What Do Day-Night Cycles Have to Do With Stroke Treatment?

Post by Anastasia Sares

What's the science?

Rats and mice are nocturnal: they are active during the night-time and sleep during the day. Human researchers, on the other hand, are diurnal; active in the day and sleeping at night. This simple fact means that a lot of pre-clinical trials (testing medication or treatment on an animal before it is tested in humans) happen during an animal’s sleep cycle, while most human stroke cases occur while the individual is awake. Sometimes a treatment’s effectiveness can vary depending on what point in the sleep cycle, or circadian rhythm, it is administered. This has recently proven to be the case with stroke, which happens when blood flow is blocked from one region of the brain (for example, by a blood clot). This week in Journal of Cerebral Blood Flow & Metabolism, Boltze and colleagues published a commentary about why circadian cycles matter for stroke treatment, signaling that we may have to adapt our methods for clinical and pre-clinical trials to accommodate these day-night cycles.

What do we already know?

In June of 2020, another team of researchers (Esposito and colleagues) examined a number of new stroke treatments that had passed the pre-clinical phase but failed at the clinical phase. In other words, these treatments seemed to work in rats or mice, but they didn’t benefit humans in the same way. The team showed that when the rodents were tested during their “active” phase (night-time) instead of their “inactive phase” (daytime), many of the treatments were not effective, just as they had seen in humans during the day.

Esposito and colleagues found that the penumbra, the brain tissue at the edge of the zone affected by a stroke, was smaller if the animals were awake at the time of injury. The neurons in the middle of the stroke zone will almost certainly die off, but the penumbra is alive for a little longer. It too, however, can die off in the hours following a stroke if treatment is not delivered quickly. The team suspected that the pre-clinical treatments didn’t work during the animal’s active time of day because the penumbra was smaller and there simply wasn’t much brain tissue left to treat.

What’s new?

Boltze proposed some ways of addressing circadian rhythm in future experiments. Some ways forward include testing diurnal animals like dogs or testing nocturnal animals during their active cycle (reversing the light/dark cycle in animal facilities so that human and rodent cycles align). Stroke treatments may also need to differ depending on the time of day the stroke occurs. The authors suggest that, for pre-clinical trials of new treatments, “the effect of intervention time should be systematically investigated,” documenting how well the treatment works during different times of the day. Then, during the clinical phase, a patient who presents with a stroke at night-time could be assigned to a different clinical trial than someone who comes in during the day, making sure that circadian rhythm is accounted for.

What's the bottom line?

Though humans share many features with our mammal cousins, it is important to remember that no animal model is perfect. This work provides an example of how small differences between human and rodent physiology can result in different responses to treatment. This recent research brings awareness to circadian rhythms as an important factor in pre-clinical trial development.

Boltze et al. Circadian effects on stroke outcome – Did we not wake up in time for neuroprotection? Journal of Cerebral Blood Flow & Metabolism (2020). Access the recent commentary here, and theoriginal Nature article by Esposito et al. here.