Additive neuroprotective effect of 3-hydroxypyridine derivatives and human erythropoetin analogue on a hemorrhagic stroke model in rats
- 作者: Kolesnichenko P.1, Shcheblykina O.1, Nesterova N.1,2, Shcheblykin D.1, Nesterov A.1, Pokrovsky M.1, Zhuchenko M.3, Tverskoy A.1, Reznikov K.4
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隶属关系:
- Belgorod State National Research University
- Forensic-histological department of Belgorod Bureau of Forensic Medical Examination”
- Sector of development and preclinical research of State Pharmaceutical Foundation of officinal medicines “PHARMAPARK”
- Voronezh State Medical University n.a. N.N. Burdenko
- 期: 卷 8, 编号 3 (2020)
- 页面: 169-180
- 栏目: Articles
- URL: https://journals.rcsi.science/2307-9266/article/view/111640
- DOI: https://doi.org/10.19163/2307-9266-2020-8-3-169-180
- ID: 111640
如何引用文章
详细
The correction of free radical oxidation processes is one of the most promising strategies of neuroprotection in acute cerebrovascular disorders.
The aim of the study is an experimental study of the neuroprotective effects of 3-hydroxypyridine and erythropoietin derivatives, as well as their combined use.
Materials and methods. The study was performed on 109 male Wistar rats. The neuroprotective effect of the substances was studied on a hemorrhagic stroke model. The study drugs were administered to the animals intraperitoneally. Carbamylated darbepoetin was administered three times in advance at the dose of 100 µg/kg within intervals of 3 days, the last injection took place 1 hour before the operation (the total dose was 300 mg/kg). Etoxidol was administered once 1 hour before the surgery at the dose of 50 mg/kg. The survival rate, behavioral features and the state of the animals on the 1st, 3rd, 7th and 14th days were recorded, and the morphological assessment of the brain was carried out.
Results and discussion. The investigated substances had a positive effect on both the survival rate of the animals during the first day and on the 14th day. The best survival rates on the 14th day were recorded in the group of a combined use of ethoxydol and carbamylated darbepoetin (75%). Thus, in this group of rats, a faster recovery of neurological disorders was already distinguished from the first day on. By the 7th day, more than 50% of the rats receiving the combination of the studied drugs, had had a slight neurological deficit (up to 3 points on the McGrow scale); by the 14th day there had been only minor changes in the neurological status in the rats of this group. A pronounced neuroprotective effect of the combination of 3-hydroxypyridine and erythropoietin derivatives has been confirmed by a histological examination of brain slices – a more rapid decrease in the size of perifocal edema and microcirculation disorders, less damage to neurons and glial elements, and faster processes of resorption and organization of hemorrhage. A macroscopic examination of the brain sections stained with triphenyltetrazolium chloride of the dying rats, showed that perifocal necrosis had been the main cause of high mortality in the control group after the 3rd day.
Conclusion. As a result of the experiment, the nephroprotective effect of the studied derivatives of 3-hydroxypyridine and erythropoietin has been proved. Moreover, the combination of these drugs has shown a greater neuroprotective activity than their isolated use. The additive effect of these drugs was due to their action mechanism resulting from the synergism of various structures and components of the cells.
作者简介
Pavel Kolesnichenko
Belgorod State National Research University
编辑信件的主要联系方式.
Email: farpavel@yandex.ru
ORCID iD: 0000-0002-2434-994X
Candidate of Sciences (Medicine), Associate Professor of the Department of Pharmacology and Clinical Pharmacology
俄罗斯联邦, 85, Pobeda St., Belgorod, 308015Olesya Shcheblykina
Belgorod State National Research University
Email: sheolvi31@gmail.com
postgraduate student of the Department of Pharmacology and Clinical Pharmacology
俄罗斯联邦, 85, Pobeda St., Belgorod, 308015Natalya Nesterova
Belgorod State National Research University; Forensic-histological department of Belgorod Bureau of Forensic Medical Examination”
Email: sushkova-nesterova@mail.ru
postgraduate student of the Department of Pharmacology and Clinical Pharmacology, legal physician of the forensic histological department
俄罗斯联邦, 85, Pobeda St., Belgorod, 308015; 159, Volchanskaya St., Belgorod, 308017Dmitry Shcheblykin
Belgorod State National Research University
Email: dmitryshch1@gmail.com
ORCID iD: 0000-0002-2420-2243
postgraduate student of the Department of Pharmacology and Clinical Pharmacology
俄罗斯联邦, 85, Pobeda St., Belgorod, 308015Arkady Nesterov
Belgorod State National Research University
Email: nesterov_a@bsu.edu.ru
Candidate of Sciences (Medicine), Associate Professor of the Department of Pathology
俄罗斯联邦, 85, Pobeda St., Belgorod, 308015Mikhail Pokrovsky
Belgorod State National Research University
Email: mpokrovsky@yandex.ru
ORCID iD: 0000-0002-1493-3376
Doctor of Sciences (Medicine), Professor of the Department of Pharmacology and Clinical Pharmacology, the Head of Research Institute of Pharmacology of Living Systems
俄罗斯联邦, 85, Pobeda St., Belgorod, 308015Maxim Zhuchenko
Sector of development and preclinical research of State Pharmaceutical Foundation of officinal medicines “PHARMAPARK”
Email: maksim.zhuchenko@pharmapark.ru
Candidate of Sciences (Biology), the head of the sector of development and preclinical research of officinal medicines
俄罗斯联邦, 8 (Bld. 1), Nauchny proezd, Moscow, 117246Alexey Tverskoy
Belgorod State National Research University
Email: tverskoy@bsu.edu.ru
ORCID iD: 0000-0003-1537-6564
Candidate of Sciences (Medicine), the head of the Department of Human Anatomy and Histology
俄罗斯联邦, 85, Pobeda St., Belgorod, 308015Konstantin Reznikov
Voronezh State Medical University n.a. N.N. Burdenko
Email: vrkmf@yandex.ru
Doctor of Sciences (Medicine), Professor of the Department of Pharmacology
俄罗斯联邦, 10, Studencheskaya St., Voronezh, 394036参考
- Kesarev OG, Danilenko LM, Pokrovskii MV, Timokhina AS, Khavanskii AV. Study of dose-dependent effect of 2-ethyl-6-methyl-3 hydroxypyridine succinate on the contractile function of isolated rat heat. Research Result in Pharmacology. 2017;3(1):3–9. doi: 10.18413/2500-235X-2017-3-1-3-9.
- Skvorcova VI, Chazova IE, Stahovskaja LV. [Vtorichnaja profilaktika insul’ta]. M.: PAGRI. 2002: 120p. Russian
- Karpov SM, Dolgova IN, Vishlova IA. The main issues of topical diagnosis of nervous system diseases. Stavropol. Stavropol State Medical University. 2015:120p.
- Reznikov KM, Gorbunova NS, Kolesnichenko PD, Tverskoy AV, Kostina DA, Bashkatova DA, Nikitina VA. Search of new pharmaceuticals on the basis of darbepoetin in the treatment of ischemic stroke (review of literature). Research Result: Pharmacology and Clinical Pharmacology. 2017;3(1):125–136. doi: 10.18413/2500-235X-2017-3-1-125-136
- Zhu L, Bai X, Wang S, Hu Y, Wang T, Qian L, Jiang L. Recombinant human erythropoietin augments angiogenic responses in a neonatal rat model of cerebral unilateral hypoxia-ischemia. Neonatology. 2014;106(2):143–148. doi: 10.1159/000362262.
- Fisher JW. Erythropoietin: physiology and pharmacology update. Experimental Biology and Medicine (Maywood). 2003;228(1):1–14. doi: 10.1177/153537020322800101.
- Shabelnikova AS. Correction of ischemic damage to the retina on application of pharmacological preconditioning of recombinant erythropoietin. Research Result in Pharmacology. 2016;2(2):67–90. doi: 10.18413/2313-8971-2016-2-2-67-90.
- Catlin DH, A. Breidbach, Elliott S, Glaspy J. Comparison of darbepoetin alfa, recombinant human erythropoietin, and endogenous erythropoietin from human urine. Clinical Chemistry. 2002;48(11):2057–2059. doi: 10.1093/clinchem/48.11.2057.
- Alehin SA, Kolmykov DI, Pokrovskii MV. Human recombinant erythropoietin gradient dosage in-fluence on ischemic and reperfusion liver injury. Research Result in Pharmacology. 2015;1(1):9–12. doi: 10.18413/2500-235X-2015-1-4-9-14.
- Makarenko AN, Kositsin NS, Pasikova NV, Svinov VV. Simulation of local cerebral hemorrhage in different brain structures of experimental animals. Journal of Higher Nervous Activity. 2002;52(6):765–768.
- [Patent 2721289. Rossijskaja Federacija, MPK G09B 23/28. Sposob modelirovanija gemorragicheskogo insul’ta u krys / Nesterov A.V., Kolesnichenko P.D., Pokrovskij M.V., Nesterova N.I., Markovskaja V.A., Ivanova M.I., Karagodina A.Ju., Saparboeva N.M., Murashev B.V., Proshin A.Ju., Patrahanov E.A., Arhipov I.S., Pokrovskij V.M.; zajavitel’ i patentoobladatel’ federal’noe gosudarstvennoe avtonomnoe obrazovatel’noe uchrezhdenie vysshego obrazovanija “Belgorodskij gosudarstvennyj nacional’nyj issledovatel’skij universitet” (NIU “BelGU”) – № 2019134892; zajavl. 30.10.2019; Published: 2020 May 18]. Russian
- Gannushkina IV. The pathophysiological mechanisms of disorders of cerebral circulation and the new directions in their prevention and treatment. Journal. Neuropatol. and psychiatrist. 1996. 1:14–18.
- Ermohin PN. Gistopatologija central’noj nervnoj sistemy: atlas mikrofotografij. PN. Ermohin; pod red. A.P. Avcyna. – Moskva: Medicina, 1969:243. Russian
- Djumaev KM, Voronina TA, Smirnov LD. Antioksidanty v profilaktike i terapii patologij CNS. – M.: Medicina, 1995:65. Russian
- Peresypkina A, Pazhinsky A, Pokrovskii M, Beskhmelnitsyna E, Pobeda A, Korokin M. Correction of experimental retinal ischemia by l-isomer of ethylmethylhydroxypyridine malate. Antioxidants. 2019;8(2):34. doi: 10.3390/antiox8020034. Russian
- Kolesnichenko PD, Reznikov KM, Zhhernakova NI, Stepchenko AA, Popova IA. The Value Changes Redox System the Body Fluid Media for Life Processes and the Action of Drugs. Journal of International Pharmaceutical. 2018; 45:440–444. Russian
- Livanov GV, Aleksandrov MV, Vasilyev SA, Batotsyrenova KV, Batotsyrenov BV, Lodyagin AN, Lutsyk MA, Nosov AV. Metabolic Desynchronization in Critical Conditions: Experimental Study. General Reanimatology. 2006;2(1):42–46. doi: 10.15360/1813-9779-2006-1-42-46.
- Sanchis-Gomar F, Perez-Quilis C, Lippi G. Erythropoietin Receptor (EpoR) Agonism Is Used to Treat a Wide Range of Disease. Molecular Medicine. 2013;19(1):62–64. doi: 10.2119/molmed.2013.00025.
- Tjurenkov IN, Kurkin DV, Bakulin DA, Volotova EV. Studying the Neuroprotective Effect of the Novel Glutamic Acid Derivative Neiroglutam on Focal Cerebral Ischemia in Rats Russian Journal of Experimental and Clinical Pharmacology. 2014;77(9):8–12. doi: 10.30906/0869-2092-2014-77-9-8-12.
- Celik M, Gokmen N, Erbayraktar S, Akhisaroglu M, Konakc S, Ulukus C, Genc S, Genc K, Sagiroglu E, Cerami A, Brines M. Erythropoietin prevents motor neuron apoptosis and neurologic disability in experimental spinal cord ischemic injury. PNAS. 2002;99(4):2258–2263. doi: 10.1073/pnas.042693799.
- Basov AA, Elkina AA, Samkov AA, Volchenko NN, Moiseev AV, Fedulova LV, Baryshev MG, Dzhimak SS. Influence of deuterium-depleted water on the isotope D/H composition of liver tissue and morphological development of rats at different periods of ontogenesis. Iranian Biomedical Journal. 2019;23(2):129–141. doi: 10.29252/.23.2.129.
- Tverskoy AV, Kolesnichenko PD, Shcheblykina OV, Gorbunova NS, Morozov VN, Mukhina TS. Morphology of the rat’s brain in four vessels model of ischemic stroke after administration of carbamylated darbepoetin. Drug Invention Today. 2018;10(5):3897–3900.
- Middleton SA, Barbone FP, Johnson DL, Thurmond RL, You Y, McMahon FJ, Jin R, Livnah O, Tullai J, Farrell FX, Goldsmith MA, Wilson IA, Jolliffe LK. Shared and unique determinants of the erythropoietin (EPO) receptor are important for binding EPO and EPO mimetic peptide. Journal of Biological Chemistry. 1999;274(20):14163–14169.
- Kolesnichenko PD, Dolzhikov AA, Zhernakova NI, Shaposhnikov AA, Stepchenko AA, Batishcheva GA, Reznikov KM. Preclinical study of the allergenic properties of carbamylated darbepoetin. Indo American Journal of Pharmaceutical Sciences. 2017;4(10):3798–3802.
- Gaudard A, Varlet-Marie E, Bressolle F, Audran M. Drugs for Increasing Oxygen Transport and Their Potential Use in Doping. Sports Medicine. 2003;33(3):187–212.
- Pozdniakova NV, Turobov V, Garanina EE, Ryabaya OA. Temporal dynamics of cytokines in the blood of rats with experimentally induced autoimmune encephalomyelitis. Bulletin of RSMU. 2017; 6:69–77. doi: 10.24075/brsmu.2017-06-12.
- Basov AA, Kozin SV, Bikov IM, Popov KA, Moissev AV, Elkina AA, Dzhimak SS. Changes in Prooxidant-Antioxidant System Indices in the Blood and Brain of Rats with Modelled Acute Hypoxia Which Consumed a Deuterium-Depleted Drinking Diet. Biology Bulletin. 2019;46(6):531–535. doi: 10.1134/S1062359019060049.