Neuroprotective effects of local surface hypothermia during endothelin-1-induced focal ischemia in rat cerebral cortex. I. Electrophysiological analysis

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Local therapeutic hypothermia (LTH) is one of the most promising methods for neuroprotection in cerebral ischemia. However, the efficacy of superficial LTH at clinically relevant delays after the onset of ischemic attack remains poorly understood. In the present study, we investigated the neuroprotective effects of LTH in a model of focal ischemia induced by epipial application of the vasoconstrictor Endothelin-1 in the somatosensory cortex region of the rat brain. The neuroprotective effects of LTH were assessed by the level of spontaneous and sensory-evoked electrical activity at different cortical depths using linear electrode arrays. We found that cooling the cortical surface to 28°C using a Peltier element starting from 0, 10, and 60 minutes after Endothelin-1 application caused a significant reduction in the degree of suppression of electrical activity in the ischemic focus formed in the cerebral cortex 3 hours after Endothelin-1 application. The neuroprotective effects of LTH were manifested by a higher level of spontaneous multinit activity, higher power of the local field potential oscillations in theta, alpha and beta bands, as well in a greater amplitude and higher multiunit activity during sensory evoked responses. The neuroprotective effects of LTH were inversely correlated with the delay of LTH onset and were most pronounced with LTH initiated with minimal (0 and 10 minutes) delay after Endothelin-1 application. We also found that only LTH initiated simultaneously with Endothelin-1 application delayed the onsets of spreading depolarization waves and that LTH did not affect the amplitude of negative ultraslow potentials evoked by Endothelin-1. Taken together, the results of the electrophysiological analysis suggest neuroprotective effects of surface LTH, which are particularly pronounced when LTH is minimally delayed from the onset of the ischemic insult in the Endothelin-1-induced focal ischemia model.

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作者简介

G. Zakirova

Kazan Federal University

Email: roustem.khazipov@inserm.fr
俄罗斯联邦, Kazan

К. Chernova

Kazan Federal University

Email: roustem.khazipov@inserm.fr
俄罗斯联邦, Kazan

R. Khazipov

Kazan Federal University; Aix-Marseille University, INMED, IINSERM

编辑信件的主要联系方式.
Email: roustem.khazipov@inserm.fr
俄罗斯联邦, Kazan; Marseille, France

А. Zakharov

Kazan Federal University; Department of Normal Physiology, Kazan State Medical University

Email: roustem.khazipov@inserm.fr
俄罗斯联邦, Kazan; Kazan

参考

  1. Shamalov NA, Stakhovskaya LV, Ivanova GE, Shekhovtsova KV, Lee SC, Skvortsova VI (2013) Results of the federal anti-stroke program in the Russian Federation. Cerebrovasc Diseas 35: 88–88.
  2. Lapchak PA, Zhang JH (2017) The high cost of stroke and stroke cytoprotection research. Translat Stroke Res 8: 307–317. https://doi.org/10.1007/s12975-016-0518-y
  3. Jauch EC, Saver JL, Adams HP, Bruno A, Connors JJ, Demaerschalk BM, Khatri P, Mcmullan PW, Qureshi AI, Rosenfield K, Scott PA, Summers DR, Wang DZ, Wintermark M, Yonas H, Amer Heart Assoc Stroke C, Council Cardiovasc N, Council Peripheral Vasc D, Council Clinical C (2013) Guidelines for the early management of patients with acute ischemic stroke a guideline for healthcare professionals from the American Heart Association. American Stroke Association. Stroke 44: 870–947. https://doi.org/10.1161/STR.0b013e318284056a
  4. Ginsberg MD (2016) Expanding the concept of neuroprotection for acute ischemic stroke: The pivotal roles of reperfusion and the collateral circulation. Progr Neurobiol 145: 46–77. https://doi.org/10.1016/j.pneurobio.2016.09.002
  5. Al-Ajlan FS, Alkhiri A, Alamri AF, Alghamdi BA, Almaghrabi AA, Alharbi AR, Alansari N, Almilibari AZ, Hussain MS, Audebert HJ, Grotta JC, Shuaib A, Saver JL, Alhazzani A (2024) Golden hour intravenous thrombolysis for acute ischemic stroke: a systematic review and meta-analysis. Ann Neurol 96: 582–590. https://doi.org/10.1002/ana.27007
  6. Saver JL, Smith EE, Fonarow GC, Reeves MJ, Zhao X, Olson DM, Schwamm LH, Investig GW-SSC (2010) The "Golden hour" and acute brain ischemia presenting features and lytic therapy in > 30 000 patients arriving within 60 minutes of stroke onset. Stroke 41: 1431–1439. https://doi.org/10.1161/STROKEAHA.110.583815
  7. Di Biase L, Bonura A, Caminiti ML, Pecoraro PM, Di Lazzaro V (2022) Neurophysiology tools to lower the stroke onset to treatment time during the golden hour: microwaves, bioelectrical impedance and near infrared spectroscopy. Ann Med 54: 2658–2671. https://doi.org/10.1080/07853890.2022.2124448
  8. Reeves MJ, Fonarow GC, Smith EE, Sheth KN, Messe SR, Schwamm LH (2024) Twenty years of get with The Guidelines-Stroke: celebrating past successes, lessons learned, and future challenges. Stroke 55: 1689–1698. https://doi.org/10.1161/STROKEAHA.124.046527
  9. Kurisu K, Yenari MA (2017) Therapeutic hypothermia for ischemic stroke; pathophysiology and future promise. Neuropharmacology 134: 302–309. https://doi.org/10.1016/j.neuropharm.2017.08.025
  10. Polderman KH (2009) Mechanisms of action, physiological effects, and complications of hypothermia. Crit Care Med 37(7): 186–202. https://doi.org/10.1097/CCM.0b013e3181aa5241
  11. Wassink G, Davidson JO, Dhillon SK, Zhou K, Bennet L, Thoresen M, Gunn AJ (2019) Therapeutic hypothermia in neonatal hypoxic-ischemic encephalopathy. Curr Neurol Neurosci Rep 19(2): 2. https://doi.org/10.1007/s11910-019-0916-0
  12. Sekhon MS, Ainslie PN, Griesdale DE (2017) Clinical pathophysiology of hypoxic ischemic brain injury after cardiac arrest: a “two-hit” model. Crit Care 21(90): 1–10. https://doi.org/10.1186/s13054-017-1670-9
  13. Бутров АВ, Торосян БД, Чебоксаров ДВ, Махмутова ГР (2019) Терапевтическая гипотермия при поражениях головного мозга различного генеза. Вестн интенсивн терапии им АИ Салтанова 2: 75–81. [Butrov AV, Torosyan BD, Cheboksarov DV, Makhmutova GR (2019) Therapeutic hypothermia in treatment of different cerebral injuries. Ann Сritical Care 2: 75–81. (In Russ)]. https://doi.org/10.21320/1818-474X-2019-2-75-81
  14. Sun YJ, Zhang ZY, Fan B, Li GY (2019) Neuroprotection by therapeutic hypothermia. Front Neurosci 13: 586. https://doi.org/10.3389/fnins.2019.00586.
  15. Cattaneo G, Meckel S (2019) Review of selective brain hypothermia in acute ischemic stroke therapy using an intracarotid, closed-loop cooling catheter. Brain Circ 5(4): 211–217. https://doi.org/10.4103/bc.bc_54_19.
  16. Zhao J, Mu H, Liu L, Jiang X, Wu D, Shi Y (2018) Transient selective brain cooling confers neurovascular and functional protection from acute to chronic stages of ischemia/reperfusion brain injury. J Cereb Blood Flow Metab 39: 1215–1231. https://doi.org/10.1177/0271678X18808174
  17. Assis FR, Narasimhan B, Ziai W, Tandri H (2019) From systemic to selective brain cooling – Methods in review. Brain Circ 5: 179–186. https://doi.org/10.4103/bc.bc_23_19
  18. Nasretdinov A, Evstifeev A, Vinokurova D, Burkhanova-Zakirova G, Chernova K, Churina Z, Khazipov R (2021) Full-Band EEG recordings using hybrid AC/DC-divider filters. eNeuro 8(4): ENEURO.0246-21.2021. https://doi.org/10.1523/ENEURO.0246-21.2021
  19. Mitra PP, Pesaran B (1999) Analysis of dynamic brain imaging data. Biophys J 2: 691–708. https://doi.org/10.1016/S0006-3495(99)77236-X
  20. Захаров АВ, Захарова ЮП (2023) Eview – программа с открытым исходным кодом для преобразования и визуализации многоканальных электрофизиологических сигналов. Гены и клетки 18(4): 323–330. [Zakharov AV, Zakharova JP (2023) Eview – an open-source program for conversion and visualisation of multichannel electrophysiological signals. Genes and Cells 18(4): 323–330. (In Russ)].
  21. Pettersen KH, Devor A, Ulbert I, Dale AM, Einevoll GT (2006) Current-source density estimation based on inversion of electrostatic forward solution: effects of finite extent of neuronal activity and conductivity discontinuities. J Neurosci Methods 154(1–2): 116–133. https://doi.org/10.1016/j.jneumeth.2005.12.005
  22. Nasretdinov A, Lotfullina N, Vinokurova D, Lebedeva J, Burkhanova G, Chernova K, Zakharov A, Khazipov R (2017) Direct current coupled recordings of Cortical Spreading Depression using silicone probes. Front Cell Neurosci 11: 408. https://doi.org/10.3389/fncel.2017.00408
  23. Sheroziya M, Timofeev I (2015) Moderate cortical cooling eliminates thalamocortical silent states during slow oscillation. J Neurosci 35: 13006–13019. https://doi.org/10.1523/JNEUROSCI.1359-15.2015
  24. Burkhanova G, Chernova K, Khazipov R, Sheroziya M (2020) Effects of cortical cooling on activity across layers of the rat barrel cortex. Front Syst Neurosci 14: 52. https://doi.org/10.3389/fnsys.2020.00052
  25. Vinokurova D, Zakharov A, Chernova K, Burkhanova-Zakirova G, Horst V, Lemale CL, Dreier JP, Khazipov R (2022) Depth-profile of impairments in endothelin-1 – induced focal cortical ischemia. J Cereb Blood Flow Metab 42(10): 1944–1960. https://doi.org/10.1177/0271678X221107422
  26. Juzekaeva E, Gainutdinov A, Mukhtarov M, Khazipov R (2020) Reappraisal of anoxic spreading depolarization as a terminal event during oxygen-glucose deprivation in brain slices in vitro. Sci Rep 10(1): 18970. https://doi.org/10.1038/s41598-020-75975-w
  27. Vinokurova D, Zakharov AV, Lebedeva J, Burkhanova GF, Chernova KA, Lotfullina N, Khazipov R, Valeeva G (2018) Pharmacodynamics of the glutamate receptor antagonists in the rat barrel cortex. Front Pharmacol 9: 698. https://doi.org/10.3389/fphar.2018.00698
  28. Dreier JP, Major S, Lemale CL, Kola V, Reiffurth C, Schoknecht K, Hecht N, Hartings JA, Woitzik J (2019) Correlates of spreading depolarization, spreading depression, and negative ultraslow potential in epidural versus subdural electrocorticography. Front Neurosci 13: 1–20. https://doi.org/10.3389/fnins.2019.00373
  29. Mingazov B, Vinokurova D, Zakharov A, Khazipov R (2023) Comparative Study of Terminal Cortical Potentials Using Iridium and Ag/AgCl Electrodes. Int J Mol Sci 24(13): 10769. https://doi.org/10.3390/ijms241310769
  30. Major S, Gajovic-Eichelmann N, Woitzik J, Dreier JP (2021) Oxygen-Induced and pH-Induced Direct Current Artifacts on Invasive Platinum/Iridium Electrodes for Electrocorticography. Neurocrit Care 35(Suppl 2): 146–159. https://doi.org/10.1007/s12028-021-01358-2

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2. Fig. 1. Experimental setup. (a) – layout of metal plate with Peltier element and silicon probe in rat barrel cortex. Arrow shows vibrissa stimulation. Inset on the right – corresponding micrograph (before agar application); (b) – 16-channel linear electrode was inserted vertically into the center of cranial window to record electrical activity of all layers (L1–L6; L – layer) of barrel cortex. Epipial application of ET1 was performed using microinjector. Metal plate with Peltier element was placed near the surface of cerebral cortex and covered with agar; (c) – time plan of experiment in 4 groups of animals.

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3. Fig. 2. Effect of local hypothermia on spontaneous electrical activity of the cerebral cortex in the ischemic focus caused by ET1. (a) – spontaneous electrical activity before ET1 application at a temperature of 39°C (control conditions). Shown are LFP in the frequency range of 0.2–1000 Hz (black lines) and MUA (red vertical segments) at different depths of the cortex; (b) – spontaneous electrical activity 3 h after ET-1 application at a temperature of 39°C. (c, d, e) – examples of electrical activity under conditions of cooling the brain surface to 28°C simultaneously (c), 10 min (d) and 60 min (e) after ET-1 application. NT – normothermia, HT – hypothermia.

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4. Fig. 3. Effect of local hypothermia on the frequency of IVD in the ischemic focus induced by ET1. (a) – IVD (MUA) of layer 5 neurons (individual action potentials – gray lines and averaged – black lines). Examples for all temperature conditions are shown. (b) – frequency of spontaneous IVDs calculated for all electrodes in the cortical column (∑MUA) after 3 h of ET1 action (1 μM) under normothermia conditions (39°C) and upon cooling to a temperature of 28°C, started simultaneously, 10 min and 1 h after ET1 application. Data are normalized to the control level before ET1 application. At the top are shown the probabilities of statistical differences between the groups and the control (from the 100% level) according to the rank sum test for paired samples (p-value), the probabilities of differences between the groups according to the Kruskal–Wallis test (KW p) and significant differences between the groups according to the Dunn test (asterisks); (c) is the dependence of ∑MUA in the ischemic focus on the cooling start time. Normothermic experiments are taken into account with a delay time of 180 min. The black dotted line shows the linear approximation. The box shows the Spearman correlation coefficient and the corresponding significance level; (d) is the level of the IVD frequency relative to the control values ​​in the ischemic focus under different temperature conditions in different layers of the cortical column. The significance level of the difference between the group and the control (from the 100% level, as in panel b) according to the rank sum test for paired samples is shown above the boxes. The boxes show the Spearman correlation coefficients of the parameter on the cooling start time and the corresponding significance levels. NT – normothermia, HT – hypothermia.

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5. Fig. 4. Effect of local hypothermia on sensory-evoked potentials in the ischemic focus induced by ET1. (a) – examples of averaged sensory-evoked potentials (SEPs) at different depths of the cortical column (LFC, black lines) against the background of color-coded SEP maps under control conditions and in ischemic foci induced by ET1 application at different LTG delays; (b) – SEP amplitude calculated for all electrodes in the cortical column (∑SEP) after 3 h of ET1 action under normothermia (39°C) and upon cooling to a temperature of 28°C, started simultaneously, 10 min and 1 h after ET1 application. Data are normalized to the control level before ET1 application. At the top are shown the probabilities of statistical differences between the groups and the control (from the 100% level) according to the rank sum test for paired samples (p-value), the probabilities of differences between the groups according to the Kruskal–Wallis test (KW p) and significant differences between the groups according to the Dunn test (asterisks); (c) is the dependence of ∑SEP in the ischemic focus on the cooling start time. Normothermic experiments are taken into account with a delay time of 180 min. The black dotted line shows the linear approximation. The box shows the Spearman correlation coefficient and the corresponding significance level; (d) is the level of the SEP amplitude relative to the control values ​​in the ischemic focus under different temperature conditions in different layers of the cortical column. The significance level of the difference between the group and the control (from the 100% level, as in panel b) according to the rank sum test for paired samples is shown below the boxes. The boxes show the Spearman correlation coefficients of the parameter on the cooling start time and the corresponding significance levels. NT – normothermia, HT – hypothermia.

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6. Fig. 5. Effect of local hypothermia on sensory-evoked IVDs in the ischemic focus induced by ET1. (a) – examples of sensory-evoked IVD frequency (SE-MUA) graphs at different depths of the cortical column (white lines) against the background of color-coded IVD density maps under control conditions and in ischemic foci induced by ET1 application at different LTG delays; (b) – IVD frequency calculated for all electrodes in the cortical column (∑MUA during SEP), in the time window of 0–30 ms from the onset of SEP, after 3 h of ET1 action under normothermia (39°C) and upon cooling to a temperature of 28°C, started simultaneously, 10 min and 1 h after ET1 application. Data are normalized to the control level before ET1 application. At the top are shown the probabilities of statistical differences between the groups and the control (from the 100% level) according to the rank sum test for paired samples (p-value), the probabilities of differences between the groups according to the Kruskal–Wallis test (KW p) and significant differences between the groups according to the Dunn test (asterisks); (c) – correlation of the degree of recovery of sensory-evoked IVDs from the time of cooling start. Normothermic experiments are taken into account with a delay time of 180 min. The black dotted line shows the linear approximation. The box shows the Spearman correlation coefficient and the corresponding significance level; (d) – the frequency level of sensory-evoked IVDs relative to the control values ​​in the ischemic focus under different temperature conditions in different layers of the cortical column. The significance level of the difference between the group and the control (from the 100% level, as in panel b) according to the rank sum test for paired samples is shown below the boxes. The boxes show the Spearman correlation coefficients of the parameter from the time of cooling start and the corresponding significance levels. NT – normothermia, HT – hypothermia.

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7. Fig. 6. Effect of local hypothermia on the waves of spreading depolarization caused by ET1. (a) – examples of waves of spreading depolarization (SD) at the depth of the 4th layer of the cortex, arising during the first minutes after the application of ET1 for different experimental groups of LTG; (b) – the delay time of the waves of spreading depolarization (SD delay) from the moment of ET1 application depending on the time of LTG onset. The Spearman correlation coefficient and the corresponding level of reliability are shown in the box. NT – normothermia, HT – hypothermia.

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8. Fig. 7. Effect of local hypothermia on negative ultraslow potentials evoked by ET1. (a) – examples of negative ultraslow potentials (NUP) (0–1000 Hz) recorded at the depth of the 4th cortex layer under normothermia and at different LTG delays. Black arrows indicate RD waves; (b) – averaged amplitude of infraslow negative potentials over all cortical layers at different LTG delays. Spearman’s correlation coefficient and the corresponding significance level are shown in the box. NT – normothermia, HT – hypothermia.

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