2,2,2-Tribromoethanol Phase-Shifts the Circadian Rhythm of the Liver Clock in Per2::Luciferase Knockin Mice: Lack of Dependence on Anesthetic Activity

Abstract

Comprehensive gene expression profiling in mice in response to the inhalation of sevoflurane has revealed that circadian clock gene expression is affected strongly in the liver, heart, lung, and kidney, in this order, but moderately in the spleen and slightly in the brain. Therefore, we examined whether the administration of general anesthetics at different times of the day induces phase shifts of the liver clock in Per2::Luciferase knockin mice. One to 4 days of intraperitoneal injection of 2,2,2-tribromoethanol (240 mg/kg, anesthetic time 60 min) or 2,2,2-trichloroethanol (240 mg/kg, 60 min), common anesthetics in veterinary surgery, caused phase delays when injected during the daytime and phase advances when injected during the nighttime. Inhalation administration of isoflurane for 30 or 60 min during the daytime did not induce a phase delay. Injection of propofol (300 mg/kg, 17 min) during the daytime induced an insignificant phase delay of the Per2 bioluminescence rhythm. Injection of 2,2,2-tribromoethanol did not induce a phase shift in the suprachiasmatic nucleus, the main oscillator, or in behavioral locomotor rhythms, suggesting that 2,2,2-tribromoethanol induced phase shifts of the liver clock independent of the main suprachiasmatic clock. The expression of clock genes, such as Bmal1 and Clock, in mouse liver was decreased strongly 1 and 4 h after a single injection of 2,2,2-tribromoethanol. These results demonstrate that 2,2,2-tribromoethanol or 2,2,2-trichloroethanol produce phase shifts of the peripheral clock, independent of anesthetic activity. These anesthetics may cause circadian rhythm disorders in peripheral organs when administered as general anesthetics several times during the day.

Direct and Specific Effect of Sevoflurane Anesthesia on rat Per2 Expression in the Suprachiasmatic Nucleus

“…Various anesthetics directly and competitively inhibit luciferase activity [26]–[28], an action thought to occur immediately after application of these agents. However, using intermittent application of anesthetics, we observed no obvious immediate repression of bioluminescence in the SCN, suggesting that competitive inhibition by anesthetics in our system is negligible.…”

2,2,2-Trichloroethanol lengthens the circadian period of Bmal1 -driven circadian bioluminescence rhythms in U2OS cells

“…Instead, sevoflurane may modulate clock machinery by blocking neuronal communications and/or by regulating GABA receptor in the SCN. SCN response to TCOH has yet to be determined; however, our study and the work by Kubo et al [4] clearly indicate that TCOH can modulate peripheral clock in vivo and in vitro, suggesting that TCOH may regulate molecular clock with a mechanism different from sevoflurane. The underlying mechanism for this regulation warrants further study.…”

“…In a recent publication, it was reported that both tribromoethanol and TCOH can regulate the phase of Per2 expression in the liver [4]. Because that study was carried out in intact animals there exists the possibility that this regulation is indirect.…”

“…TCOH was reported to cause a significant phase delay of Per2 expression in mouse liver when injected intraperitoneally daily over the course of 4 days [4]. These findings suggest that TCOH might be a regulator of molecular clock.…”

Chrono-biology, Chrono-pharmacology, and Chrono-nutrition

“…Lithium lengthens the locomotor activity rhythm in rodents by inhibiting GSK3b in the SCN (51). General anesthesia also affects circadian rhythms; some types of anesthesia phase shift, while others reduce the rhythmic amplitude of clock gene expression in mice (62). Taken together, many central nervous system drugs are able to modulate circadian rhythm through their target receptors and enzymes (Fig.…”