Skip to main content
SpringerLink
Log in

Brain to blood efflux as a mechanism underlying the neuroprotection mediated by rapid remote preconditioning in brain ischemia

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Glutamate represents the main excitatory neurotransmitter in the mammalian brain; however, its excessive elevation in the extracellular space is cytotoxic and can result in neuronal death. The ischemia initiated brain damage reflects changes in glutamate concentration in peripheral blood. This paper investigated the role of the brain in blood efflux of the glutamate in an improved tolerance of the brain tissue to ischemic conditions. In the rat model of focal brain ischemia, the neuroprotection was initiated by rapid remote ischemic preconditioning (rRIPC). Our results confirmed a strong neuroprotective effect of rRIPC. We observed reduced infarction by about 78% related to improved neuronal survival by about 70% in the ischemic core. The level of tissue glutamate in core and penumbra dropped significantly and decreased to control value also in the core region of the contralateral hemisphere. Despite significant improvement of blood–brain barrier integrity (by about 76%), the additional gain of glutamate content in the peripheral blood was caused by rRIPC. Based on our results, we can assume that neuroprotection mediated by rapid remote ischemic preconditioning could lie in the regulated, whole-brain release of glutamate from nerve tissue to the blood, which preserves neurons from the exposure to glutamate toxicity and results in reduced infarction.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Dong XX, Wang Y, Qin ZH (2009) Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases. Acta Pharmacol Sin 30(4):379–387. https://doi.org/10.1038/aps.2009.24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Mark LP, Prost RW, Ulmer JL, Smith MM, Daniels DL, Strottmann JM, Brown WD, Hacein-Bey L (2001) Pictorial review of glutamate excitotoxicity: fundamental concepts for neuroimaging. AJNR 22(10):1813–1824

    CAS  PubMed  Google Scholar 

  3. Bonova P, Burda J, Danielisova V, Nemethova M, Gottlieb M (2013) Delayed post-conditioning reduces post-ischemic glutamate level and improves protein synthesis in brain. Neurochem Int 62(6):854–860. https://doi.org/10.1016/j.neuint.2013.02.019

    Article  CAS  PubMed  Google Scholar 

  4. Bonova P, Burda J, Danielisova V, Nemethova M, Gottlieb M (2013) Development of a pattern in biochemical parameters in the core and penumbra during infarct evolution after transient MCAO in rats. Neurochem Int 62(1):8–14. https://doi.org/10.1016/j.neuint.2012.10.015

    Article  CAS  PubMed  Google Scholar 

  5. Bona M, Hvizdosova N, Jachova J, Bonova P, Kluchova D (2019) Response of distant regions affected by diaschisis commissuralis in one of the most common models of transient focal ischemia in rats. J Chem Neuroanat 101:101666. https://doi.org/10.1016/j.jchemneu.2019.101666

    Article  CAS  PubMed  Google Scholar 

  6. Kravcukova P, Danielisova V, Nemethova M, Burda J, Gottlieb M (2010) Effects of one-day reperfusion after transient forebrain ischemia on circulatory system in the rat. Gen Physiol Biophys 29(2):113–121

    Article  Google Scholar 

  7. Kravcukova P, Danielisova V, Nemethova M, Burda J, Gottlieb M (2009) Transient forebrain ischemia impact on lymphocyte DNA damage, glutamic acid level, and SOD activity in blood. Cell Mol Neurobiol 29(6–7):887–894. https://doi.org/10.1007/s10571-009-9371-9

    Article  CAS  PubMed  Google Scholar 

  8. Castellanos M, Sobrino T, Pedraza S, Moldes O, Pumar JM, Silva Y, Serena J, Garcia-Gil M, Castillo J, Davalos A (2008) High plasma glutamate concentrations are associated with infarct growth in acute ischemic stroke. Neurology 71(23):1862–1868. https://doi.org/10.1212/01.wnl.0000326064.42186.7e

    Article  CAS  PubMed  Google Scholar 

  9. Aliprandi A, Longoni M, Stanzani L, Tremolizzo L, Vaccaro M, Begni B, Galimberti G, Garofolo R, Ferrarese C (2005) Increased plasma glutamate in stroke patients might be linked to altered platelet release and uptake. J Cerebral Blood Flow Metab 25(4):513–519. https://doi.org/10.1038/sj.jcbfm.9600039

    Article  CAS  Google Scholar 

  10. O’Kane RL, Martinez-Lopez I, DeJoseph MR, Vina JR, Hawkins RA (1999) Na(+)-dependent glutamate transporters (EAAT1, EAAT2, and EAAT3) of the blood–brain barrier. A mechanism for glutamate removal. J Biol Chem 274(45):31891–31895. https://doi.org/10.1074/jbc.274.45.31891

    Article  PubMed  Google Scholar 

  11. Cohen-Kashi-Malina K, Cooper I, Teichberg VI (2012) Mechanisms of glutamate efflux at the blood–brain barrier: involvement of glial cells. J Cerebral Blood Flow Metab 32(1):177–189. https://doi.org/10.1038/jcbfm.2011.121

    Article  CAS  Google Scholar 

  12. Gottlieb M, Wang Y, Teichberg VI (2003) Blood-mediated scavenging of cerebrospinal fluid glutamate. J Neurochem 87(1):119–126. https://doi.org/10.1046/j.1471-4159.2003.01972.x

    Article  CAS  PubMed  Google Scholar 

  13. Jachova J, Gottlieb M, Nemethova M, Macakova L, Bona M, Bonova P (2019) Neuroprotection mediated by remote preconditioning is associated with a decrease in systemic oxidative stress and changes in brain and blood glutamate concentration. Neurochem Int 129:104461. https://doi.org/10.1016/j.neuint.2019.05.005

    Article  CAS  PubMed  Google Scholar 

  14. Astrup J, Siesjo BK, Symon L (1981) Thresholds in cerebral ischemia: the ischemic penumbra. Stroke 12(6):723–725. https://doi.org/10.1161/01.str.12.6.723

    Article  CAS  PubMed  Google Scholar 

  15. Liu S, Levine SR, Winn HR (2010) Targeting ischemic penumbra: part I: from pathophysiology to therapeutic strategy. J Exp Stroke Transl Med 3(1):47–55. https://doi.org/10.6030/1939-067x-3.1.47

    Article  PubMed  PubMed Central  Google Scholar 

  16. Leigh R, Knutsson L, Zhou J, van Zijl PC (2018) Imaging the physiological evolution of the ischemic penumbra in acute ischemic stroke. J Cerebral Blood Flow Metab 38(9):1500–1516. https://doi.org/10.1177/0271678X17700913

    Article  Google Scholar 

  17. Bonova P, Danielisova V, Nemethova M, Matiasova M, Bona M, Gottlieb M (2015) Scheme of ischaemia-triggered agents during brain infarct evolution in a rat model of permanent focal ischaemia. J Mol Neurosci 57(1):73–82. https://doi.org/10.1007/s12031-015-0578-6

    Article  CAS  PubMed  Google Scholar 

  18. Longa EZ, Weinstein PR, Carlson S, Cummins R (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20(1):84–91

    Article  CAS  Google Scholar 

  19. Bederson JB, Pitts LH, Tsuji M, Nishimura MC, Davis RL, Bartkowski H (1986) Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke 17(3):472–476. https://doi.org/10.1161/01.str.17.3.472

    Article  CAS  PubMed  Google Scholar 

  20. Hu S, Dong H, Zhang H, Wang S, Hou L, Chen S, Zhang J, Xiong L (2012) Noninvasive limb remote ischemic preconditioning contributes neuroprotective effects via activation of adenosine A1 receptor and redox status after transient focal cerebral ischemia in rats. Brain Res 1459:81–90. https://doi.org/10.1016/j.brainres.2012.04.017

    Article  CAS  PubMed  Google Scholar 

  21. Callaway JK, Knight MJ, Watkins DJ, Beart PM, Jarrott B, Delaney PM (2000) A novel, rapid, computerized method for quantitation of neuronal damage in a rat model of stroke. J Neurosci Methods 102(1):53–60. https://doi.org/10.1016/s0165-0270(00)00278-8

    Article  CAS  PubMed  Google Scholar 

  22. Schmued LC, Hopkins KJ (2000) Fluoro-Jade B: a high affinity fluorescent marker for the localization of neuronal degeneration. Brain Res 874(2):123–130. https://doi.org/10.1016/s0006-8993(00)02513-0

    Article  CAS  PubMed  Google Scholar 

  23. Ashwal S, Tone B, Tian HR, Cole DJ, Pearce WJ (1998) Core and penumbral nitric oxide synthase activity during cerebral ischemia and reperfusion. Stroke 29(5):1037–1046 (discussion 1047)

    Article  CAS  Google Scholar 

  24. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254. https://doi.org/10.1006/abio.1976.9999

    Article  CAS  Google Scholar 

  25. Graham LT Jr, Aprison MH (1966) Fluorometric determination of aspartate, glutamate, and gamma-aminobutyrate in nerve tissue using enzymic methods. Anal Biochem 15(3):487–497. https://doi.org/10.1016/0003-2697(66)90110-2

    Article  CAS  PubMed  Google Scholar 

  26. Cho YJ, Kim WH (2019) Perioperative cardioprotection by remote ischemic conditioning. Int J Mol Sci. https://doi.org/10.3390/ijms20194839

    Article  PubMed  PubMed Central  Google Scholar 

  27. Giannopoulos G, Vrachatis DA, Panagopoulou V, Vavuranakis M, Cleman MW, Deftereos S (2017) Remote ischemic conditioning and renal protection. J Cardiovasc Pharmacol Therap 22(4):321–329. https://doi.org/10.1177/1074248417702480

    Article  Google Scholar 

  28. Bonova P, Gottlieb M (2015) Blood as the carrier of ischemic tolerance in rat brain. J Neurosci Res 93(8):1250–1257. https://doi.org/10.1002/jnr.23580

    Article  CAS  PubMed  Google Scholar 

  29. Bonova P, Nemethova M, Matiasova M, Bona M, Gottlieb M (2016) Blood cells serve as a source of factor-inducing rapid ischemic tolerance in brain. Eur J Neurosci 44(11):2958–2965. https://doi.org/10.1111/ejn.13422

    Article  PubMed  Google Scholar 

  30. Bonova P, Jachova J, Nemethova M, Macakova L, Bona M, Gottlieb M (2019) Rapid remote conditioning mediates modulation of blood cell paracrine activity and leads to the production of a secretome with neuroprotective features. J Neurochem. https://doi.org/10.1111/jnc.14889

    Article  PubMed  Google Scholar 

  31. Ren C, Gao X, Steinberg GK, Zhao H (2008) Limb remote-preconditioning protects against focal ischemia in rats and contradicts the dogma of therapeutic time windows for preconditioning. Neuroscience 151(4):1099–1103. https://doi.org/10.1016/j.neuroscience.2007.11.056

    Article  CAS  PubMed  Google Scholar 

  32. Zhou G, Li MH, Tudor G, Lu HT, Kadirvel R, Kallmes D (2018) Remote ischemic conditioning in cerebral diseases and neurointerventional procedures: recent research progress. Front Neurol 9:339. https://doi.org/10.3389/fneur.2018.00339

    Article  PubMed  PubMed Central  Google Scholar 

  33. Nemethova M, Danielisova V, Gottlieb M, Kravcukova P, Burda J (2010) Ischemic postconditioning in the rat hippocampus: mapping of proteins involved in reversal of delayed neuronal death. Arch Ital Biol 148(1):23–32

    CAS  PubMed  Google Scholar 

  34. Krzyzanowska W, Pomierny B, Filip M, Pera J (2014) Glutamate transporters in brain ischemia: to modulate or not? Acta Pharmacol Sin 35(4):444–462. https://doi.org/10.1038/aps.2014.1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Teichberg VI, Cohen-Kashi-Malina K, Cooper I, Zlotnik A (2009) Homeostasis of glutamate in brain fluids: an accelerated brain-to-blood efflux of excess glutamate is produced by blood glutamate scavenging and offers protection from neuropathologies. Neuroscience 158(1):301–308. https://doi.org/10.1016/j.neuroscience.2008.02.075

    Article  CAS  PubMed  Google Scholar 

  36. Romera C, Hurtado O, Botella SH, Lizasoain I, Cardenas A, Fernandez-Tome P, Leza JC, Lorenzo P, Moro MA (2004) In vitro ischemic tolerance involves upregulation of glutamate transport partly mediated by the TACE/ADAM17-tumor necrosis factor-alpha pathway. J Neurosci 24(6):1350–1357. https://doi.org/10.1523/JNEUROSCI.1596-03.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ellinger JJ, Lewis IA, Markley JL (2011) Role of aminotransferases in glutamate metabolism of human erythrocytes. J Biomol NMR 49(3–4):221–229. https://doi.org/10.1007/s10858-011-9481-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zoia C, Cogliati T, Tagliabue E, Cavaletti G, Sala G, Galimberti G, Rivolta I, Rossi V, Frattola L, Ferrarese C (2004) Glutamate transporters in platelets: EAAT1 decrease in aging and in Alzheimer’s disease. Neurobiol Aging 25(2):149–157. https://doi.org/10.1016/s0197-4580(03)00085-x

    Article  CAS  PubMed  Google Scholar 

  39. Winterberg M, Rajendran E, Baumeister S, Bietz S, Kirk K, Lingelbach K (2012) Chemical activation of a high-affinity glutamate transporter in human erythrocytes and its implications for malaria-parasite-induced glutamate uptake. Blood 119(15):3604–3612. https://doi.org/10.1182/blood-2011-10-386003

    Article  CAS  PubMed  Google Scholar 

  40. Begni B, Tremolizzo L, D’Orlando C, Bono MS, Garofolo R, Longoni M, Ferrarese C (2005) Substrate-induced modulation of glutamate uptake in human platelets. Br J Pharmacol 145(6):792–799. https://doi.org/10.1038/sj.bjp.0706242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Simard JM, Kent TA, Chen M, Tarasov KV, Gerzanich V (2007) Brain oedema in focal ischaemia: molecular pathophysiology and theoretical implications. Lancet Neurol 6(3):258–268. https://doi.org/10.1016/S1474-4422(07)70055-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hossmann KA, Schuier FJ (1980) Experimental brain infarcts in cats. I. Pathophysiological observations. Stroke 11(6):583–592

    Article  CAS  Google Scholar 

  43. Sist B, Baskar Jesudasan SJ, Winship IR (2012) Diaschisis, degeneration, and adaptive plasticity after focal ischemic stroke. In: Rodriguez JC (ed) Acute ischemic stroke. InTech, Rijeka

    Google Scholar 

Download references

Acknowledgements

The authors gratefully acknowledge the excellent technical assistance of Dana Jurusova. This study was supported by the Slovak Grant Agencies VEGA 1/0218/18 and VEGA 2/0029/18.

Author information

Authors and Affiliations

  1. Institute of Neurobiology, Biomedical Research Center of the Slovak Academy of Sciences, Šoltésovej 4-6, 040 01, Košice, Slovak Republic

    Jana Jachova, Miroslav Gottlieb, Miroslava Nemethova & Petra Bonova

  2. Department of Medical Physiology, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, tr. SNP 1, 040 11, Košice, Slovak Republic

    Martin Bona

Authors
  1. Jana Jachova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Miroslav Gottlieb
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Miroslava Nemethova
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Martin Bona
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Petra Bonova
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Petra Bonova.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article contains studies with animals. The experiments were carried out following the protocol for animal care approved by European Communities Council Directive (2010/63/EU) with permission of The State Veterinary and Food Administration of the Slovak Republic (4451/14–221 and 4247/15–221) under the supervision of Ethical council of Institute of Neurobiology SAS. Every effort was made to reduce the number of animals used and to minimize animal suffering; all operations were performed by an experienced surgeon. Minimal handling and analgetic drug were used to minimalize animal pain and distress.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jachova, J., Gottlieb, M., Nemethova, M. et al. Brain to blood efflux as a mechanism underlying the neuroprotection mediated by rapid remote preconditioning in brain ischemia. Mol Biol Rep 47, 5385–5395 (2020). https://doi.org/10.1007/s11033-020-05626-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-020-05626-w

Keywords

Search

Navigation