Neuroprotective and anti-amnestic effects of a combination therapy in a model of photochemical ischemic damage in the prefrontal cortex
Keywords:
erythropoietin mutant molecules; dipeptide mimetic of human nerve growth factor; GK-2H; photothrombosis; prefrontal cortex; neuroprotection, rats
Abstract
The aim of this study was to investigate the effect of combination therapy, including mutant erythropoietin molecules (EPO) and a dipeptide mimetic of the nerve growth factor, GK-2H, on the conditioned passive avoidance (PA) reflex and the volume of injury induced by bilateral ischemia of the prefrontal cortex in rats. Using the method of genetic engineering the mutant molecules of EPO, MERO-TR and MEPO-Fc, with strongly reduced erythropoietic and pronounced cytoprotective activity were created. The used human nerve growth factor mimetic, an endogenous regulatory protein based on the β-bend of loop 4, which is a dimeric substituted dipeptide of bis- (N-monosuccinyl-glycyl-lysine) hexamethylenediamine, GK-2 human (GK-2H), has proven neuroprotective in in vitro experiments. Methods. Bilateral focal ischemic infarction was modeled in the rat prefrontal cortex by photochemically induced thrombosis. The PA test was performed according to a standard method. Volume of brain injury was estimated using MRI. MEPO-TR, and MEPO-Fc (50 µg/kg, intranasally) were administered once, one hour after the injury. GK-2Н (1 mg/kg, i.p.) was injected four hours after the injury and then for next four days. Results. The study showed that the complex therapy provided statistically significant retention of the PA reflex developed prior to ischemia and a significant decrease in the volume of injury. The anti-amnestic and neuroprotective effects of combination therapy were most pronounced at doses of MEPO-Fc 50 μg/kg and GK-2H 1 mg/kg. Conclusion. This study has confirmed the neuroprotective effect and enhancement of the anti-amnestic effect exerted by the combination of mutant erythropoietin derivatives, MEPO-TR and MEPO-Fc, and the dipeptide mimetic of human growth factor GK-2H.
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References
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28. Solev I. N., Balabanian V. Y., Volchek I. A., Elizarova O. S., Litvinova S. A., Garibova T. L. Studying the involvement of BDNF and NGF in the mechanism of neuroprotective effectto nanoform of human recombinant erythropoietin. Byulleten’ Eksperimental’noy Biologii i Meditsiny. 2013; 155 (2): 210-3.
29. Fumagalli F., Madaschi L., Brenna P., Caino L., Marfia G., Di Giulio A. et al. Single exposure to erythropoietin modulates Nerve Growth Factor expression in the spinal cord following traumatic injury: comparison with methylprednisolone. Eur J Pharmacol. 2008; 578(1): 19-27.
30. Villa P., van Beek J., Larsen A.K., Gerwien J., Christensen S., Cerami A. et al. Reduced functional deficits, neuroinflammation and secondary tissue damage after treatment of stroke by nonerythropoietic erythropoietin derivatives. J Cereb Blood Flow Metab. 2007; 27: 552-63.
31. Chen H.S., Lipton S.A. The chemical biology of clinically tolerated NMDA receptor antagonists. J Neurochem. 2006; 97: 1611-26.
2. Starodubtseva O. S., Begichev S. V. Аnalysis of the incidence of stroke with the use of information technology. Fundamental'nye issledovaniya. 2012; 8(2): 424-7. (in Russian)
3. Vereshchagin N.V. Varakin Y.Y. Stroke registers in Russia: results and methodological basis of the problem. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova (prilozhenie «Insul't»). 2001; 1: 34-40. (in Russian)
4. Suslina Z.A., Piradov M.A. Stroke: diagnosis, treatment, prevention. [Insul't: diagnostika, lechenie, profilaktika]. Moscow; Medpress-inform; 2008. (in Russian)
5. Piradov M. A., Tanashyan M. M., Domashenko M. A., Sergeev D. V., Maksimova M. Y. Neuroprotection in cerebrovascular diseases: the search for life on Mars or perspektivnoe the direction of the treatment? Part 1. Acute disorders of cerebral circulation. Annals of neurology. 2015; 9 (1): 41-50.
6. Maslov L.N., Khaliulin I.G., Podoksenov Yu.K. Neuroprotective and cardioprotective effects of hypother mic preconditioning. Patologicheskaya Fiziologiya i Eksperimental'naya Terapiya. 2012; 1: 67-72. (in Russian)
7. Tsygan N.V., Trashkov A.P. Brain functional state and cytoprotective potential in model of acute cerebral hypoxia (experimental research). Patologicheskaya Fiziologiya i Eksperimental'naya Terapiya. 2013; 4: 10-6. (in Russian)
8. Kalinina T. I., Cheremnykh A. M., Yurin V. L., Romanov G. A., Shakova F. M. Neuroprotective effect of carbamoilirovaniem erythropoietin and its derivatives. VIII Moscow international Congress "Biotechnology: state and prospects of development". 17-20 March 2015, Moscow. The book of abstracts. [Neyroprotektivnyy ehffekt karbamilirovannogo ehritropoehtina i ego proizvodnykh. VIII Moskovskiy mezhdunarodnyy kongress «Biotekhnologiya: sostoyanie i perspektivy razvitiya»]. 17-20 marta 2015, Moscow. Sbornik tezisov. 114-6. (in Russian)
9. Mannie L. Rocco, L. M., Bianchi P., Soligo M., S. S. P., Aloe L. nerve growth factor: basic studies and possible therapeutic applications growth factor. 2013; 31 (4): 115-22.
10. Allen S. J., Dawbarn, Allen D. the Clinical significance of neurotrophins and their receptors. Wedge. Science. 2006; 110 (2): 175-91.
11. Gudasheva T.A., Antipova MT.A. Seredenin B.S. a New low molecular weight mimetics of the nerve growth factor. Reports of the Academy of Sciences. 2010; 434 (4): 549-52. (in Russian)
12. Gudasheva, T.A., And Tarasiuk. In. With Pomogaibo.In. And Logvinov. About., P Povarnina.Yu., T Antipova.A. Seredenin S. B. Design and synthesis of dipeptide mimetics of brain-derived neurotrophic factor. Bioorganicheskaya khimiya. 2012; 38 (3): 280-90. (in Russian)
13. Paxinos G., Watson S. anatomy Atlas of the rat brain. In: the Rat brain in stereotaxic coordinates. 3rd San Diego, CA. Academic Press; 1997.
14. Watson, D. B., and W. D. Dietrich, R. Busto et al. Induction of reproducible brain infarction by photochemically initiated thrombosis. Ann. Assessment.1985; 17 (5): 497-504.
15. Buresh Y., Bureshova O.J., Houston A.P. Techniques and basic experiments on the brain and behavior. [Metodiki i osnovnye eksperimenty po izucheniyu mozga i povedeniya]. Moscow: Higher School; 1991. (in Russian)
16. Silachev D.N., Uchevatkin A.A., Pirogov Y.A., Zorov D.B., Isaev N.K. Comparison of MRI detection of brain damage as the research methods of experimental focal ischemia. Byulleten’ Eksperimental’noy Biologii i Meditsiny. 2009; 147 (2): 232-7. (In Russian)
17. Shakova F.M., Kalinina T.I., Gulyaev M.V., Cheremnykh A.M., Jurin V.L., Romanova G.A. Neuroprotective and antiamnestic effects of mutant erythropoietin molecules on the photochemical model of ischaemic damage in prefrontal cortex of rat brain. Patologicheskaya Fiziologiya i Eksperimental`naya Terapiya. 2016; 4: 34-8. (in Russian)
18. Seredinin S. B., Gudasheva T. A., Romanova G. A. Neuroprotective and posed anti-amnesic action dipeptides of human mimetic of nerve growth factor GK-2H in experimental ischemic infarction of the cerebral cortex of rats. Byulleten’ Eksperimental’noy Biologii i Meditsiny. 2010; 150 (10): 406-9. (in Russian)
19. Levi-Montalcini R. The nerve growth factor 35 years later. Review. Science. 1987; 237 (4819): 1154-62.
20. Lee T.H., Kato H., Chen S.T., Kogure K., Itoyama Y. Expression of nerve growth factor and trkA after transient focal cerebral ischemia in rats. Stroke. 1998; 29: 1687-96.
21. Guégan C., Ceballos-Picot I., Nicole A., Kato H., Onténiente B., Sola B. Recruitment of several neuroprotective pathways after permanent focal ischemia in mice. Exp Neuro. 1998; 154: 371-80.
22. Guégan C., Onténiente B., Makiura Y., Merad-Boudia M., Ceballos-Picot I., Sola B. Reduction of cortical infarction and impairment of apoptosis in NGF-transgenic mice subjected to permanent focal ischemia. Mol. Brain Res. 1998; 55: 133-40.
23. Lindvall O., Ernfors P., Bengzon J., Kokaia Z., Smith M.L., Siesjö B.K. Differential regulation of mRNAs for nerve growth factor, brainderived neurotrophic factor, and neurotrophin 3 in the adult rat brain following cerebral ischemia and hypoglycemic coma. Proc. Natl Acad Sci USA. 1992; 89: 648-52.
24. Gusev E. I., Skvortsova V. I. Сerebral Ischemia. [Ishemiya golovnogo mozga]. Moscow; Meditsina; 2001. (in Russian)
25. Ehrenreich H, Weissenborn K, Prange H, Schneider D, Weimar C, Wartenberg K. et al. Recombinant human erythropoietin in the treatment of acute ischemic stroke. Stroke. 2009; 40 (12): 647-56.
26. Belayev L., Khoutorova L., Zhao W., Vigdorchik A., Belayev A., Busto R. et al. Neuroprotective effect of darbepoetin alfa, a novel recombinant erythropoietic protein, in focal cerebral ischemia in rats. Stroke. 2005; 36 (5): 1071-6.
27. Morishita E., Masuda S., Nagao M., et al. Erythropoietin receptor is expressed in rat hippocampal and cerebral cortical neurons, and erythropoietin prevents in vitro glutamate-induced neuronal death. Neuroscience. 1997; 76 (1): 105-16.
28. Solev I. N., Balabanian V. Y., Volchek I. A., Elizarova O. S., Litvinova S. A., Garibova T. L. Studying the involvement of BDNF and NGF in the mechanism of neuroprotective effectto nanoform of human recombinant erythropoietin. Byulleten’ Eksperimental’noy Biologii i Meditsiny. 2013; 155 (2): 210-3.
29. Fumagalli F., Madaschi L., Brenna P., Caino L., Marfia G., Di Giulio A. et al. Single exposure to erythropoietin modulates Nerve Growth Factor expression in the spinal cord following traumatic injury: comparison with methylprednisolone. Eur J Pharmacol. 2008; 578(1): 19-27.
30. Villa P., van Beek J., Larsen A.K., Gerwien J., Christensen S., Cerami A. et al. Reduced functional deficits, neuroinflammation and secondary tissue damage after treatment of stroke by nonerythropoietic erythropoietin derivatives. J Cereb Blood Flow Metab. 2007; 27: 552-63.
31. Chen H.S., Lipton S.A. The chemical biology of clinically tolerated NMDA receptor antagonists. J Neurochem. 2006; 97: 1611-26.
Published
2018-05-30
How to Cite
Shakova F. M., Kalinina T. I., Gulyaev M. V., Romanova G. A. Neuroprotective and anti-amnestic effects of a combination therapy in a model of photochemical ischemic damage in the prefrontal cortex // Patologicheskaya Fiziologiya i Eksperimental’naya Terapiya (Pathological physiology and experimental therapy). 2018. VOL. 62. № 2. PP. 39–45.
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Original research
