Creation of a new combined drug based on gamma-aminobutyric acid and thiotriazoline

Abstract

General anesthesia, especially ketamine, can cause damage to the central nervous system (CNS) in the postoperative period, among which a special place is occupied by postoperative cognitive dysfunction (POCD), which can develop in patients of different age groups, including in cases with an unburdened neuropsychiatric history. Neuroprotective therapy becomes essential for preventing neuronal damage or eliminating already existing cognitive dysfunction in the early postoperative period, when these changes are still potentially reversible. Influencing the course of cerebral metabolism, it prevents or interrupts pathological cascades that cause dysfunction or death of neurons. A special place in neuroprotection is occupied by neurometabolic drugs - nootropics. Studies in neurochemistry have established that the use of general anesthetics leads to disruption of the GABA-ergic system of the brain, a decrease in the affinity of GABA receptors. All this directs the search for pharmacologists in the development of nootropics effective in POCD towards structural analogs of gamma-aminobutyric acid (GABA). Thiotriazoline, being an antioxidant and antiischemic agent, is able to regulate ROS/NO-dependent mechanisms of cellular signaling, the affinity of central receptors, incl. and GABA. Therefore, it is important to develop a combination drug based on GABA and thiotriazoline, which will have significantly higher efficacy in the correction of cognitive dysfunction after ketamine anesthesia, as well as demonstrate a significant reduction in side effects. Objectives: to study the pharmacological action of a combination drug based on GABA with thiotriazoline in the correction of cognitive dysfunction after ketamine anesthesia.Materials and methods: the substance GABA and thiotriazoline was used in the study. The study was carried out on 80 white outbred rats weighing 180-190 grams of both sexes. Ketamine anesthesia was carried out by intraperitoneal administration of 100 mg/kg ketamine. The studied drugs were administered in the following doses: a combination of GABA + thiotriazoline 1:1; 2:1; 3:1; 4:1; 5:1, piracetam 500 mg/kg, intragastrically. Results. The administration of piracetam (500 mg/kg) did not have a significant effect on such indicators of the cognitive-mnestic functions of animals as errors in the reference memory, as well as on the indicator of general activity when examining the labyrinth on day 10 after ketamine anesthesia. The administration of combinations of GABA with thiotriazoline (1:1; 2:1; 3:1; 4:1 and 5:1) had a significant effect on the cognitive-mnestic functions of the central nervous system after ketamine anesthesia. Thus, the studied combinations of GABA with thiotriazoline (1:1; 2:1; 3:1; 4:1 and 5:1) exhibit pronounced nootropic and antiamnestic effects, increasing the general activity during learning and reducing the number of errors in the reference and working memory during reproducing learning skills. Findings: Thus, after analyzing the results of the conducted studies, it was found that in terms of the efficiency, all combinations of GABA with thiotriazoline significantly exceed the reference drug – piracetam. The most effective combinations were GABA + thiotriazoline in ratios of 3:1 and 4:1, respectively.