Significance of Basic Fibroblast Growth Factor (BFGF) in The Development of Postresuscitation Changes in Population of Cerebellar Purkinje Cells

Objective: to evaluate the relationship of postresuscitation changes in the level of bFGF protein expression and morphological patterns of the cerebellar Purkinje cells.

Materials and methods. Albino adult male rats were subjected to 10 minutes of systemic circulatory arrest caused by cardiac vascular fascicle ligation. The status of a hypoxiasensitive neuronal population of cerebellar Purkinje cells were investigated in different postresuscitation periods. Total numbers of Purkinje cells per mm of their layer length were estimated by a histological analysis of the specimens stained with cresyl violet after the Nissl procedure. An immunocytochemical analysis was performed to determine the number of bFGFpositive (weakly and strongly stained) and GDNFnegative neurons per mm of their layer length and the total population density.

Results. Dynamics of the process of neuronal death and changes of bFGF expression level in the population of the Purkinje cells were determined postresuscitation. Next day after the resuscitation the level of expression of bFGF in the neuronal population significantly increased. At the same time point, the neuronal death did not occur. However, on day 4 the level of bFGF expression decreased and overall density of the population declined. Immunohistochemical study revealed that bFGFnegative cells undergone death. In the later stages of the process postresuscitation (days 7 and 14) the bFGF expression level increased again. At the same time deepening and/or enhancing of the pathological changes in the neuronal population were not observed.

Conclusion. The data indicate that ischemiareperfusion significantly affect the expression of bFGF protein, inducing its elevation within the Purkinje cell population of resuscitated animals. The initial rise in the level of bFGF protein within the neuronal population might prevent the development of a nerve cell death process. The subsequent reduction in the bFGF level is accompanied by the neuronal loss. Therefore, the ability to produce bFGF is an important factor affecting the resistance of neurons to postresuscitation damage. Moreover, the bFGF is considered as promising candidate molecule for developing alternative therapeutic strategies to prevent and/or treatment posthypoxic encephalopathies.

1. Avrushchenko M.Sh., Ostrova I.V., Volkov A.V., Zarzhetsky Yu.V. Postreanimatsionnye izmeneniya morfofunktsionalnogo sostoyaniya nervnykh kletok: znachenie v patogeneze entsefalopatii. Obshchaya Reanimatologiya. [Postresuscitative changes in the morphofunctional state of nerve cells: implication in the pathogenesis of encephalopathies. General Reanimatology]. 2006; 2 (5—6): 85—96. http://dx.doi.org/10.15360/18139779200668596. [In Russ.]

2. Avrushchenko M.Sh., Moroz V.V., Ostrova I.V. Postreanimatsionnye izmeneniya mozga na urovne neironalnykh populyatsii: zakonomernos ti i mekhanizmy. Obshchaya Reanimatologiya. [Postresuscitation changes in the brain at the level of neuronal populations: patterns and mechanisms. General Reanimatology]. 2012; 8 (4): 69—78. http://dx.doi.org/10.15360/181397792012469. [In Russ.]

3. GómezPinilla F., Lee J.W., Cotman C.W. Basic FGF in adult rat brain: cellular distribution and response to entorhinal lesion and fimbria fornix transection. J. Neurosci. 1992; 12 (1): 345—355. PMID: 1309575

4. Wolf W.A., Martin J.L., Kartje G.L., Farrer R.G. Evidence for fibroblast growth factor2 as a mediator of amphetamineenhanced motor improvement following stroke. PLoS One. 2014; 9 (9): e108031. http://dx.doi.org/10.1371/journal.pone.0108031. PMID: 25229819

5. Zechel S., Werner S., Unsicker K., von Bohlen und Halbach O. Expression and functions of fibroblast growth factor 2 (FGF2) in hippocampal formation. Neuroscientist. 2010; 16 (4): 357—373. http://dx.doi.org/10.1177/1073858410371513. PMID: 20581332

6. Feng C., Zhang C., Shao X., Liu Q., Qian Y., Feng L., Chen J., Zha Y., Zhang Q., Jiang X. Enhancement of nosetobrain delivery of basic fibroblast growth factor for improving rat memory impairments induced by coinjection of вamyloid and ibotenic acid into the bilat eral hippocampus. Int. J. Pharm. 2012; 423 (2): 226—234. http://dx.doi.org/10.1016/j.ijpharm.2011.12.008. PMID: 22193058

7. Ma J., Qiu J., Hirt L., Dalkara T., Moskowitz M.A. Synergistic protective effect of caspase inhibitors and bFGF against brain injury induced by transient focal ischaemia. Br. J. Pharmacol. 2001; 133 (3): 345—350. PMID: 11375250

8. Katsouri L., Ashraf A., Birch A.M., Lee K.K., Mirzaei N., Sastre M. Systemic administration of fibroblast growth factor2 (FGF2) reduces BACE1 expression and amyloid pathology in APP23 mice. Neurobiol. Aging. 2015; 36 (2): 821—831. http://dx.doi.org/10.1016/j.neurobiolaging.2014.10.004. PMID: 25457554

9. Noshita N., Lewén A., Sugawara T., Chan P.H. Evidence of phosphoryla tion of Akt and neuronal survival after transient focal cerebral ischemia in mice. J. Cereb. Blood Flow Metab. 2001; 21 (12): 1442—1450. http://dx.doi.org/10.1097/0000464720011200000009. PMID: 11740206

10. Grothe C., Timmer M. The physiological and pharmacological role of basic fibroblast growth factor in the dopaminergic nigrostriatalsystem. Brain Res. Rev. 2007; 54 (1): 80—91. PMID: 17229467

11. Goldshmit Y., Frisca F., Pinto A.R., Pébay A., Tang J.K., Siegel A.L., Kaslin J., Currie P.D. Fgf2 improves functional recoverydecreasing gliosis and increasing radial glia and neural progenitor cells after spinal cord injury. Brain Behav. 2014; 4 (2): 187—200. http://dx.doi.org/10.1002/brb3.172. PMID: 24683512

12. Comeau W.L., Hastings E., Kolb B. Pre and postnatal FGF2 both facil itate recovery and alter cortical morphology following early medial prefrontal cortical injury. Behav. Brain Res. 2007; 180 (1): 18—27. http://dx.doi.org/10.1016/j.bbr.2007.02.026. PMID: 17408762

13. Nemati F., Kolb B. FGF2 induces behavioral recovery after early adolescent injury to the motor cortex of rats. Behav. Brain Res. 2011; 225 (1): 184—191. http://dx.doi.org/10.1016/j.bbr.2011.07.023. PMID: 21801753

14. Speliotes E.K., Caday C.G., Do T., Weise J., Kowall N.W., Finklestein S.P. Increased expression of basic fibroblast growth factor (bFGF) following focal cerebral infarction in the rat. Brain Res. Mol. Brain Res. 1996; 39 (1—2): 31—42. http://dx.doi.org/10.1016/0169328X(95)00351 R. PMID: 8804711

15. Lin T.N., Te J., Lee M., Sun G.Y., Hsu C.Y. Induction of basic fibroblast growth factor (bFGF) expression following focal cerebral ischemia. Brain Res. Mol. Brain Res. 1997; 49 (1—2): 255—265. PMID: 9387885

16. Wei O.Y., Huang Y.L., Da C.D., Cheng J.S. Alteration of basic fibroblast growth factor expression in rat during cerebral ischemia. Acta Pharmacol. Sin. 2000; 21 (4): 296—300. PMID: 11324453

17. Negovsky V.A., Gurvich A.M., Zolotokrylina E.S. Postreanimatsionnaya bolezn. [Postresuscitative disease]. Moscow: Meditsina Publishers; 1987: 480. [In Russ.]

18. Korpachev V.G., Lysenkov S.P., Tel L.Z. Modelirovanie klinicheskoi smerti i postreanimatsionnoi bolezni u krys. [Modeling clinical death and postresuscitation disease in rats]. Patologicheskaya Fiziologiya i Eksperimentalnaya Terapiya. 1982; 3: 78—80. PMID: 7122145. [In Russ.]

19. Yarygin N.E., Yarygin V.N. Patologicheskie i prisposobitelnye izmeneniya neirona. [Pathological and adaptive changes in neurons]. Moscow: Meditsina Publishers; 1973: 189. [In Russ.]

20. Popova E.N., Lapin S.K., Krivitskaya G.N. Morfologiya prisposobitelnykh izmenenii nervnykh struktur. [Morphology of adaptive changes of neuronal structures]. Moscow: Meditsina Publishers; 1976. [In Russ.]

21. Kiprianova I., Schindowski K., von Bohlen und Halbach O., Krause S., Dono R., Schwaninger M., Unsicker K. Enlarged infarct volume and loss of BDNF mRNA induction following brain ischemia in mice lacking FGF2. Exp. Neurol. 2004; 189 (2): 252—260. http://dx.doi.org/10.1016/j.expneurol.2004.06.004. PMID: 15380477

22. Okada T., Kataoka Y., Takeshita A., Mino M., Morioka H., Kusakabe K.T., Kondo T. Effects of transient forebrain ischemia on the hippocam pus of the Mongolian gerbil (Merionesunguiculatus): an immunohisto chemical study. Zoolog. Sci. 2013; 30 (6): 484—489. http://dx.doi.org/10.2108/zsj.30.484. PMID: 23725314

23. Leker R.R., Soldner F., Velasco I., Gavin D.K., AndroutsellisTheotokis A., McKay R.D. Longlasting regeneration after ischemia in the cerebral cortex. Stroke. 2007; 38 (1): 153—161. PMID: 17122419

24. Watanabe T., Okuda Y., Nonoguchi N., Zhao M.Z., Kajimoto Y., Furutama D.,Yukawa H., Shibata M.A., Otsuki Y., Kuroiwa T., Miyatake S. Postischemic intraventricular administration of FGF2 expressing adenoviral vectors improves neurologic outcome and reduces infarct volume after transient focal cerebral ischemia in rats. J. Cereb. Blood Flow Metab. 2004; 24 (11): 1205—1213. http://dx.doi.org/10.1097/01.WCB.0000136525.75839.41. PMID: 15545913

25. Ye J., Lin H., Mu J., Cui X., Ying H., Lin M.,Wu L., Weng J., Lin X. Effect of basic fibroblast growth factor on hippocampal cholinergic neurons in a rodent model of ischaemic encephalopathy. Basic Clin. Pharmacol. Toxicol. 2010; 107 (6): 931—939. http://dx.doi.org/10.1111/j.17427843.2010.00603.x. PMID: 20618306

26. Srivastava N., Seth K., Srivastava N., Khanna V.K., Agrawal A.K. Functional restoration using basic fibroblast growth factor (bFGF) infusion in Kainic acid induced cognitive dysfunction in rat: neurobehaviour al and neurochemical studies. Neurochem. Res. 2008; 33 (7): 1169—1177. http://dx.doi.org/10.1007/s1106400794787. PMID: 17955369

27. Zhang M., Ma Y.F., Gan J.X., Jiang G.Y., Xu S.X., Tao X.L., Hong A., Li J.K. Basic fibroblast growth factor alleviates brain injury following global ischemia reperfusion in rabbits. J. Zhejiang Univ. Sci. B. 2005; 6 (7): 637—643. http://dx.doi.org/10.1631/jzus.2005.B0637. PMID: 15973765

28. Wang Z.L., Cheng S.M., Ma M.M., Ma Y.P., Yang J.P., Xu G.L., Liu X.F. Intranasally delivered bFGF enhances neurogenesis in adult rats following cerebral ischemia. Neurosci. Lett. 2008; 446 (1): 30—35. http://dx.doi.org/10.1016/j.neulet.2008.09.030. PMID: 18822350

29. Chen J., Li Y., Katakowski M., Chen X., Wang L., Lu D., Lu M., Gautam S.C., Chopp M. Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat. J. Neurosci. Res. 2003; 73 (6): 778—786. http://dx.doi.org/10.1002/jnr.10691. PMID: 12949903

30. Jinqiao S., Bin S., Wenhao Z., Yi Y. Basic fibroblast growth factor stimulates the proliferation and differentiation of neural stem cells in neonatal rats after ischemic brain injury. Brain Dev. 2009; 31 (5): 331—340. http://dx.doi.org/10.1016/j.braindev.2008.06.005. PMID: 18657919

31. Lenhard T., Schober A., SuterCrazzolara C., Unsicker K. Fibroblast growth factor2 requires glialcelllinederived neurotrophic factor for exerting its neuroprotective actions on glutamatelesioned hippocampal neurons. Mol. Cell Neurosci. 2002; 20 (2): 181—197. http://dx.doi.org/10.1006/mcne.2002.1134. PMID:12093153

32. Avrushchenko M.Sh., Ostrova I.V., Volkov A.V. Postreanimatsionnye izmeneniya ekspressii glialnogo neirotroficheskogo faktora (GDNF): vzaimosvyaz s povrezhdeniem kletok Purkinye mozzhechka (eksperimentalnoe issledovanie). Obshchaya Reanimatologiya. [Postresuscitation changes in the expression of GlialDerived Neurotrophic Factor (GDNF): association with cerebellar Purkinje cell damage (an experimental study). General Reanimatology]. 2014; 10 (5): 59—68. http://dx.doi.org/10.15360/18139779201455968. [In Russ.]

33. Avrushchenko M.Sh., Ostrova I.V., Zarzhetsky Yu.V., Moroz V.V., Gudasheva T.A., Seredenin S.B. Vliyanie mimetika faktora rosta nervov GK2 na postreanimatsionnuyu ekspressiyu neirotroficheskikh faktorov. [Effect of the nerve growth factor mimetic GK2 on postresus citation expression of neurotrophic factors]. Patologicheskaya Fiziologiya i Eksperimentalnaya Terapiya. 2015; 59 (2): 13—18. PMID: 26571801. [In Russ.]