Bìol. Tvarin, 2017, volume 19, issue 4, pp. 50–58             



A. Pastukhov, N. Krisanova, T. Borisova

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Institute of Biochemistry named after O. V. Palladin NAS of Ukraine,
9 Leontovycha str., Kyiv 01601, Ukraine

Hypothermia (deep and profound) is successfully used in medical practice for the prevention of consequences of ischemic stroke and in aortic arch cardiac surgery that involved reduction of cerebral circulation in order to facilitate operations. Discernment of the influence of deep/profound hypothermia (27 °C/17 °C, respectively) at the neurochemical level on normal and ischemia-associated mechanisms of glutamate transport was accomplished in the presynapse. The experiments were conducted with isolated rat cerebral hemisphere nerve terminals (synaptosomes). Synaptosomal glutamate transport characteristics were examined with radiolabelled L-[14C] glutamate.

Transporter-mediated uptake by the nerve terminals and tonic release of L-[14C]glutamate (dynamic balance of these oppositely directed processes determines the definite ambient levels of the neurotransmitter) reduced with different ranges under conditions of deep/profound hypothermia. Transporter-mediated release of L-[14C] glutamate stimulated by depolarization of the plasma membrane and by protonophore FCCP (that induced dissipation of the synaptic vesicle proton gradient) were gradually reduced from deep to profound hypothermia.

It has been established that in brain regions suffering from a reduction of blood circulation during cardiooperations, the direction of hypothermia-induced changes in the extracellular glutamate level in the nerve terminals depended on sensitivity of uptake and tonic release to hypothermia. Therefore, test parameters and clinical criteria for neuromonitoring aiming the evaluation of hypothermia-induced effects should be developed and provided in cardiac surgery medical practice. Also, the consequent decrease in the pathological transporter-mediated glutamate release determined the neuroprotective effect of hypothermia in stroke therapy.


  1. Berger C., Schäbitz W.-R., Georgiadis D., Steiner T., Aschoff A., Schwab S. Effects of hypothermia on excitatory amino acids and metabolism in stroke patients: a microdialysis study. Stroke, 2002, vol. 33, pp. 519–524.
  2. Boris-Möller F., Wieloch T. Changes in the extracellular levels of glutamate and aspartate during ischemia and hypoglycemia. Effects of hypothermia. Exp. brain Res., 1998, vol. 121, pp. 277–284.
  3. Borisova T. Permanent dynamic transporter-mediated turnover of glutamate across the plasma membrane of presynaptic nerve terminals: arguments in favor and against. Rev. Neurosci., 2016, vol. 27, pp. 71–81.
  4. Borisova T. Cholesterol and Presynaptic Glutamate Transport in the Brain. New York, Springer Science & Business Media, 2013. 75 p.
  5. Borisova T. A., Himmelreich N. H. Centrifuge-induced hypergravity: [3H]GABA and L-[ 14C]glutamate uptake, exocytosis and efflux mediated by high-affinity, sodium-dependent transporters. Adv. Sp. Res., 2005, vol. 36, pp. 1340–1345.
  6. Borisova T. A., Krisanova N. V. Presynaptic transporter-mediated release of glutamate evoked by the protonophore FCCP increases under altered gravity conditions. Adv. Sp. Res., 2008, vol. 42, pp. 1971–1979.
  7. Borisova T., Borysov A. Putative duality of presynaptic events. Rev. Neurosci., 2016, vol. 27, pp. 377–383.
  8. Borisova T., Krisanova N., Himmelreich N. Exposure of animals to artificial gravity conditions leads to the alteration of the glutamate release from rat cerebral hemispheres nerve terminals. Adv. Sp. Res., 2004, vol. 33, pp. 1362–1367.
  9. Borisova T., Sivko R., Borysov A., Krisanova N. Diverse Presynaptic Mechanisms Underlying Methyl-β-Cyclodextrin-Mediated Changes in Glutamate Transport. Cell. Mol. Neurobiol., 2010, vol. 30, pp. 1013–1023.
  10. Cotman C.W. Isolation of synaptosomal and synaptic plasma membrane fractions. Methods Enzymol., 1974, vol. 31, pp. 445–452.
  11. Danbolt N.C. Glutamate uptake. Prog. Neurobiol., 2001, vol. 65, pp. 1–105.
  12. Englum B. R., Andersen N. D., Husain A. M., Mathew J. P., Hughes G. C. Degree of hypothermia in aortic arch surgery — optimal temperature for cerebral and spinal protection: deep hypothermia remains the gold standard in the absence of randomized data. Ann. Cardiothorac. Surg., 2013, vol. 2, pp. 184–193.
  13. Grewer C., Gameiro A., Zhang Z., Tao Z., Braams S., Rauen T. Glutamate forward and reverse transport: From molecular mechanism to transporter-mediated release after ischemia. IUBMB Life, 2008, vol. 60, pp. 609–619.
  14. Hertog H. M., van der Worp H. B., van Gemert H. M. A., Algra A., Kappelle L. J., van Gijn J., Koudstaal P. J., Dippel D. W. J. An early rise in body temperature is related to unfavorable outcome after stroke: data from the PAIS study. J. Neurol., 2011, vol. 258, pp. 302–307.
  15. Kammersgaard L. P., Jørgensen H. S., Rungby J. A., Reith J., Nakayama H., Weber U. J., Houth J., Olsen T. S. Admission body temperature predicts long-term mortality after acute stroke: the Copenhagen Stroke Study. Stroke, 2002, vol. 33, pp. 1759–1762.
  16. Kumral E., Yüksel M., Büket S., Yagdi T., Atay Y., Güzelant A. Neurologic complications after deep hypothermic circulatory arrest: types, predictors, and timing. Texas Hear. Inst. J., 2001, vol. 28, pp. 83–88.
  17. Lakhan S. E., Pamplona F. Application of mild therapeutic hypothermia on stroke: a systematic review and meta-analysis. Stroke Res. Treat, 2012, vol. 2012, pp. 295906.
  18. Larson E., Howlett B., Jagendorf A. Artificial reductant enhancement of the Lowry method for protein determination. Anal. Biochem., 1986, vol. 155, pp. 243–248.
  19. Liu L., Yenari M. A. Therapeutic hypothermia: neuroprotective mechanisms. Front. Biosci., 2007, vol. 12, pp. 816–825.
  20. Liu L., Yenari M. A. Clinical application of therapeutic hypothermia in stroke. Neurol. Res., 2009, vol. 31, pp. 331–335.
  21. Millán M., Grau L., Castellanos M., Rodríguez-Yáñez M., Arenillas J. F., Nombela F., Pérez de la Ossa N., López-Manzanares L., Serena J., Castillo J., Dávalos A. Body temperature and response to thrombolytic therapy in acute ischaemic stroke. Eur. J. Neurol., 2008, vol. 15, pp. 1384–1389.
  22. Mrozek S., Vardon F., Geeraerts T. Brain temperature: Physiology and pathophysiology after brain injury. Anesthesiol. Res. Pract., 2012, vol. 2012, pp. 989487.
  23. Nakashima K., Todd M. M. Effects of hypothermia, pentobarbital, and isoflurane on postdepolarization amino acid release during complete global cerebral ischemia. Anesthesiology, 1996, vol. 85, pp. 161–168.
  24. Percy A., Widman S., Rizzo J. A., Tranquilli M., Elefteriades J. A. Deep hypothermic circulatory arrest in patients with high cognitive needs: full preservation of cognitive abilities. Ann. Thorac. Surg., 2009, vol. 87, pp. 117–123.
  25. Pozdnyakova N., Dudarenko M., Yatsenko L., Himmelreich N., Krupko O., Borisova T. Perinatal hypoxia: different effects of the inhibitors of GABA transporters GAT1 and GAT3 on the initial velocity of [3H]GABA uptake by cortical, hippocampal, and thalamic nerve terminals. Croat. Med. J., 2014, vol. 55, pp. 250–258.
  26. Pozdnyakova N., Pastukhov A., Dudarenko M., Galkin M., Borysov A., Borisova T. Neuroactivity of detonation nanodiamonds: dose-dependent changes in transporter-mediated uptake and ambient level of excitatory/inhibitory neurotransmitters in brain nerve terminals. J. Nanobiotechnology, 2016, vol. 14, pp. 25.
  27. Rosen A. D. Temperature modulation of calcium channel function in GH3 cells. Am. J. Physiol., 1996, vol. 271, pp. C863–868.
  28. Rosen A. D. Nonlinear temperature modulation of sodium channel kinetics in GH(3) cells. Biochim. Biophys. Acta, 2001, vol. 1511, pp. 391–396.
  29. Soldatkin O., Nazarova A., Krisanova N., Borуsov A., Kucherenko D., Kucherenko I., Pozdnyakova N., Soldatkin A., Borisova T. Monitoring of the velocity of high-affinity glutamate uptake by isolated brain nerve terminals using amperometric glutamate biosensor. Talanta, 2015, vol. 135, pp. 67–74.
  30. Sudhof T. C. The synaptic vesicle cycle. Annu. Rev. Neurosci., 2004, vol. 27, pp. 509–547.
  31. Volgushev M., Kudryashov I., Chistiakova M., Mukovski M., Niesmann J., Eysel U. T. Probability of transmitter release at neocortical synapses at different temperatures. J. Neurophysiol, 2004, vol. 92, pp. 212–220.
  32. Volgushev M., Vidyasagar T. R., Chistiakova M., Eysel U. T. Synaptic transmission in the neocortex during reversible cooling. Neuroscience, 2000, vol. 98, pp. 9–22.
  33. Worp H. B., Sena E. S., Donnan G. A., Howells D. W., Macleod M. R. Hypothermia in animal models of acute ischaemic stroke: a systematic review and meta-analysis. Brain, 2007, vol. 130, pp. 3063–3074.
  34. Xing C., Arai K., Lo E. H., Hommel M. Pathophysiologic cascades in ischemic stroke. Int. J. Stroke, 2012, vol. 7, pp. 378–385.

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