Scientists Revisiting Existing Drugs Find Promising Molecules for Jet Lag Symptoms
Sleep Review: The Journal for Sleep Specialists
Using drug repurposing, a team of researchers led by animal biologists at
The experiments were carried out through a joint research collaboration between researchers at
Many frequent flyers who travel across time zones tend to suffer from jet lag, which is caused by a mismatch between external time cues (shifted day/night cycle) and their biological (circadian) clock. The circadian clock in humans has an approximate 24-hour rhythm, and the circadian rhythm plays an important role in regulating sleep/wake cycles, hormone secretion, and metabolism. Therefore, chronic disruption of the circadian rhythm arising from jet lag or shift work (circadian desynchrony) may lead to various symptoms, such as sleep disorders, obesity, and an increased risk of cancer in the long term.
Although jet lag usually triggers a number of undesirable symptoms, effective drugs or supplements to cure it remain scarce. Most of the drugs discovered so far by circadian biologists that reduce jet lag in mice require injection of the drug into a specific region of the brain (which is not very practical).
Developing of new pharmaceuticals is usually highly costly and time-consuming. So drug repurposing is a popular approach to develop new drugs. Famous examples of drug repurposing include the redevelopment of minoxidil, originally launched on the market as a vasodilator, repurposed for hair growth; as well as sildenafil, an antihypertensive, repurposed for the treatment for erectile dysfunction and marketed as Viagra.
“In 2015, we had reported the synthesis of a molecule with demonstrated period-shortening activities on mammalian circadian clocks discovered through a collaboration between ITbM’s chronobiologists, synthetic chemists, and theoretical scientists,” says Yoshimura in a release. “Unfortunately, this compound was rather toxic, which led me to think more about the safety of molecules. I then considered that drug repurposing would be a better approach to identify compounds that can be used to treat jet lag, as the toxicity and mode of action of existing drugs would have already been investigated.”
The research group conducted high throughput screening of over 1,000 compounds consisting of existing drugs, including those approved in the
The research team screened various drug libraries by setting up a system where they observed the daily transcription of the clock gene Bmal1 through monitoring of a bioluminescent rhythm using the firefly’s bioluminescence (luciferase) gene. Each drug was added to a 384-well plate containing human cells (U2OS) transfected with the luciferase gene.
As a result of high throughput screening of over 1,000 existing drugs, the team found 59 hit compounds that affected the bioluminescent rhythm. Among these drugs, 46 compounds lengthened the circadian period, and 13 compounds shortened the period. These hit compounds contained bioactive molecules that are used as anti-cancer, antibacterial, and contraceptive agents, hormones, vitamins, as well as for the treatment of diseases related to the central nervous system, digestive system, heart, and skin. The results of their studies suggest that approximately 5% of the drugs currently on the market may have some effect on our circadian rhythms, depending on their dose and duration of administration.
“I was really excited to find hit compounds that had period-changing effects on human cells and wanted to test them immediately in mice to see if the drugs could relieve jet lag symptoms,” says Yoshimura. “Many members in our group were hesitant though, as they thought that the effects observed in cells were too small, but I had no doubt that the results would translate from the cell level (in vitro) to the animal level (in vivo).”
For most travelers, flying west (eg, from
Among the 13 circadian period-shortening compounds that the group identified, the researchers focused on a steroid hormone, dehydroepiandrosterone (DHEA), which is commercially available as an anti-aging supplement in USA. In humans, DHEA is produced in the adrenal gland, gonads, and brain, and is a precursor for testosterone and estrogen. DHEA is one of the most abundant circulating hormones in the blood stream, but its concentration usually decreases with age. This is why DHEA is sold as a supplement for anti-aging and for boosting metabolism.
Further investigation showed that DHEA shortens the period of the circadian clock in cultured human cells in a dose-dependent manner. The team found that DHEA speeds up the circadian rhythm in human cells, as well as in cultured cells and tissues of mice. As previous studies have demonstrated the safety of orally administering DHEA in mice, experiments were carried out to test whether DHEA had an effect on the circadian rhythm of mice.
“When we fed DHEA mixed with powdered food to mice, we were surprised and pleased to find that DHEA shortened the circadian period in mice,” says
“I started this research in 2016, and being a biologist who worked mainly with fish, I was afraid at first to test the drugs out on mice, but
The simple solution appears to be to take DHEA to cure jet lag, but one important issue is that the circulating levels of DHEA in mice and humans is different. The reason why DHEA may have been so effective in mice may be because the initial circulating concentration of DHEA is significantly lower in mice (approximately 15%) compared to humans. Also, extremely high doses of DHEA have actually led to lengthening of the circadian period. So further investigation is required to evaluate the actual effectiveness of DHEA for the treatment of jet lag in humans.
“Our studies have shown that DHEA probably acts primarily on the peripheral circadian clocks rather than on the master clock in the central nervous system, which has control over clocks in the entire body,” Yoshimura says. “In order to completely relieve jet lag, it is necessary to adjust both the central and peripheral circadian clocks. We envisage that DHEA may be effective when taken along with another drug that acts upon the central circadian clock.”
Using drug repurposing, Yoshimura’s group not only identified circadian rhythm changing drugs, but also succeeded in identifying genes that are involved in the regulation of the circadian clock. The group identified several tyrosine kinase inhibitors that affected circadian rhythms and found evidence suggesting that the ABL (Abelson murine leukemia) and BCR (breakpoint cluster region) protein kinases are involved in the regulation of the mammalian circadian clock. Tyrosine is an amino acid present in proteins that contains a hydroxyl moiety, and kinases are enzymes that catalyze phosphorylation (addition of a phosphate group) of various substrates in the cell. Hydroxyl, amine, and carboxyl moieties in proteins can be phosphorylated, which modifies the proteins to switch them on or off for various functions.
Previous reports have shown that in a genetic abnormality called
“We are currently expanding our chemical libraries and are now screening food additives and natural products to find compounds that can regulate the circadian rhythm in humans,” says Yoshimura. “We hope to develop and be able to deliver new and safe compounds that can be taken orally to cure jet lag.”
Image credit: ITbM,