Nature - Inspired! Effect of circadian rhythm on the transformation of neuroprotective research results.

Exploring the mysteries of neuroscience with rigorous academic logic thinking. Wang Sizhen edited Wang Sizhen's circadian rhythms affect the mechanism of diseases, and also affect the treatment of diseases [1-2].up to now, almost all the rodent model experiments of stroke with neuroprotectant are carried out in the daytime [1-2].we know that these rodents are usually inactive during the day, and their activities mainly occur at night.therefore, to some extent, the experimental results of these models do not match the clinical trial data.because, in the relevant clinical studies, most of the stroke patients recruited are almost daytime onset, which is also because, compared with night onset, daytime onset is easier to be studied, that is, daytime onset is more conducive to determining the onset time [1-2]. Br / > only a few patients with ischemic stroke at night accounted for only a few of the patients with ischemic stroke at night (only about 7% of the total number of patients with ischemic stroke at night were involved in the large-scale clinical trials of < 7 points).in conclusion, the neuroprotective mechanisms (/ strategies) that play a role in rodent models of stroke have not yielded consistent results in clinical trials.was published online in nature on June 3, 2020 under the title of potential circular effects on translational failure for neuroprotection Professor Lo's team and his collaborators reported that the opposite circadian rhythms of nocturnal rodents and diurnal humans may be responsible for the failure of this conversion, that is, the mismatch between animal model results and clinical trial results.in this study, the authors aimed to explore the reasons why the neuroprotective mechanisms of inactive (daytime) rodent models did not match the results of active (daytime) clinical subjects.in brief, the authors independently tested three neuroprotective agents in mice (C57BL / 6, male) and rat (Sprague – Dawley, male) models of focal cerebral ischemia, namely normobaric hyperoxia (NBO), free radical scavenger N-tert-butyl - α - phenylnitrone (α PBN), and antagonist of N-methyl-D-aspartate (NMDA), MK801 [4]- 6】。the results showed that the three protective agents could reduce the cerebral infarction in the daytime stroke mouse model (i.e. inactive phase), but could not reduce the cerebral infarction in the nighttime model (i.e. active phase) (Fig. 1).this suggests that neuroprotection may be more difficult to achieve in active rodent models.however, these active animal models are more similar to stroke patients with daytime onset (i.e., active phase) in clinical trials.this result also suggests that the circadian rhythm of animal model (night activity, daytime rest) is consistent with that of clinical patients (daytime activity, nocturnal rest) in the study.therefore, the neuroprotective effects embodied in the model cannot be matched (or applied / transformed) into clinical trials.this is also a big dilemma of the related research progress.Fig. 1 neuroprotection in a rodent model of stroke (photo: ELGA Esposito, et al., nature 2020). On the other hand, the penumbra after focal cerebral ischemia was compared by laser speckle imaging.the results showed that the penumbra of mice with active cerebral ischemia was narrower than that of mice in inactive phase (Fig. 2). furthermore, it was further found that the smaller (/ narrow) penumbra was associated with a small number of dying cells with positive TUNEL staining, and the narrowing of penumbra could delay (12-72 h) infarction (TUNEL, terminal DEOXYNUCLEOTIDYLTRANSFERASE dUTP nick end labeling, TUNEL staining is an in situ apoptosis detection method) (Fig. 2). these results indirectly indicate that the results of active mouse model may limit the time (daytime) range of neuroprotective agents in clinical application. because the neuroprotective effect was better when the model was tested at 15:00-21:00, and during this period, the activity frequency of patients was lower than that of other time periods in the day. Fig. 2 Comparison of penumbra after focal cerebral ischemia between active and inactive mice (photo: ELGA Esposito, et al., nature 2020). The above results show that the neuroprotection in the model can not be well matched in clinical trials. the authors also noted that the circadian rhythm of the model was not consistent with that of the clinical patients. therefore, the authors want to further explore whether circadian rhythm directly affects the neurosensitivity and neuroprotective response to ischemia. Compared with perxasone and perhasone (2) and perhasone (2) phases, the expression of glutamate (Glu) was significantly lower in the period of non oxygen deprivation (perhasone) and perhasone Lower levels of activation of factors (Fig. 3). moreover, α PBN and MK801 only reduced neuronal death in "inactive" neurons (Fig. 3). these results indicate that circadian rhythm has different potential effects on the active and inactive phases of stroke animal models and clinical subjects. Fig. 3 Effects of circadian rhythm on oxygen / glucose deprivation (OGD) response and neuroprotection (photo: ELGA Esposito, et al, The paper suggests that (1) the difference of circadian rhythm is not the only reason for the mismatch between model experiment and clinical trial. Other aspects of rodent model, including age, hypertension and metabolic diseases, may also be mismatched with clinical subjects. (2) this study shows that circadian rhythm affects the penumbra, but the underlying mechanism of this effect is not clear. for example, how circadian rhythm affects the neurovascular coupling in normal and ischemic tissues needs further investigation. (3) the authors also found that circadian rhythm affects neurons in response to oxygen / glucose deprivation via nerve cells. Therefore, further research is needed to analyze how the interaction between circadian rhythm genes and cell survival or death genes regulates neuroprotection. (4) circadian physiology may interact with pathophysiology of stroke in many aspects, including glial reaction, cytokines and chemokines, endothelial or hemostatic mechanism, immune response, temperature regulation, blood-brain barrier, drug delivery or metabolism, etc. (5) finally, the differences between these aspects of circadian rhythm in active and inactive rodent models still need further study. conclusion in conclusion, this study suggests that the effect of circadian rhythm on neuroprotection must be considered in the transformation of neuroprotective agents for stroke and central nervous system diseases (model studies to clinical trials). [1] Logan, R. W. & amp; McClung, C. A. rhythms of life: Circular disruption and brain disorders across the lifespan. NAT. Rev. Neurosci. 20, 49 – 65 (2019). [2] cederoth, C. R. et al. Medicine in the fourth dimension. Cell Metab. 30, 238 – 250 (2019). [3] Vista database (2019).【4】Ding, J. et al. The effect of normobaric oxygen in patients with acute stroke: a systematic review and meta-analysis. Neurol. Res. 40, 433–444 (2018).【5】Green, A. R., Ashwood, T., Odergren, T. & Jackson, D. M. Nitrones as neuroprotective agents in cerebral ischemia, with particular reference to NXY-059. Pharmacol. Ther. [6] balsalobre, A. et al. Resetting of circular time in peripheral tis sues by glucocorticoid signaling. Science 289, 2344 – 2347 (2000)