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A pharmacological composition for induction of a reversible torpor-like state and hypothermia in rats

Zakharova, Nadezhda M., Tarahovsky, Yury S., Fadeeva, Irina S., Komelina, Natalia P., Khrenov, Maxim O., Glushkova, Olga V., Prokhorov, Dmitry A., Kutyshenko, Viktor P., Kovtun, Anatoly L.
Life sciences 2019 v.219 pp. 190-198
ambient temperature, brain, cardiac arrest, drugs, emulsions, heart rate, hemorrhage, hibernation, hypothermia, intravenous injection, ischemia, lipids, medicine, oxygen consumption, rats, rearing, respiratory rate, survival rate, therapeutics, xenon
To initiate a state of artificial torpor we suggested a pharmacological multi-targeting strategy for simulation of the physiological pattern of natural hibernation including a significant reduction in heart rate, respiratory rate, body temperature and oxygen consumption as well as a decline in brain activity known as torpor.We have developed a composition which initiates a pharmacologically induced torpor-like state (PITS-composition), made up of eight therapeutic agents, inert gas xenon and lipid emulsion served as a drug vehicle.After a single intravenous injection to rats, PITS-composition causes a rapid decline in heart rate followed by a steady decrease in body temperature from about 38.5 °C to 31.5 °C, at ambient temperature of 22 °C–23 °C. The hypothermic state may continue on average for 16–17 h with the subsequent spontaneous return of heart rate and body temperature to the initial values. In the open field test at torpor the motility, rearing and grooming were suppressed but 4–8 days later they were restored.Suspended animation states, including natural hibernation or pharmacologically induced synthetic torpor are of special attention of medicine, since it may improve survival rate after cardiac arrest, brain hemorrhage and ischemia, and during long-term space traveling. The suggested here multi-targeting strategy made possible to develop the pharmacological composition able, after a single intravenous injection, to initiate long, stable and reversible hypothermia and torpor at room temperature. After the torpor, animals were able to spontaneously restore both physiological parameters, and behavioral reactions.