Study Suggests Epilepsy Drugs Are More Effective at Night

Study findings have identified a new mechanism of circadian regulation of the blood-brain barrier (BBB) in Drosophila that makes drugs targeted to the brain more effective when administered at night. The BBB is a highly selective membrane barrier with tight junctions that only allows certain molecules to pass through and prevents harmful toxins and bacteria from reaching the brain. However, this strict gatekeeping can prevent medications from effectively treating brain-related disorders, such as epilepsy. The study was published in Cell.

Two key findings were discovered in the study. The first one was that the permeability of the BBB in Drosophila is higher at night than during the day. The second finding showed that the cells that make up the barrier have a molecular clock mechanism that controls this daily rhythm and changed how the fruit flies responded to phenytoin, an anti-epileptic drug.

The researchers used a dye, foreign to fruit flies, in their experiments and followed its course. They found that gap junctions in the BBB are cyclically expressed. They’re made up ion channels that allow ions and small molecules to pass through. During the night, gap junctions reduce intracellular magnesium (Mg²⁺) which is a positive regulator of efflux. Since efflux is downregulated at night due to less Mg²⁺ in the cell, administering the anti-epileptic at night proved to be more effective at treating the Drosophila seizure model. Flies given the drug had a much shorter recovery time after the seizure than flies given the drug during the day.

"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," says Amita Sehgal, PhD, a professor of Neuroscience in the Perelman School of Medicine at the University of Pennsylvania and leader of the study. "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."

Image: The 24-hour rhythm of permeability of a fly's blood (hemolymph) brain barrier, courtesy of The lab of Amita Sehgal, PhD, Perelman School of Medicine, University of Pennsylvania.