Study of metabolic disorders in rats under exposure to hypobaric hypoxia and development of correction approaches by simultaneous action on different elements of pathogenesis
- Authors: Semina II1, Baychurina AZ1, Shilovskaya EV1, Tikhonova NE2, Nikitin DO1, Begichev EV3, Ovchinnikova AG1
-
Affiliations:
- Kazan State Medical University
- Hospital for War Veterans
- Republican Clinical Hospital
- Issue: Vol 102, No 5 (2021)
- Pages: 654-662
- Section: Experimental medicine
- URL: https://journal-vniispk.ru/kazanmedj/article/view/63559
- DOI: https://doi.org/10.17816/KMJ2021-654
- ID: 63559
Cite item
Abstract
Aim. To study the indicators of metabolic changes in the blood and brain structures of rats after exposure to hypobaric hypoxia and to determine possible pharmacological approaches to correction these changes.
Methods. Hypobaric hypoxia in rats was simulated for 30 minutes in a pressure chamber, simulating an ascent to 8500 m. 3 and 24 hours after hypoxia, the activity of alanine aminotransferase, aspartic aminotransferases, alkaline phosphatase, creatine phosphokinase, lactate dehydrogenase, the content of glucose, total protein, triglycerides, cholesterol, β-lipoproteins, iron and uric acid were determined in the blood serum. The level of malondialdehyde in the hippocampus and frontal cortex was examined. The studies of the effect of 2-chloroethoxy-aryl-dimethyl-aminophenylphosphorylacetohydrazide (CAPAH) (1 mg/kg) and Рiracetam (100 mg/kg) after intraperitoneal injection 40 minutes before hypoxia and 1 hour after removing the rats from the pressure chamber were carried out. Statistical analysis was carried out using the GraphPad Prism software version 8.0.1, and the Student's t-test was used to test statistical significance.
Results. After 3 hours of hypobaric hypoxia, rats showed hyperenzymemia and dyslipidemia, the activity of almost all studied enzymes in the blood serum of rats was increased, the content of triglycerides was decreased, and the concentration of cholesterol was increased, the content of malondialdehyde in the hippocampus and frontal cortex was increased. In 24 hours after hypoxia, an increased level of creatine phosphokinase in the blood serum and malondialdehyde in the brain structures were noted. The use of 2-chloroethoxy-aryl-dimethyl-aminophenylphosphorylacetohydrazide prevented the development of hyperenzymemia, dyslipidemia and corrected the increased level of creatine phosphokinase after 24 hours; in both modes of administration, it reduced the serum level of malondialdehyde. Piracetam showed little effect only when administered prophylactically, preventing an increase in serum alkaline phosphatase activity and cholesterol levels.
Сonclusion. The revealed efficacy of 2-chloroethoxy-aryl-dimethyl-aminophenylphosphorylacetohydrazide and its previously studied complex mechanism of action suggest that 2-chloroethoxy-aryl-dimethyl-aminophenylphosphorylacetohydrazide is a potential drug for the prevention of hypoxic disorders and acceleration of adaptation to high-altitude hypoxia.
Full Text
##article.viewOnOriginalSite##About the authors
I I Semina
Kazan State Medical University
Author for correspondence.
Email: seminai@mail.ru
Russian Federation, Kazan, Russia
A Z Baychurina
Kazan State Medical University
Email: seminai@mail.ru
Russian Federation, Kazan, Russia
E V Shilovskaya
Kazan State Medical University
Email: seminai@mail.ru
Russian Federation, Kazan, Russia
N E Tikhonova
Hospital for War Veterans
Email: seminai@mail.ru
Russian Federation, Kazan, Russia
D O Nikitin
Kazan State Medical University
Email: seminai@mail.ru
Russian Federation, Kazan, Russia
E V Begichev
Republican Clinical Hospital
Email: seminai@mail.ru
Russian Federation, Kazan, Russia
A G Ovchinnikova
Kazan State Medical University
Email: seminai@mail.ru
Russian Federation, Kazan, Russia
References
- Zarubina I.V. Modern view on pathogenesis of hypoxia and its pharmacological corection. Оbzory po klinicheskoy farmakologii i lekarstvennoy terapii. 2011; 9 (3): 31–48. (In Russ.)
- Chen P.S., Chiu W.T., Hsu P.L., Lin S.C., Peng I.C., Wang C.Y., Tsai S.J. Pathophysiological implications of hypoxia in human diseases. J. Biomed. Sci. 2020; 27 (1): 63–81. doi: 10.1186/s12929-020-00658-7.
- Woods D.R., O’Hara J.P., Boos C.J., Hodkinson P.D., Tsakirides C., Hill N.E., Jose D., Hawkins A., Phillipson K., Hazlerigg A., Arjomandkhah N., Gallagher L., Holdsworth D., Cooke M., Donald N., Green C., Mellor A. Markers of physiological stress during exercise under conditions of normoxia, normobaric hypoxia, HH, and genuine high altitude. Eur. J. Appl. Physiol. 2017; 117 (5): 893–900. doi: 10.1007/s00421-017-3573-5.
- Wang X.B., Hou Y., Li Q.Y., Li X., Wang W., Ai X., Kuang T., Chen X., Zhang Y., Zhang J., Hu Y., Meng X. Rhodiola crenulata attenuates apoptosis and mitochondrial energy metabolism disorder in rats with HH-induced brain injury by regulating the HIF-1α/microRNA 210/ISCU1/2(COX10) signaling pathway. J. Ethnopharmacol. 2019; 241: 111801. doi: 10.1016/j.jep.2019.03.028.
- Hernández R., Blanco S., Peragón J., Pedrosa J.Á., Peinado M.Á. Hypobaric hypoxia and reoxygenation induce proteomic profile changes in the rat brain cortex. Neur. Mol. Med. 2013; 15 (1): 82–94. doi: 10.1007/s12017-012-8197-7.
- Li N., Li Q., Bai J., Chen K., Yang H., Wang W., Fan F., Zhang Y., Meng X., Kuang T., Fan G. The multiple organs insult and compensation mechanism in mice exposed to hypobaric hypoxia. Cell. Stres. Chaperon. 2020; 25: 779–791. doi: 10.1007/s12192-020-01117-w.
- Voronina T.A. Antioxidants/antihypoxants: the missing puzzle piece in effective pathogenetic therapy for COVID-19. Infektsionnye bolezni. 2020; 18 (2): 97–103. (In Russ.) doi: 10.20953/1729-9225-2020-2-97-102.
- Semina I.I., Tihonova N.A., Baichurina A.Z., Tarasova R.I., Pavlov V.A., Garaev R.S., Shilovskaya E.V. The neuroprotective effect of CAPAH, a representative of a new class of nootropics — non-anticholinesterase organophosphorus compounds. Vestnik RAMN. 1999; (3): 32–36. (In Russ.)
- Semina I.I., Baychurina A.Z. Development of new potential drugs with psychotropic activity among phosphorylacetohydrazides and other phosphorylated carboxylic acids derivatives - priority area of Kazan school of psychopharmacologists. Kazan Medical Journal. 2016; 97 (1): 148–155. (In Russ.) doi: 10.17750/KMJ2016-148.
- Losev A.S., Alybaev A.M., Karpova T.D. Vosstanovlenie posle ostroj gipobaricheskoj gipoksii kak metod izucheniya antigipoksicheskoj aktivnosti himicheskih soedinenij. In: Farmakologicheskaya regulyaciya sostoyanij dezadaptacii. (Pharmacological regulation of maladjustment states.) M.: AMN SSSR. 1986; 54–67. (In Russ.)
- Stal'naya I.D., Garshvili T.G. Opredelenie malonovogo dial'degida (MDA) v biohimii. M.: Medicina. 1977; 66–68. (In Russ.)
- Liu P., Zou D., Chen K., Zhou Q., Gao Y., Huang Y., Zhu J., Zhang Q., Mi M. dihydromyricetin improves hypobaric hypoxia-induced memory impairment via modulation of SIRT3 signaling. Mol. Neurobiol. 2016; 53: 7200–7212. doi: 10.1007/s12035-017-0399-4.
- Bärtsch P., Swenson E.R. Acute high-altitude illnesses. N. Engl. J. Med. 2013; 368 (24): 2294–2302. doi: 10.1056/NEJMcp1214870.
- Xi D., Zhang R., Ye S., Liu F., Jiang P., Yu X., Xu J., Ma L., Cao H., Shen Y., Lin F., Wang Z., Li C. Alterations of human plasma proteome profile on adaptation to high-altitude. J. Proteome Res. 2019; 18 (5): 2021–2031. doi: 10.1021/acs.jproteome.8b00911.
- Karkishchenko N.N., Karkishchenko V.N., Shustov E.B., Kapanadze G.D., Revyakin A.O., Semenov H.H., Bolotova V.C., Dulya M.S. Teoreticheskie osnovy farmakologicheskih effektov antigipoksantov. In: Biomedicinskoe (doklinicheskoe) izuchenie antigipoksicheskoj aktivnosti lekarstvennyh sredstv. (Biomedical (preclinical) study of the antihypoxic activity of drugs.) M.: NCBT FMBA. 2017; 97 p. (In Russ.)
- Gangwar A., Sharma M., Singh K., Patyal A., Bhaumik G., Bhargava K., Sethy N.K. Intermittent normobaric hypoxia facilitates high altitude acclimatization by curtailing hypoxia-induced inflammation and dyslipidemia. Eur. J. Physiol. 2019; 471 (7): 949–959. doi: 10.1007/s00424-019-02273-4.
- Mylonis I., Simos G., Paraskeva E. Hypoxia-inducible factors and the regulation of lipid Metab. Cells. 2019; 8 (3): 214–240. doi: 10.3390/cells8030214.
- Hou Y., Wang X., Chen X., Zhang J., Ai X., Liang Y., Yu Y., Zhang Y., Meng X., Kuang T., Hu Y. Establishment and evaluation of a simulated high-altitude hypoxic brain injury model in SD rats. Mol. Med. Rep. 2019; 19: 2758–2766. doi: 10.3892/mmr.2019.9939.
- Bong S.M., Moon J.H., Nam K.H., Lee K.S., Chi Y.M., Hwang K.Y. Structural studies of human brain-type creatine kinase complexed with the ADP-Mg2+-NO3 — creatine transition-state analogue complex. FEBS lett. 2008; 582 (28): 3959–3965. doi: 10.1016/j.febslet.2008.10.039.
- Semina I.G., Semina I.I., Azancheev N.M., Shilovskaya E.V., Tarasova R.I., Pavlov V.A., Il'yasov A.V., Fedotov V.D. On the issue and membrane mechanisms of action of nootropic drugs. Biol. Membr. 2001; 18 (5): 363–369. (In Russ.)
- Li Y., Zhang Y., Zhang Y. Research advances in pathogenesis and prophylactic measures of acute high altitude illness. Resp. Med. 2018; 145: 145–152. doi: 10.1016/j.rmed.2018.11.004.
- Singh A., Kukreti R., Saso L., Kukreti S. Oxidative stress: a key modulator in neurodegenerative diseases. Molecules. 2019; 24 (8): 1583–1603. doi: 10.3390/molecules24081583.
- Vostrikov V.V. Place of piracetam in the modern practice of medicine. Оbzory po klinicheskoy farmakologii i lekarstvennoy terapii. 2017; 15 (1): 14–25. (In Russ.) doi: 10.17816/RCF15114-25.
Supplementary files
