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New synthetic peptide protects neurons from death induced by toxic influence of activated mast cells via protease-activated receptor

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Biochemistry (Moscow) Supplement Series A: Membrane and Cell Biology Aims and scope

Abstract

The present study focuses on possible ways to protect brain neurons during neuroinflammation. For the first time it is shown that peptide NPNDKYEPF amide, similar to activated protein C (APC), protects hippocampal neurons in a model of neuroinflammation induced by the toxic effects of endotoxin (lipopolysaccharide)-activated mast cells on neurons. It was found that the incubation of hippocampal neurons with mast cells activated by proinflammatory factors leads to neuronal apoptosis within 24 h after the exposure. Preincubation of mast cells with peptide NPNDKYEPF amide or with APC, before the toxin’s treatment, abolishes the toxic effects of the activated mast cells on neurons. By the blockade of protease-activated receptors of type 1 (PAR1), the receptor mechanism of the peptide action on mast cells and on neurons was identified. It was shown that PAR1 is required for the protective effect of the peptide in the conditions of neuroinflammation. Thus, peptide NPNDKYEPF amide is a neuroprotector, similar to APC, and can be used for the development of new approaches of the therapy of inflammatory processes accompanying different types of traumatic and ischemic brain damage.

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References

  1. Mina Y., Rinkevich-Shop S., Konen E., Goitein O., Kushnir T., Epstein F.H., Feinberg M.S., Leor J., Landa-Rouben N. 2013. Mast cell inhibition attenuates myocardial damage, adverse remodeling, and dysfunction during fulminant myocarditis in the rat. J. Cardiovasc. Pharmacol. Ther. 18 (2), 152–161.

    Article  CAS  PubMed  Google Scholar 

  2. Zheng J., Wei C.C., Hase N., Shi K., Killingsworth C.R., Litovsky S.H., Powell P.C., Kobayashi T., Ferrario C.M., Rab A., Aban I., Collawn J.F., Dell’Italia L.J. 2014. Chymase mediates injury and mitochondrial damage in cardiomyocytes during acute ischemia/reperfusion in the dog. PLoS One. 9 (4), e94732.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Strbian D., Kovanen P.T., Karjalainen-Lindsberg M.L., Tatlisumak T., Lindsberg P.J. 2009. An emerging role of mast cells in cerebral ischemia and hemorrhage. Ann. Med. 41 (6), 438–450.

    Article  CAS  PubMed  Google Scholar 

  4. Jin Y., Silverman A.J., Vannucci S.J. 2009. Mast cells are early responders after hypoxia-ischemia in immature rat brain. Stroke. 40 (9), 3107–3112.

    Article  CAS  PubMed  Google Scholar 

  5. Lindsberg P.J., Strbian D., Karjalainen-Lindsberg M.L. 2010. Mast cells as early responders in the regulation of acute blood-brain barrier changes after cerebral ischemia and hemorrhage. J. Cereb. Blood Flow Metab. 30 (4), 689–702.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Nelissen S., Lemmens E., Geurts N., Kramer P., Maurer M., Hendriks J., Hendrix S. 2013. The role of mast cells in neuroinflammation. Acta Neuropathol. 125 (5), 637–650.

    Article  CAS  PubMed  Google Scholar 

  7. Biran V., Cochois V., Karroubi A., Arrang J.M., Charriaut-Marlangue C., Heron A. 2008. Stroke induces histamine accumulation and mast cell degranulation in the neonatal rat brain. Brain Pathol. 18 (1), 1–9.

    Article  CAS  PubMed  Google Scholar 

  8. Shibata M., Kumar S.R., Amar A., Fernandez J.A., Hofman F., Griffin J.H., Zlokovic B.V. 2001. Antiinflammatory, antithrombotic, and neuroprotective effects of activated protein C in a murine model of focal ischemic stroke. Circulation. 103 (13), 1799–1805.

    Article  CAS  PubMed  Google Scholar 

  9. Gorbacheva L., Pinelis V., Ishiwata S., Strukova S., Reiser G. 2010. Activated protein C prevents glutamate-and thrombin-induced activation of nuclear factor-κB in cultured hippocampal neurons. Neuroscience. 165, 1138–1146.

    Article  CAS  PubMed  Google Scholar 

  10. Wildhagen K.C., Schrijver R., Beckers L., ten Cate H., Reutelingsperger C.P., Lutgens E., Nicolaes G.A. 2014. Effects of exogenous recombinant APC in mouse models of ischemia reperfusion injury and of atherosclerosis. PLoS One. 9 (7), e101446.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Konanki R., Gulati S., Saxena R., Gupta A.K., Seith A., Kumar A., Saxena A., Kabra M., Kalra V., Lakshmy R. 2014. Profile of prothrombotic factors in Indian children with ischemic stroke. J. Clin. Neurosci. 21 (8), 1315–1318.

    Article  CAS  PubMed  Google Scholar 

  12. Berny-Lang M.A., Hurst S., Tucker E.I., Pelc L.A., Wang R.K., Hurn P.D., Di Cera E., McCarty O.J., Gruber A. 2011. Thrombin mutant W215A/E217A treatment improves neurological outcome and reduces cerebral infarct size in a mouse model of ischemic stroke. Stroke. 42 (6), 1736–1741.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gorbacheva L.R., Storozhevykh T.P., Pinelis V.G., Davydova O., Ishiwata Sh., Strukova S.M. 2008. Activated protein C regulates neuronal survival at glutamate excitotoxicity via PAR1. Biokhimia (Rus.). 73 (6), 893–902.

    Google Scholar 

  14. Coughlin S.R. 2005. Protease-activated receptors in hemostasis, thrombosis and vascular biology. J. Thromb. Haemost. 3, 1800–1814.

    Article  CAS  PubMed  Google Scholar 

  15. Griffin J.H., Zlokovic B.V., Mosnier L.O. 2012. Protein C anticoagulant and cytoprotective pathways. Int. J. Hematol. 95, 333–345.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Shpacovitch V., Feld M., Hollenberg M.D., Luger T.A., Steinhoff M. 2008. Role of protease-activated receptors in inflammatory responses, innate and adaptive immunity. J. Leukoc. Biol. 83 (6), 1309–1322.

    Article  CAS  PubMed  Google Scholar 

  17. Gorbacheva L., Davidova O., Sokolova E., Ishiwata S., Pinelis V., Strukova S., Reiser G. 2009. Endothelial protein C receptor is expressed in rat cortical and hippocampal neurons and is necessary for protective effect of activated protein C at glutamate excitotoxicity. J. Neurochem. 111, 967–975.

    Article  CAS  PubMed  Google Scholar 

  18. Rusanova A.V., Vasilyeva T.V., Smirnov M.D., Strukova S. 2009. Mast cells as a target for anti-inflammatory action of APC. Tsitokiny i vospalenie (Rus.). 8 (3), 48–54.

    Google Scholar 

  19. Strukova S.M. 2001. Thrombin as a regulator of inflammation and reparative processes in tissues. Biochemistry (Mosc). 66 (1), 8–18.

    Article  CAS  PubMed  Google Scholar 

  20. Mosnier L.O., Sinha R.K., Burnier L., Bouwens E.A., Griffin J.H. 2012. Biased agonism of protease-activated receptor 1 by activated protein C caused by noncanonical cleavage at Arg46. Blood. 120, 5237–5246.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bouwens E.A., Stavenuiter F., Mosnier L.O. 2013. Mechanisms of anticoagulant and cytoprotective actions of the protein C pathway. J. Thromb. Haemost. 11 (1), 242–253.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Blank U., Madera-Salcedo I.K., Danelli L., Claver J., Tiwari N., Sanchez-Miranda E., Vazquez-Victorio G., Ramirez-Valadez K.A., Macias-Silva M., Gonzalez-Espinosa C. 2014. Vesicular trafficking and signaling for cytokine and chemokine secretion in mast cells. Front Immunol. 22 (5), 1–18.

    Google Scholar 

  23. da Silva E.Z., Jamur M.C., Oliver C. 2014. Mast cell function: A new vision of an old cell. J. Histochem. Cytochem. 62 (10), 698–738.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Metcalfe D.D., Baram D., Mekori Y.A. 1997. Mast cells. Physiol. Rev. 77 (4), 1033–1079.

    CAS  PubMed  Google Scholar 

  25. Schulke S., Flaczyk A., Vogel L., Gaudenzio N., Angers I., Loschner B., Wolfheimer S., Spreitzer I., Qureshi S., Tsai M., Galli S., Vieths S., Scheurer S. 2015. MPLA shows attenuated pro-inflammatory properties and diminished capacity to activate mast cells in comparison with LPS. Allergy. 70 (10), 1259–1268.

    Article  CAS  PubMed  Google Scholar 

  26. Brenner S.A., Zacheja S., Schaffer M., Feilhauer K., Bischoff S.C., Lorentz A. 2014. Soluble CD14 is essential for lipopolysaccharide-dependent activation of human intestinal mast cells from macroscopically normal as well as Crohn’s disease tissue. J. Immunology. 143 (2), 174–183.

    Article  CAS  Google Scholar 

  27. Idriss H.T., Naismith J.H. 2000. TNF alpha and the TNF receptor superfamily: Structure-function relationship( s). Microsc. Res. Tech. 50 (3), 184–195.

    Article  CAS  PubMed  Google Scholar 

  28. Khodorov B.I., Storozhevykh T.P., Surin A.M., Sorokina E.G., Jurevicius A.I., Borodin A.V., Vinskya N.P., Khaspekov L.G., Pinelis V.G. 2001. Mitochondrial depolarization plays a dominant role in the mechanism of glutamate-induced disruption of neuronal calcium homeostasis. Biol. membrany (Rus.). 18 (6), 421–432.

    CAS  Google Scholar 

  29. Strbian D., Kovanen P.T., Karjalainen-Lindsberg M.L., Tatlisumak T., Lindsberg P.J. 2009. An emerging role of mast cells in cerebral ischemia and hemorrhage. Ann. Med. 41 (6), 438–450.

    Article  CAS  PubMed  Google Scholar 

  30. Gingrich M.B., Junge C.E., Lyuboslavsky P., Traynelis S.F. 2000. Potentiation of NMDA receptor function by the serine protease thrombin. J. Neurosci. 20 (12), 4582–4595.

    CAS  PubMed  Google Scholar 

  31. Han K.S., Mannaioni G., Hamill C.E., Lee J., Junge C.E., Lee C.J., Traynelis S.F. 2011. Activation of protease activated receptor 1 increases the excitability of the dentate granule neurons of hippocampus. Mol. Brain. 10, 4–32.

    Google Scholar 

  32. Ide J., Aoki T., Ishivata S., Glusa E., Strukova S.M. 2007. Proteinase-activated receptor agonists stimulate the increase in intracellular Ca2+ in cardiomyocytes and proliferation of cardiac fibroblasts from chick embryos. Bull. Exp. Biol. Med. 144 (6), 760–763.

    Article  CAS  PubMed  Google Scholar 

  33. Mao Y., Jin J., Kunapuli S.P. 2008. Characterization of a new peptide agonist of the protease-activated receptor-1. Biochem. Pharmacol. 75 (2), 438–447.

    Article  CAS  PubMed  Google Scholar 

  34. He Q., Bao L., Zimering J., Zan K., Zhang Z., Shi H., Zu J., Yang X., Hua F., Ye X., Cui G. 2015. The protective role of (–)-epigallocatechin-3-gallate in thrombininduced neuronal cell apoptosis and JNK-MAPK activation. Neuroreport. 26, 416–423.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zundorf G., Reiser G. 2011. The phosphorylation status of extracellular-regulated kinase 1/2 in astrocytes and neurons from rat hippocampus determines the thrombin-induced calcium release and ROS generation. J. Neurochem. 119, 1194–1204.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Biological Faculty, Moscow Lomonosov State University, Leninskie Gory 1, build. 12, Moscow, 119991, Russia

    I. I. Babkina, S. M. Strukova & L. R. Gorbacheva

  2. Pirogov Russian National Research Medical University, ul. Ostrovitianova 1, Moscow, 117997, Russia

    L. R. Gorbacheva

  3. Scientific Center of Children’s Health, Ministry of Health of Russian Federation, Lomonosovsky pr. 2, build. 1, Moscow, 119991, Russia

    V. G. Pinelis

  4. Institute for Inflammation and Neurodegeneration, Otto-von-Guericke University, Medical Faculty, Magdeburg, 39120, Germany

    G. Reiser

Authors
  1. I. I. Babkina
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  2. S. M. Strukova
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  3. V. G. Pinelis
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  4. G. Reiser
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  5. L. R. Gorbacheva
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Corresponding author

Correspondence to L. R. Gorbacheva.

Additional information

Original Russian Text © I.I. Babkina, S.M. Strukova, V.G. Pinelis, G. Reiser, L.R. Gorbacheva, 2016, published in Biologicheskie Membrany, 2016, Vol. 33, No. 1, pp. 70–79.

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Babkina, I.I., Strukova, S.M., Pinelis, V.G. et al. New synthetic peptide protects neurons from death induced by toxic influence of activated mast cells via protease-activated receptor. Biochem. Moscow Suppl. Ser. A 10, 126–134 (2016). https://doi.org/10.1134/S1990747816010037

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  • DOI: https://doi.org/10.1134/S1990747816010037

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