The Period 2 Enhancer Nobiletin as Novel Therapy in Murine Models of Circadian Disruption Resembling Delirium*

Gile, Jennifer; Scott, Benjamin; Eckle, Tobias

doi:10.1097/ccm.0000000000003077

Cited by 34 publications

(35 citation statements)

References 51 publications

(63 reference statements)

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“…While midazolam is the benzodiazepine most frequently used for procedural sedation, recent clinical data suggest that midazolam is associated with severe clinical complications. As such midazolam has been associated with the occurrence of delirium and is therefore not recommended anymore as first line sedative on critical care units [29–32]. Moreover, a recent study found that continuous infusion of benzodiazepines is linked to an increased likelihood of death among patients who receive mechanical ventilation, when compared to the sedative propofol [11].…”

Section: Discussionmentioning

confidence: 99%

The Circadian PER2 Enhancer Nobiletin Reverses the Deleterious Effects of Midazolam in Myocardial Ischemia and Reperfusion Injury

Oyama

Bartman

Gile

et al. 2018

CPD

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Background: Recently, we identified the circadian rhythm protein Period 2 (PER2) in robust cardioprotection from myocardial ischemia (MI). Based on findings that perioperative MI is the most common major cardiovascular complication and that anesthetics can alter the expression of PER2, we hypothesized that an anesthesia mediated downregulation of PER2 could be detrimental if myocardial ischemia and reperfusion (IR) would occur. Methods and Results: We exposed mice to pentobarbital, fentanyl, ketamine, propofol, midazolam or isoflurane and determined cardiac Per2 mRNA levels. Unexpectedly, only midazolam treatment resulted in an immediate and significant downregulation of Per2 transcript levels. Subsequent studies in mice pretreated with midazolam using an in-situ mouse model for myocardial (IR)-injury revealed a significant and dramatic increase in infarct sizes or Troponin-I serum levels in the midazolam treated group when compared to controls. Using the recently identified flavonoid, nobiletin, as a PER2 enhancer completely abolished the deleterious effects of midazolam during myocardial IR-injury. Moreover, nobiletin treatment alone significantly reduced infarct sizes or Troponin I levels in wildtype but not in Per2−/− mice. Pharmacological studies on nobiletin like flavonoids revealed that only nobiletin and tangeritin, both found to enhance PER2, were cardioprotective in our murine model for myocardial IR-injury. Conclusion: We identified midazolam mediated downregulation of cardiac PER2 as an underlying mechanism for a deleterious effect of midazolam pretreatment in myocardial IR-injury. These findings highlight PER2 as a cardioprotective mechanism and suggest the PER2 enhancers nobiletin or tangeritin as preventative therapy for myocardial IR-injury in the perioperative setting where midazolam pretreatment occurs frequently.

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Section: Discussionmentioning

confidence: 99%

The Circadian PER2 Enhancer Nobiletin Reverses the Deleterious Effects of Midazolam in Myocardial Ischemia and Reperfusion Injury

Oyama

Bartman

Gile

et al. 2018

CPD

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“…pharmacologic approach to induce Per2 has been previously demonstrated to treat metabolic dysfunction (23). As a therapeutic strategy, inducing Per2 circadian rhythms with nobiletin, a nontoxic flavonoid, has been identified as advantageous in treating circadian dysfunctional diseases such as obesity and oxidative stress in mice (23,40). Nobiletin is a flavonoid derived from a citrus plant, which suggests that potent antioxidative effects can function to reduce reactive oxygen species, which contribute to disease progression (23,41).…”

Section: Discussionmentioning

confidence: 99%

Circadian period 2: a missing beneficial factor in sickle cell disease by lowering pulmonary inflammation, iron overload, and mortality

Adebiyi¹,

Zhao²,

Ye³

et al. 2019

FASEB j.

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The circadian clock is important for cellular and organ function. However, its function in sickle cell disease (SCD), a life‐threatening hemolytic disorder, remains unknown. Here, we performed an unbiased microarray screen, which revealed significantly altered expression of circadian rhythmic genes, inflammatory response genes, and iron metabolic genes in SCD Berkeley transgenic mouse lungs compared with controls. Given the vital role of period 2 (Per2) in the core clock and the unrecognized role of Per2 in SCD, we transplanted the bone marrow (BM) of SCD mice to Per2Luciferase mice, which revealed that Per2 expression was up‐regulated in SCD mouse lung. Next, we transplanted the BM of SCD mice to period 1 (Per1)/Per2 double deficient [Per1/Per2 double knockout (dKO)] and wild‐type mice, respectively. We discovered that Per1/Per2 dKO mice transplanted with SCD BM (SCD → Per1/Per2 dKO) displayed severe irradiation sensitivity and were more susceptible to an early death. Although we observed an increase of peripheral inflammatory cells, we did not detect differences in erythrocyte sickling. However, there was further lung damage due to elevated pulmonary congestion, inflammatory cell infiltration, iron overload, and secretion of IL‐6 in lavage fluid. Overall, we demonstrate that Per1/Per2 is beneficial to counteract elevated systemic inflammation, lung tissue inflammation, and iron overload in SCD.—Adebiyi, M. G., Zhao, Z., Ye, Y., Manalo, J., Hong, Y., Lee, C. C., Xian, W., McKeon, F., Culp‐Hill, R., D' Alessandro, A., Kellems, R. E., Yoo, S.‐H., Han, L., Xia, Y. Circadian period 2: a missing beneficial factor in sickle cell disease by lowering pulmonary inflammation, iron overload, and mortality. FASEB J. 33, 10528–10537 (2019). http://www.fasebj.org

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“…For example, nocturnal light exposure decreases the secretion of melatonin, a hormone secreted by the pineal gland in response to darkness, which can ultimately result in sleep disruption [2]; the disruption of the circadian rhythm seen in patients with severe sepsis ( n = 7) was reflected in the first 48 h of ICU admission by disordered diurnal variation of urinary 6-SMT excretion [10]. In animal models, circadian rhythm disruption due to constant light exposure led to reduced expression of Per-2 in the SCN and subsequent behavioral symptoms of delirium (i.e., executive dysfunction and memory impairment) [11]. Clinical symptoms were reversed with nobiletin, a known enhancer of Per-2 function [11].…”

Section: Mechanisms and Physiological Consequences Of Sleep Disturbanmentioning

confidence: 99%

“…In animal models, circadian rhythm disruption due to constant light exposure led to reduced expression of Per-2 in the SCN and subsequent behavioral symptoms of delirium (i.e., executive dysfunction and memory impairment) [11]. Clinical symptoms were reversed with nobiletin, a known enhancer of Per-2 function [11]. Findings of diurnal disruption have been reported in traumatic brain injury (TBI), trauma and medical patient populations [12]; any association between diurnal disruption and resultant outcome (e.g., sedative use, incidence delirium or length of stay) in these patient populations has yet to be demonstrated.…”

Section: Mechanisms and Physiological Consequences Of Sleep Disturbanmentioning

confidence: 99%

Sleep and Circadian Rhythm in Critical Illness

Telias

Wilcox

2019

Crit Care

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This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2019. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2019 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901 .

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The Period 2 Enhancer Nobiletin as Novel Therapy in Murine Models of Circadian Disruption Resembling Delirium*

Cited by 34 publications

References 51 publications

The Circadian PER2 Enhancer Nobiletin Reverses the Deleterious Effects of Midazolam in Myocardial Ischemia and Reperfusion Injury

The Circadian PER2 Enhancer Nobiletin Reverses the Deleterious Effects of Midazolam in Myocardial Ischemia and Reperfusion Injury

Circadian period 2: a missing beneficial factor in sickle cell disease by lowering pulmonary inflammation, iron overload, and mortality

Sleep and Circadian Rhythm in Critical Illness

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