Intensive Care Medicine Experimental (Jul 2024)

Investigation of fingolimod-induced lymphocyte sequestration on inflammatory response and neurological damages after cardiac arrest

  • Yara Abi Zeid Daou,
  • Fanny Lidouren,
  • Antoine Bois,
  • Naoto Watanabe,
  • Ali Jendoubi,
  • Estelle Faucher,
  • Mathieu Surenaud,
  • Sophie Chateau-Joubert,
  • Sophie Hue,
  • Bijan Ghaleh,
  • Matthias Kohlhauer,
  • Renaud Tissier

DOI
https://doi.org/10.1186/s40635-024-00645-4
Journal volume & issue
Vol. 12, no. 1
pp. 1 – 10

Abstract

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Abstract Background A sepsis-like syndrome is known to occur after cardiac arrest, leading to cerebral infiltration by white blood cells (WBC). We hypothesized that pharmacological sequestration of WBC, and more specifically lymphocytes within lymphoid tissues, could reduce the cerebral infiltration by these inflammatory cells and subsequent acute brain injury in a porcine model of cardiac arrest. Lymphocyte sequestration was induced by the sphingosine-1 phosphate receptors agonist fingolimod. Methods In a first set of experiments, anesthetized pigs underwent a sham instrumentation with no cardiac arrest (n = 4). They received an administration of fingolimod (1 mg/kg, i.v.) in order to confirm its effect on WBC. In a second set of experiments, animals randomly received fingolimod or saline two hours prior to an episode of ventricular fibrillation (14 min) with subsequent resuscitation (n = 6 in each group). Neurological injury was assessed 24 h after resuscitation. Results In the first set of experiments, WBC and blood lymphocyte counts were significantly reduced by − 61 ± 10% and − 75 ± 6% two hours after fingolimod administration. In the second set of experiments, blood lymphocyte counts, but not WBC, were also significantly reduced after cardiac arrest in Fingolimod vs Control group. However, most cytokine blood levels were not different among groups, including Interleukin (IL)-1ra, IL-8 or IL-18 blood levels. A difference was only observed for IL-6, which decreased in Fingolimod vs Control (e.g., 5.6 ± 4.8 vs 59.4 ± 20.6 pg/ml at 2 h after cardiac arrest, respectively; p = 0.126). Neurofilament light chain (NFL) blood levels were not different among groups (57 ± 25 vs 84 ± 41 pg/ml in Fingolimod vs Control at 6 h after resuscitation, respectively). After awakening, 3 and 2 animals were prematurely euthanized for ethical reasons due to recurrent seizures in Fingolimod and Control groups, respectively. At Day 1, neurological dysfunction score was not different between groups (87 ± 7 vs 87 ± 5% in Fingolimod vs Control, respectively). Conversely, a decrease in the number of CD3 + cells was observed in the brain of surviving animals in Fingolimod vs Control group (3.10 ± 0.50 vs 7.53 ± 0.57 CD3 + cells/field, respectively; p = 0.0286). Conclusion Fingolimod-induced WBC sequestration, and more specifically lymphocytes sequestration, did not improve clinical neurological dysfunction following cardiac arrest although it reduced cerebral infiltration by lymphocytes.

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