Nature: Does circadian rhythm cause clinical failure of neuroprotective drugs?

Learn about the latest progress in neuroscience ● click the blue word to pay attention to us ● circadian rhythm is equivalent to installing a "clocked alarm clock" to remind the human body of what to do next.take a long-distance flight as an example. When traveling to a new time zone, although you are in a foreign country, the body's biological clock still stays at home. The brain does not allow such disharmony. Through a series of regulatory functions, the biological clock is adjusted to the new time zone of the other country, so as to better carry out physiological activities.Photo quoted from: often staying up late can cause circadian rhythm disorder, increase the risk of cardiovascular disease, promote aging and other adverse effects.it's normal for researchers to stay up late and work overtime. What I want to tell you today is that the circadian rhythm of animals may also affect your experimental results.on June 3, 2020, the team of Eng h. lo, Massachusetts General Hospital, Harvard Medical College, USA published an article in the journal Nature, and found a very interesting thing: neuroprotective agents for stroke do not work in clinical trials, which may be due to the wrong administration time of animal models.pictures are quoted from reference 1. When studying the neuroprotective effects of stroke, it is usually selected to conduct experiments in the daytime, because mice are animal species that are active at night and rest during the day, so mice in daytime are inactive.however, most stroke patients are recruited in the daytime, at this time, the patients are in a conscious state.therefore, even drugs with neuroprotective effects in stroke model mice may fail in clinical trials.normobaric hyperoxia is effective in the treatment of stroke animal models, but it is not effective in clinical practice (2).the researchers found that 100% oxygen could significantly reduce cerebral infarction in stroke rats during the daytime (inactive period of rats, i.e., zt3-zt9 time period), while 100% oxygen treatment at night (active period of rats, namely zt15-zt21 period) had no effect.this indicates that the treatment does not work in the active phase of rats, which also explains why it does not work in stroke patients with daytime onset.the most serious ischemic damage is in the ischemic core, and the penumbra is near the core.studies have found that the penumbra region maintains blood flow, so neurons may survive temporarily and are considered as the target area for neuroprotection (3).then whether the active and inactive phases of circadian rhythm affect the penumbra.using laser speckle imaging, the researchers found that the blood perfusion was steeper in the active phase of stroke model mice, while the area of penumbra was smaller.therefore, there is a possibility that the area of the penumbra is larger in the inactive phase, so the drug is easy to play a role, and the area of the penumbra in the active phase is smaller, and the drug effect is worse.the researchers found that the infarct size increased from 12 hours to 72 hours after the successful establishment of the stroke model, but the rate of infarct formation in the active phase was significantly reduced compared with that in the inactive phase. immunofluorescence showed a decrease in neuronal death in the penumbra. that is to say, the area of penumbra is reduced, the neuron death is reduced, and the infarct area is also reduced. oxygen glucose deprivation is an ideal in vitro model of stroke. in order to further study the effect of active and inactive phases on the therapeutic effect of stroke model, dexamethasone was skillfully used to induce circadian rhythm cycle. After 6 hours of dexamethasone administration, the isolated cortical neurons of mice were in the active phase, and the neurons were in the inactive phase after 12 hours. the results showed that the free radical scavenger N-tert-butyl - α - phenylnitrone (PBN) and NMDA antagonist MK801 significantly reduced neuronal death only in the inactive phase, but not in the active phase. it was further found that oxygen glucose deprivation promoted the activation of Caspase-3 and RIP3 kinase (a signal related to cell death), but the activation was stronger in the inactive phase than in the active phase. This may be one of the reasons why the neuroprotective agents for stroke play a role in the inactive phase of rodents, but not in the active phase. generally speaking, this paper reveals the possible reasons for the failure of clinical translational medicine of neuroprotective drugs for stroke from a very interesting point of view - circadian rhythm. the author also mentioned in the discussion section that circadian rhythm may not be the only reason for the failure of translational medicine, but there are other reasons. References: 1. Potential circular effects on translational failure for neuroprotection, Ding, J. et al. The effect of normobaric oxygen in patients with acute stroke: a systematic review and meta analysis. Nerve. Res. 40, 433 – 444 (2018) 3. Donnan, G. A., Baron, J. C., Ma, H. & amp; Davis, S. M. Penumbral selection of patients for trialsof acute stroke therapy. Lancet Neurol. 8, 261–269 (2009).