Toxicological evaluation of the interaction between circadian rhythm activators and general anesthetics

The circadian rhythm lasts about 24 hours and is constituted by 4 main genes/proteins; Circadian Locomotor Output Cycle Clock (Clock), Brain-Muscle-Arnt-Like protein-1 (Bmal1), Cryptochrome (Cry) and Period (Per). Many pathologies, diseases, and medications including general anesthetic agents are thought to cause a change in these genes/proteins. On the other hand the activation or inhibition of the genes/proteins can contribute to the reduction of the oxidative stress potential of anesthetic agents. We investigated the effect of combination therapy of KL001 with isoflurane. Twenty-four mice were randomly divided into 4 groups of 6 animals each as a control, KL001, isoflurane and KL001 plus isoflurane group. Animals were exposed to isoflurane for 4 hours and KL001 was administered of 100 mg/kg at night hours. The Cry levels and oxidative stress parameters including malondialdehyde (MDA) level and superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) activities were investigated in liver, kidney, brain, and erythrocyte. Our results showed decreased MDA level in erythrocyte and liver, increased GSH-Px activity in liver and brain, increased SOD activity in erythrocyte, kidney, and brain, decreased CAT activity in liver in isoflurane group. According to our findings, isoflurane changed the oxidative stress parameters remarkably in brain. We also found a decrease of Cry level in the plasma, liver, and brain in isoflurane group. KL001 increased Cry level inhibited by isoflurane and decreased the isoflurane-induced oxidative stress. In conclusion, our data indicated that we can reduce the potential oxidative stress of isoflurane or other anesthetic agents by triggering the Cry level with a synthetic activator or by arranging drug administration time at certain period of the day. Especially in early hours of the morning, KL001 may be protective against isoflurane-induced oxidative stress. In further research, the effects of Per, Clock, and Bmal1 on anesthetic agents toxicity can also be investigated. It can be determined at which time the operations are performed to create the least toxicity.