The role of astroglial proteins in the brains of rats under the influence of doxorubicin and Humilid


  • Y. V. Babets Оles Нonchar Dnipropetrovsk National University
  • G. A. Ushakova Оles Нonchar Dnipropetrovsk National University
  • L. M. Stepchenko Dnipropetrovsk State Agrarian-Economics University
Keywords: cardiomyopathy, GFAP, S-100b, hippocampus, cerebellum, cortex

Abstract

Doxorubicin causes toxic side effects which result in profound changes in various organs including the heart muscle, which leads to the development of cardiomyopathy, with further complications, as our earlier studies have shown. But there are complications in treatment by anthracycline chemotherapy. The reduction of toxicity of cytotoxic drugs without reduction of their antitumor action remains an important medical challenge. The S-100b and glial fibrillar acid protein (GFAP) are the key astroglial proteins which are widely used as biomarkers for neurotraumas and strokes. Thus the purpose of our work was to study the GFAP and S-100b levels under the experimental model of doxorubicin-induced cardiomyopathy and the effect of the cytostatic separately or combined with Humilid. The level of studied proteins was measured by ELISA using monospecific antibodies against GFAP and S-100b (Sigma, USA), secondary anti-IgG labeled with horseradish peroxidase (Sigma, USA) and GFAP and S-100b standards (Sigma, USA). The experiment was conducted on white Wistar male rats weighing 210 ±50 g, which were divided into 3 groups with 8 animals in each: 1 – control, rats received saline i/p, 2 – doxorubicin 1 mg/kg i/p once weekly during 4 weeks, 3 – doxorubicin by the same scheme plus 0.01% solution of Humilid during 4 weeks. Under impact of doxorubicin an increase of fibrillar GFAP content in the rats’ hippocampus was shown, which may have occurred as a result of the proliferation of astrocytes. An increase of concentration of S-100b to 20–26% compared with the control animals was also detected in the hippocampus, thalamus and the cerebral cortex of the studied animals. Concomitant administration of doxorubicin with Humilid partially prevented the increase in concentration of GFAP and S-100b in the rats’ hippocampus. The reciprocal change in the level of S-100b and GFAP in the peripheral nervous system of the heart tissue was defined with a high degree of correlation under impact of doxorubicin. Accordingly, we have proposed the hypothesis that the increase in of the filament GFAP in the hippocampus may occur due to the development of the ischemic state under the impact of doxorubicin-induced cardiomyopathy. Humilid with doxorubicin prevented changes in the researched astroglial proteins of the heart muscle and brain parts of rats. 

References

Babets, Y.V., Ushakova, G.A., 2013. Toksychni efekty ta bio-himichnyj kontrol’ nasoidkiv antracyklinovoi’ terapii’ [Toxic effects and biochemical control of consequence anthracycline therapy]. Archives of Clinical and Experimental Medicine 22(1), 242–248 (in Ukrainian).
Babets, Y.V., Ushakova, G.A., Shevtsova, A.I., 2015. Rozpodil astrocytspecyfichnyh bilkiv pry dii’ doksorubicynu na shhuriv [Distribution of asrtocyte and specific proteins under doxorubicin ffect on rats]. Medical and Clinical Chemistry 17(1), 36–41 (in Ukrainian).
Colangelo, A.M., Alberghina, L., Papa, M., 2014. Astrogliosis as a therapeutic target for neurodegenerative diseases. Neurosci. Lett. 565, 59–64. >> doi.org/10.1016/j.neulet.2014.01.014
Distefano, G., 2009. Molecular pathogenetic mechanisms and new therapeutic perspectives in anthracycline-induced cardiomyopathy. Ital. J. Pediatr. 35(1), 1–8. >> doi.org/10.1186/1824-7288-35-37
Faa, A., Senes, G., Locci, A., Pampaloni, P., Pais, M.E., Piras, B., d’Aloja, E., Faa, G., 2012. S100B protein expression in the heart of deceased individuals by overdose: A new forensic marker? Clinics 67(7), 821–826. >> doi.org/10.6061/clinics/2012(07)19
Frias, C.P., Wierenga, C.J., 2013 Activity-dependent adaptations in inhibitory axons. Front. Cell Neurosci. 7, 1–16. >> doi.org/10.3389/fncel.2013.00219
Gabel, S., Koncina, E., Dorban, G., Heurtaux, T., Birck, C., Glaab, E., Michelucci, A., Heuschling, P., Grandbarbe, L., 2016. Inflammation promotes a conversion of astrocytes into neural progenitor cells via NF-κB activation. Mol. Neurobiol. 53(8), 5041–5055. >> doi.org/10.1007/s12035-015-9428-3
Gordienko, Y.A., Baklanova, Y.V., Kovalenko, M.V., Stepchenko, L.M., Shevtsova, A.I., Ushakova, G.A., 2012. Zminy fiziologichnyh ta biohimichnyh pokaznykiv u shhuriv z doksorubicyn-indukovanoju kardiomiopatijeju na tli zastosuvannja preparativ z antyoksydantnoju dijeju [Changes of phisiological and biochemical parameters in rats with doxorubicin-induced cardiopathy under influence of substances with anti-oxidant action]. Anim. Biol. 14, 74–79 (in Ukrainian).
Gupta, R, Mala, T.A., Mathur, P., 2014. Stage 4S bilateral adrenal neuroblastoma in a newborn. APSP J. Case Rep. 5(1), 9–11.
Han, Y., Pan, H., Mao, J., Zhou, Y., Zhang, Y., Wang, H., Bao, Y., Zhao, L., Liu, L., Zhang, G., 2013. Expression and role of S100B on the injury of cardiomyocytes induced by doxorubicin. Journal of Jiangsu University 23(3), 216–220.
Inoue, S., Setoyama, Y., Odaka, A., 2014. Doxorubicin treatment induces tumor cell death followed by immunomodulation in a murineneuroblastomamodel. Exp. Ther. Med. 7(3), 703–708. >> doi.org/10.3892/etm.2014.1489
Kovalenko, T.N., Ushakova, G.A., Osadchenko, I., Skibo, G.G., Pierzynowski, S.G., 2011. The neuroprotective effect of 2-oxoglutarate in the experimental ischemia of hippocampus. J. Physiol. Pharmacol. 62(2), 239–246.
Li, H., Guo, Y., Teng, J., Ding, M., Yu, A.C., Chen, J., 2006. 14-3-3gamma affects dynamics and integrity of glial filaments by binding to phosphorylated GFAP. J. Cell Sci. 119, 4452–4461. >> doi.org/10.1242/jcs.03219
Mao, X., Schwend, T., Conrad, G.W., 2012. Expression and localization of neural cell adhesion molecule and polysialic acid during chick corneal development. Invest. Ophthalmol. Vis. Sci. 53(3), 1234–1243. >> doi.org/10.1167/iovs.11-8834
Paronik, V., Stepchenko, L., Diachenko, L., Lievykh, A., Shevtsova, A., 2015. Vplyv korvitynu ta gumilidu na stan oksydantno-antyoksydantnoi’ systemy shhuriv na foni vvedennja adrenalinu [Influence of corvitin and humilid on the oxidant-antioxidant system in rats after injectoin of adrenalin]. Anim. Biol. 17(4), 109–114 (in Ukrainian).
Rajkowska, G., Stockmeiera., C.A., 2013. Astrocyte pathology in major depressive disorder: insights from human postmortem brain tissue. Curr. Drug Targets 14(11), 1225–1236. >> doi.org/10.2174/13894501113149990156
Skrebickiy, V.G., Shtark, M.B., 2012. Fundamental’nyye osnovyy plastychnosty nervnoj tkany [The fundaments of neuronal plasticity]. Annals of the Russian Academy of Medical Sciences 9, 39–44 (in Russian).
Sorci, G., Bianchi, R., Riuzzi, F., Tubaro, C., Arcuri, C., Giambanco, I., Donato, R., 2010. S100B Protein, a damage-associated molecular pattern protein in the brain and heart, and beyond cardiovasc psychiatry. Neurology 2010, Pii 656481. >> doi.org/10.1155/2010/656481
Sorci, G., Riuzzi, F., Arcuri, C., 2013. S100B protein in tissue development, repair and regeneration. World J. Biol. Chem. 4(1), 1–12. >> doi.org/10.4331/wjbc.v4.i1.1
Tsoporis, J.N. Mohammadzadeh, F., Parker, T.G., 2010. Intracellular and extracellular effects of S100B in the cardiovascular response to disease. Cardiovasc. Psychiatry Neurol. 10, 6073–6079. >> doi.org/10.1155/2010/206073
Wohlfart, S., Khalansky, A.S., Gelperina, S., Maksimenko, O., Bernreuther, C., Glatzel, M., Kreuter, J., 2011. Efficient chemotherapy of rat glioblastoma using doxorubicinloaded PLGA nanoparticles with different stabilizers. PLoS One 6(5), e19121. >> doi.org/10.1371/journal.pone.0019121
Yang, Z., Wang, K.W., 2015. Glial fibrillary acidic protein: From intermediate filament assembly and gliosis to neurobiomarker. Trends Neurosci. 38(6), 364–374. >> doi.org/10.1016/j.tins.2015.04.003
Yardan, T., Erenler, A.K., Baydin, A., Aydin, K., Cokluk, C., 2011. Usefulness of S100B protein in neurological disorders. J. Pak. Med. Assoc. 61(3), 276–281.
Ziegler, D.R., Innocente, C.E., Leal, R.B., Rodnight, R., Gonсalves, C.A., 1998. The S100B protein inhibits phosphorylation of GFAP and vimentin in a cytoskeletal fraction from immature rat hippocampus. Neurochem. Res. 23(10), 1259–1263. >> doi.org/10.1023/a:1020740115790
Published
2016-09-29
Section
Articles