Date Published: July 5, 2017
Publisher: Public Library of Science
Author(s): O. B. Shevelev, N. B. Illarionova, D. V. Petrovski, A. P. Sarapultsev, O. N. Chupakhin, M. P. Moshkin, Thiruma V. Arumugam.
The aim of the present study was to examine how administration of a compound of 1,3,4- thiadiazine class 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide (L-17) with hypothermia inducing properties affects the brain metabolism. The mechanism by which L-17 induces hypothermia is unknown; it may involve hypothalamic central thermoregulation as well as act via inhibition of energy metabolism. We tested the hypothesis that L-17 may induce hypothermia by directly inhibiting energy metabolism. The study in vivo was carried out on Sprague-Dawley adult rats. Two doses of L-17 were administered (190 mg/kg and 760 mg/kg). Brain metabolites were analyzed in control and treated groups using magnetic resonance spectroscopy, along with blood flow rate measurements in carotid arteries and body temperature measurements. Further in vitro studies on primary cultures from rat hippocampus were carried out to perform a mitochondria function test of L-17 pre-incubation (100 μM, 30 min). Analysis of brain metabolites showed no significant changes in 190 mg/kg treated group along with a significant reduction in body temperature by 1.5°C. However, administration of L-17 in higher dose 760 mg/kg provoked changes in brain metabolites indicative of neurotoxicity as well as reduction in carotid arteries flow rate. In addition, a balance change of excitatory and inhibitory neurotransmitters was observed. The L-17 pre-incubation with cell primary cultures from rat brain showed no significant changes in mitochondrial function. The results obtained in the study indicate that acute administration of L-17 190 mg/kg in rats induces mild hypothermia with no adverse effects onto brain metabolism.
Therapeutic hypothermia is an intentional lowering of core body temperature that is used in the clinic. The recovery benefit of mild (33–36°C), to moderate (28–33°C) therapeutic hypothermia is reported for neurological complications associated with cardiac arrest  and hypoxic ischemic neonatal encephalopathy  as well as in animal studies for traumatic brain injury and stroke [3–5]. The mechanisms of therapeutic hypothermia action may be attributed to the preservation of metabolic stores and lowering of excitatory neurotransmitters and other cytotoxic products release as well as anti-inflammatory processes [6, 7]. Therapeutic hypothermia may be achieved by external methods of cooling by using cooling systems, like cooling blankets, helmets, cold water or ice. However human body temperature protective mechanisms, like shivering thermogenesis, increases in heart rate and metabolism and redirection of blood flow from limbs and skin to vital organs, compromise these methods of achieving hypothermia results. In addition, an unintentional overcooling is a possible outcome.
Previously L-17 compound was shown to benefit recovery after experimentally induced cardiac infarction and pancreatitis in rats [20–22]. Apart from these properties, we have confirmed that L-17 acutely reduces body temperature in rats. Regulation of body temperature depends among others on cellular metabolism. Therefore, in this study we were looking for a link between L-17 induced body temperature decrease and changes in brain metabolism. We found no significant influence of L-17 compound in low dose 190 mg/kg onto a balance of rat brain metabolites, but a significant reduction of body temperature. A similar level of brain metabolites compared to control group indicates physiological brain function under L-17 190 mg/kg treatment, despite induced hypothermia.