FRIGOPROTECTIVE PROPERTIES OF 5,7-DIACYL-3-H(ALKYL)-6-ARYL-5H-[1,2,4]TRIAZOL[3,4-B][1,3,4]THIADIAZINE DERIVATIVES IN THE EXPERIMENT
DOI:
https://doi.org/10.11603/mcch.2410-681X.2024.i3.14912Keywords:
cold injury, experiment, 5,7-diacyl-3-H(alkyl)-6-aryl-5H-[1,2,4]triazol[3,4-b][1,3,4]thiadiazine derivatives, body temperature, hemostasis system, markers of inflammationAbstract
Introduction. The widespread occurrence of cold injuries, along with the insufficient effectiveness of prevention and treatment of acute cold trauma, underscores the relevance of searching for new cryoprotective agents, among which anti-inflammatory drugs play a significant role.
The aim of the study - to perform research of 5,7-diacyl-3-H(alkyl)-6-aryl-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines (laboratory codes IFT-180, IFT-247, IFT-251) for cryoprotective properties using an acute general cooling (AGC) model.
Research Methods. The experiments were conducted on male white non-linear mice and rats. The studied compounds at a dose of 25 mg/kg and the reference drug diclofenac sodium (14 mg/kg) were administered intragastrically 60 minutes before exposing the animals to cold at -18°C. The lifespan of the mice was determined. In the in-depth study using the AGC model (2-hour exposure at -18°C), the effect of the lead compound IFT-247 at a dose of 18 mg/kg and the reference drug diclofenac sodium (7 mg/kg) on the rectal temperature of rats was examined. The impact of the mentioned compound on the hemostasis system was also assessed. In the liver, the levels of several inflammation markers were measured using species-specific kits.
Results and Discussion. It was found that compound IFT-247 exhibited potent cryoprotective properties at the level of the reference drug, statistically significantly increasing the lifespan of mice under the AGC model. IFT-247 reduced the degree of hypothermia during a two-hour exposure at -18°C (15 mg/kg). The tested compound prevented the development of disseminated intravascular coagulation (DIC) syndrome and thrombosis, reducing the levels of D-dimer and fibrinogen in the blood serum and normalizing the prolonged thrombin time to the level of diclofenac sodium. IFT-247 inhibited the development of a systemic inflammatory response: it prevented the increase in leukotriene B4 and total leukotrienes, though to a lesser extent than diclofenac; similarly to the reference drug, it significantly reduced IL-1β levels to subnormal and TNF-α levels to normal without affecting IL-6 or the decreased levels of anti-inflammatory cytokines IL-4 and IL-10, and it normalized the elevated pro- to anti-inflammatory cytokine ratio.
Conclusion. It was established that 1-(5-acetyl-3-methyl-6-phenyl-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-7-yl)-ethanone exhibits promising cryoprotective properties.
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