Cell Journal on March 8, 2018, under the heading "A Circadian Clock in the Blood-Brain Barrier Regulates Xenobiotic Efflux." The first author of the paper is Dr. Shirley Zhang, a postdoctoral researcher at Sehgal Laboratories.

A key barrier to the development of drugs for the treatment of brain and central nervous system diseases is to design a method for efficiently passing the blood-brain barrier. Higher drug doses can help, but this strategy poses risks to other organs.

Sehgal said, “Past research has suggested that the opening of the blood-brain barrier fluctuates within 24 hours. Today, we have for the first time observed direct evidence that a local circadian clock exists in this barrier. More importantly, we A new daily regulation has been identified that may affect the timing of taking drugs against the central nervous system."

Her team used a dye to verify that the clock signal transmitted through the blood-brain barrier requires periodically generated gap junctions. This gap junction is a pathway in which protein complexes form in the cell membrane, allowing ions and small molecules to pass between cells. Specifically, at night, magnesium ions reduce their concentration in cells that form a tight blood-brain barrier through gap junctions, thus allowing substances to penetrate into the brain.

In order to test whether this periodic permeability change may lead to better results when administered brain-targeted drugs at night, they allow the epileptic Drosophila mutant to take the anti-epileptic drug phenytoin. Although the incidence of epilepsy did not change during the day and night cycle, fruit flies taking phenytoin at night had a shorter recovery time after seizures than those who took phenytoin during the day.

These findings suggest that the timing of delivery of drugs that function in the brain should consider when this blood-brain barrier opens and other cyclical aspects of neuronal physiology.

Reference materials:

Shirley L. Zhang, Zhifeng Yue, Denice M. Arnold et al. A Circadian Clock in the Blood-Brain Barrier Regulates Xenobiotic Efflux. Cell, Published online: March 8, 2018, doi:10.1016/j.cell.2018.02.017

Source: Bio Valley

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